This document contains images for the patent 2186709
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`PETITIONER FORD MOTOR COMPANY EX. 1006-1
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`PETITIONER FORD MOTOR COMPANY EX. 1006-1
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`This document contains images for the patent 2186709
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`PETITIONER FORD MOTOR COMPANY EX. 1006-2
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`2386709
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`which having 4- to 7—membered cyclic alkyleneimino such
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`as pyrrolidine ring and compounds having e.g.
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`piperidine ring are respectively described. Further,
`compounds having piperidinone ring, which have cell-
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`7,
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`5
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`adhesion inhibiting activity, are disclosed in EPA
`No.529858.
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`,
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`These known compoundsIare not satisfactory from
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`the viewpoints of the potency of their activity,
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`undesirable side effects (e.g. prolonging bleeding
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`10
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`time), absorbability, stability or durability of the
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`action. Circumstances being such as above, for
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`clinical application of?these compounds,
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`there are
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`problems still to be solved.
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`Recently, novel 2—piperazinone—l-acetic acid
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`15
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`derivatives were synthesized, which were found to
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`possess, based on the chemical structural
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`characteristic feature, a potent platelet aggregation
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`inhibiting activity and, at the same time, are safely
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`administrable, i.e. slight in undesirable side effects
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`20
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`such as prolongation of bleeding time. These compounds
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`are expected to apply to_a variety of circulatory
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`diseases (e.g.
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`thrombosis, transient cerebral ischemic
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`attack, myocardial infarction, cerebral infarction,
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`'}
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`peripheral obstruction and arteriosclerotic
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`25
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`obliteration),
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`tumors,
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`inflammatory diseases, or
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`prevention of reobstruction and restenosis of coronary
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`arteries after PTCA (percutaneous transluminal coronary
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`angioplasty), prevention of reobstruction and
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`restenosis after surgical operation for coronary artery
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`bypass and secondary prophylaxis after re—opening of
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`infarction. Especially, for patients of chronic
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`diseases, administration of drugs for a long period is
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`required. While preparations of sustained-release for
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`a long period are desired, no report on sustainede
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`35
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`release microcapsules of the above-mentioned novel
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`compounds has been found.
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`PETITIONER FORD MOTOR COMPANY EX. 1006-3
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`PETITIONER FORD MOTOR COMPANY EX. 1006-3
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`2186709
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`Exploitation of a method of preparing sustained—
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`release microcapsules which are high in entrapping
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`ratio of a 2—piperazinone—l-acetic acid compound and
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`less in initial releaseibffthe drug is expected.
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`Summary of the Invention
`
`The present inventorsihave diligently studied for
`solving the above—mentioned problems to find that a
`
`microcapsule comprising_an amorphous water—soluble 2-
`
`piperazinone—l—acetic achibompound and a polymer has a
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`compound with a relatively
`high entrapment of the as?
`less initial release thereof. Further diligent studies
`based on this finding hays reached the accomplishment
`
`of the present invention.'§
`Namely,
`the presentinvention is to provide a
`microcapsule comprisingfan amorphous water—soluble 2—
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`piperazinone—lwacetic afiid.compound, which is a
`
`compound of the formula (11:
`
`Alen— (120
`
`W3 m
`—N—thc—N
`"
`W~K
`
`N/A\Y
`o
`
`(capn—P—A2
`
`(I)
`
`wherein A} and A? independpntly are a proton—accepting
`group or a group convertible into a proton-accepting
`group; D is a spacer having a 2— to 6-atomic chain
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`optionally bonded through a hetero—atom and/or a 5— or
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`6—membered ring (providesthat the 5— or 6—membered
`
`ring is, depending on its bonding position, counted ass
`2- or 3—atomic chain); Rigs a hydrogen atom or a
`hydrocarbon group; R2 is a hydrogen atom or a residual
`
`group formed by removing’—CH(NH2)COOH from an asamino
`acid, or R} and Rzlnay be upmbined to form a 5- or 6—
`membered ring; P is a spater having a 1— to lO—atomic
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`chain optionally bonded through a hetero—atom and/or a
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`5- or 6-membered ring (Efidvided that the 5— or 6—
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`membered ring is, depending on its bonding position,
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`2186709
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`counted as 2— or 3—atomic chain); Y is an optionally
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`esterified or amidated carboxyl group; and n denotes an
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`integer of 0 to 8, or salt thereof, [hereinafter
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`sometimes simply referred to as the compound (1)] and a
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`5
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`polymer.
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`The present invention also provides a microcapsule
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`which is prepared by dispersing,
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`in an aqueous phase, a
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`dispersion of an amorphous water-soluble 2-
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`piperazinone—l—acetic acid compound which is a compound
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`of the formula (I) or a salt thereof in a solution of a
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`polymer in an organic solvent to prepare an s/o/w type
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`emulsion and subjecting the emulsion to in-water
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`drying.
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`The present invention is also to provide a method
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`15
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`of preparing a microcapsule, which comprises
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`dispersing,
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`in an aqueous phase, a dispersion of an
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`amorphous water—soluble 2—piperazinone-l—acetic acid
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`compound which is a compound of the formula (I) or a
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`salt thereof in a solution of a polymer in an organic
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`solvent to prepare an s/O/w type emulsion and
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`subjecting the emulsion to in-water drying.
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`Detailed Description of the Invention
`
`The abbreviations of amino acids, peptides,
`
`)
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`protecting groups or the like used in this
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`25
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`specification are based on those established by IUPAC—
`IUB Commission on Biochemical Nomenclature or those
`
`commonly used in the relevant fields. When optical
`
`isomers of amino acids are present,
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`they are L—isomers
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`unless otherwise specified.
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`30
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`The term "microcapsule" used in this specification
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`includes microspheres, microcapsules, microparticles,
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`nanospheres and nanocapsules.
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`The term."s/o/w type emulsion" used in this
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`specification means a solid/oil/water (solid phase in
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`35
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`oil in water type).
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`The "s“ phase means a solid phase
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`including microparticles and an aqueous phase in the
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`PETITIONER FORD MOTOR COMPANY EX. 1006-5
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`PETITIONER FORD MOTOR COMPANY EX. 1006-5
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`2186709
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`form of gel.
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`The present inventibn has made it possible to
`prepare a sustained-releaSe microcapsule which contains
`a high content of the waterssoluble compound (I) with a
`relatively small initialfrelease thereof.
`
`The amorphous compound (I) employed in the present
`invention is soluble in watir, which means that the
`
`solubility of the compound (I) in water is not less
`
`the
`than about 1 g/100 ml atl20°C. Preferably,
`compound (I) is a one whioh‘is readily soluble in
`water.
`The term "readily soluble in water” means that
`the water—solubility of Ehe compound (I) is,
`in
`general, not less than about 5 g/100 ml at 20°C.
`
`As described above,'the compound (I) of this
`invention is (1) a compound, whose characteristic
`feature in the chemical stricture lies in having
`proton—accepting groups ffisiectively at terminals of
`substituents at 3— and 4spositions on the piperazine
`ring, represented by the formula (I):
`
`(I)
`
`(CHflneP—Az
`
`wherein A} and A3 independently are a proton-accepting
`group or a group convertible into a proton-accepting
`group; D is a spacer having a 2— to 6-atomic chain
`
`optionally bonded through a hetero-atom and/or a 5- or
`6—membered ring (provided.that the 5— or 6-membered
`ring is, depending on its bonding position, counted as
`2~ or 3—atomic chain); Rlis a hydrogen atom or a
`hydrocarbon group; R2 is a hydrogen atom or a residual
`
`group formed by removing :CfilNH2)COOH from an d—amino
`acid, or R} and R?.may begiombined to form a 5— or 6-
`membered ring; P is a spacer having a l— to 10~atomic
`chain optionally bonded through a hetero—atom and/or a
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`PETITIONER FORD MOTOR COMPANY EX. 1006-6
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`2186709
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`5~ or 6—membered ring (provided that the 5- or 6»
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`membered ring is, depending on its bonding position,
`counted as 2- or 3~atomic chain); Y is an optionally
`esterified or amidated carboxyl group; and n denotes an
`integer of 0 to 8, or a salt thereof.
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`Especially,
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`the following compounds are
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`(2) a compound as described in (1)
`preferable, namely,
`above, wherein A1 and A? independently are an
`
`optionally substituted amino, amidino or guanidino
`
`group or a group convertible to them,
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`(3) a compound as described in (1) above, wherein A1
`and A} independently are an optionally substituted
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`oxadiazolyl or thiadiazolyl group,
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`(4) a compound as described in (1) above, wherein Al
`and A? independently are (1) an amidino or guanidino
`group which may be substituted with Cb, alkoxycarbonyl,
`
`or (2) an amino group which may be substituted with an
`
`,oxadiazolyl group which may be substituted with oxo or
`
`C14 alkyl which may be substituted with halogen,
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`(5) a compound as described in (1) above, wherein A1
`and A2 independently are an unsubstituted amino,
`
`amidino or guanidino group,
`
`(6) a compound as described in (1) above, wherein D is
`group of the formula:
`
`{J}.
`
`-NH—CH2-O-.
`
`sin-{c}.
`
`-(CH2)2‘@‘
`
`,
`
`(7) a compound as described in (1) above, wherein R1 is
`a hydrogen atom,
`
`(8) a compound as described in (1) above, wherein R2 is
`
`a hydrogen atom or a Ch, alkyl group substituted with
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`phenyl optionally substituted with Cb, alkoxy,
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`(9) a compound as described in (1) above, wherein P is
`a group of the formula:
`
`_z_B_
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`PETITION ER FORD MOTOR2C4OZI9IBZ'RIOY6E2X. 1006-7
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`PETITIONER FORD MOTOR COMPANY EX. 1006-7
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`2186709
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`7
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`in which Z is
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`iris
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`O
`O
`H
`_
`H
`-N-C—, —N—, ~C—,
`H
`H
`”*7
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`S
`H
`-C—,
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`-O-,
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`0 H
`
`H
`—o-c-, ~s-, —s—C-
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`0
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`in which either bond may be bonded to B, or a bond;
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`and B is
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`.
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`_
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`(i)
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`g-(c th—O-(C Hm— or —(C H2):—
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`in which a is an integer of 0 to 2, b is an integer of
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`0 to 2 and c is an integer of l to 5, or (ii) a bond,
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`excepting the case where Z and B both are a bond,
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`(10) a compound as described in (9) above, wherein Z
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`is
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`O H
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`—N-C-
`H
`
`in which either bond may be bonded to B,
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`(11) a compound as described in (9) above , wherein B
`is
`
`Q
`
`or —(CHfld- in which d is an integer of 1 to 4,
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`(12) a compound as described in (1) above, wherein Y is
`
`a carboxyl group or a C1, alkoxy—carbonyl group,
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`(13) a compound as described in (1) above, wherein n is
`an integer of l to 4,
`‘
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`(14) a compound as described in (1) above, wherein n is
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`2 or 3,
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`(15) a compound as described in (1) above, wherein A]
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`PETITIONER FORD MOTOR COMPANY EX. 1006-8
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`2186709
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`and A? independently are
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`1)
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`an amidino or guanidino group optionally
`
`substituted with Cbfi alkoxycarbonyloxy,
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`2)
`
`an amino group optionally substituted with
`
`oxadiozolyl optionally substituted with oxo or CL,
`
`alkyl optionally substituted with halogen, or
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`3)
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`an oxadiazolyl group optionally substituted
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`with oxo or Cb, alkyl optionally substituted with
`
`halogen,
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`10
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`D is a group of the formula:
`
`”{3}
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`or
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`'(CHflz *CJV
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`R} is a hydrogen atom,
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`R2 is a hydrogen atom or a Cb, alkyl group substituted
`
`with phenyl optionally substituted with Clq alkoxy,
`
`P is a group of the formula:
`
`-Z-B—
`
`a bond or
`
`—N—
`
`H
`
`, and
`
`0 l
`
`l
`-N—C—
`
`H
`
`,
`
`wherein Z is
`
`a is
`
`Q—ccsab— or —(CHz)c-
`
`in which b is 0 or 1, and c is an integer of 1 to 5,
`O
`fl
`—C—R
`wherein R7 is 1) hydroxy group, 2) a Ch8 alkoxy or C2.12
`
`Y is a group of the formula:
`
`7
`
`alkenyloxy group which may be substituted with Cb,
`
`alkoxy—csrbonyl or 5—methyl—2—oxo-l,3-dioxolen-4-yl, or
`3) a group of the formula: —OCH(R“)0COR“ in which
`Rh'is a hydrogen atom or a Cbfi alkyl group, and RF is a
`
`C1_6 alkyl group or a C54 cycloalkyloxy group, and
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`n is an integer of 1 to 4,
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`(16) a compound as described in (1) above, wherein A1
`and A? are independently
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`PETITIONER FORD MOTOR COMPANY EX. 1006-9
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`2186709
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`1)
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`'an amidino or guanidino group optionally
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`substituted with methoxycarbonyl or
`2)
`an amino groupgbptionally substituted with 5—
`
`oxo—l,2,4n0xodiazol-3-yl or 5—trifluoromethyl-l,2,4—
`
`oxadiazol—3—ylr
`
`—(CH,)[—©—
`or
`Dis @—
`R1 is a hydrogen atom,
`
`R2 is a hydrogen atom oer-methoxybenzyl,
`P is
`0
`if
`
`m—c—o
`
`Y is a carboxyl group and
`
`n is 2 or 3, and
`(17) a compound as described in (1) above, wherein A1
`
`and A? are independently an unsubstituted amino,
`
`amidino or guanidino group and R? is a hydrogen atom.
`
`In the above formula (I), A1 and A2 independently
`
`are a proton-accepting group or a group convertible
`
`into a proton—accepting group.
`
`In the above formula (I),
`
`the proton-accepting
`
`group means a group which accepts proton from a
`
`relevant group, namely a Brcnsted base as exemplified
`
`by a group containing nitrogen atom capable o£.being
`
`positively charged. Specific examples of the proton~
`
`accepting group include optionally substituted amino,
`
`amidino and guanidino groups. Preferable examples of
`
`the proton—accepting group include unsubstituted amino,
`
`amidino and guanidino groups, or secondary or tertiary
`
`amino groups (especially ethylamino), amidino or
`
`guanidino groups substituted with a Cb, alkyl group.
`
`Examples of the substituents of optionally
`
`substituted amino, amidino and guanidino groups include
`
`chain-like or cyclic hydrocarbon groups such as Che
`
`alkyl groups (e.g. methyl, ethyl, propyl,
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`isopropyl,
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`butyl, sec—butyl, tert-butyl, pentyl and hexyl), C2_6
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`isopropenyl,
`alkenyl groups (e.g. vinyl, allyl,
`butenyl,
`isobutenyl and sec—butenyl), C,_5 alkynyl
`
`groups (e.g. propargyl, ethynyl, butynyl and l—
`hexynyl), Cpfi cycloalkyl groups (e.g. cyclopropyl,
`cyclobutyl, cyclopentyl aid cyclohexyl}, Cfiu aryl
`
`groups (e.g. phenyl, tolyl, xylyl, 1—naphthyl,
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`2—
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`naphthyl, biphenyl, 2-indenyl and 2-anthryl, especially
`
`phenyl group), and C,_16 aralkyl groups (e.g. benzyl,
`
`l—
`triphenylmethyl,
`phenethyl, diphenylmethyl,
`inaphthylmethyl, 2—naphthylmethyl, 2—diphenylethyl, 3-
`phenylpropyl, 4-phenylbuty1 and 5—phenylpentyl,
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`5
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`10
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`especially benzyl group); Cb, alkyl groups (e.g.
`methyl) substituted with carbamoylcxy optionally
`substituted with CM alkyl (e.g. N,N-
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`dimethylaminocarbonyloxy), C24 alkanoyloxy (e.g.
`
`pivaloyloxy) or a 5— or Eémembered heterocyclic group
`
`(e.g. a 5—membered cyclic group containing, besides
`
`1 to 4 hetero—atoms selected from oxygen
`carbon atoms,
`atom, sulfur atom and nitrogen atom, such as 2— or 3-
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`20
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`thienyl,
`
`2— or 3—furyl,
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`1—, 2- or 3—pyrrolyl,
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`1—,
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`2— or
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`3-pyrrolidinyl, 2-,
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`4— or 5—oxazolyl,
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`2—,
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`4— or 5—
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`thiazolyl, 3-, 4- or 5-pyrazolyl, 2—, 4- or 5-
`
`)
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`imidazolyl, 1,2,3—triazolyl, 1,2,4—triazolyl and 1H- or
`ZH-tetrazolyl, a 6-membered cyclic group, preferably
`pyrrolidin-l-yl and morpholino, containing, besides
`
`carbon atoms,
`
`1 to 4 hetero—atoms selected from oxygen
`
`atom, sulfur atom and nitrogen atom, such as 2~,
`
`3— or
`
`4—pyridyl, N-oxido-2—, 3- or 4—pyridyl,
`
`2—,
`
`4— or 5—
`
`pyrimidinyl, N-oxido-2—, 4- or 5-pyrimidinyl,
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`30
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`thiomorpholinyl, morpholinyl, piperidinyl, pyranyl,
`
`thiopyranyl, 1,4-oxazinyl, 1,4—thiadinyl, 1,3—
`
`thiadinyl, piperazinyl, triazinyl,
`
`3— or 4-pyridazinyl,
`
`pyrazinyl, N-oxido-B— or 4—pyridazinyl); Cbs
`
`alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
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`35
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`propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl,
`
`n—
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`2186709
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`ll
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`hexyloxycarbonyl and n—octyloxycarbonyl); CLa
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`alkylaminocarbonyl (e.g. n-hexylaminocarbonyl and n—
`
`octylaminocarbonyl); C2“8 alkoxycarbonyloxy {e.g.
`
`methoxycarbonyloxy, ethoquarbonyloxy,
`
`propoxycarbonyloxy, butoxycarbonyloxy,
`
`pentyloxyoxycarbonyloxy, n—hexyloxycarbonyloxy and n«
`
`octyloxycarbonyloxy, preferably methoxycarbonyloxy);
`
`and 5- or 6-membered hetefbtyclic groups (e.g. a 5-
`
`membered cyclic group containing, besides carbon atoms,
`
`1 to 4 hetero—atoms selected from oxygen atom, sulfur
`
`atom and nitrogen atom, such as 2- or 3—thienyl, 2- or
`
`3~furyl, 1-, 2- or 3-pyrronl, 1-, 2- or 3-
`
`pyrrolidinyl, 2—, 4- or;5—oxazolyl, 2-,
`
`4— or 5-
`
`thiazolyl, 3-,
`4— or 5-pyrazolyl, 2—, 4- or S—
`imidazolyl, 1,2,3-triazolyli 1,2,4—triazolyl and 1H- or
`
`2H-tetrazolyl, a 6—membered cyclic group, preferably
`
`e.g.
`
`tetrahydrofuran-2-yl, containing, besides carbon
`
`atoms,
`
`1 to 4 heterowatoms selected from oxygen atom,
`
`sulfur atom and nitrogen atom, such as 2—, 3- or 4—
`
`pyridyl, N—oxido—2—, 3n ori4-pyridyl,
`
`2—, 4- or 5—
`
`pyrimidinyl, N—oxido-2—,
`
`4— or 5—pyrimidinyl,
`
`thiomorpholinyl, morpholinyl, piperidinyl, pyranyl,
`
`thiopyranyl, 1,4-oxazinyl, 1,4-thiadinyl, 1,3-
`
`thiadinyl, piperazinyl, triazinyl, 3- or 4—pyridazinyl,
`
`pyrazinyl, N—oxido-3—rorefl—pyridazinyl). And,
`
`in the
`
`case where two or more substituents of the amino,
`
`amidino or guanidino grOup exist,
`
`they may be combined
`
`to form a 5- or 6-membered heterocyclic.group (e.g.
`
`pyrrolidine, piperidine, morpholine or imidazoline).
`
`Preferable groups convertible into proton—
`
`accepting groups include groups which convert into
`
`proton—accepting groups in a living body and can accept
`
`physiologically active free proton. Examples of these
`
`groups include amidoxime groups optionally having
`
`substituents on oxygen atom (specific examples of the
`
`substituents include lower (Cb4) alkyl (e.g. methyl,
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`2186709
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`ethyl, propyl), acyl (erg. C2_5 alkanoyl (e.g. pivaloyl)
`
`and benzoyl),
`
`lower (CfiQ) alkoxycarbonyl (e.g.
`
`methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl),
`
`lower (Cb4) alkylthiocarbonyl (e.g. methylthiocarbonyl,
`ethylthiocarbonyl), acyloxycarbonyl (e.g. Cbs
`
`alkanoyloxycarbonyl (e.g. pivaloyloxycarbonyl) and
`
`benzoyloxycarbonyl), optionally substituted Cpu
`
`aryloxycarbonyl (e.g. phenoxycarbonyl) or CL“
`
`aralkyloxycarbonyl (e.g. benzyloxycarbonyl)
`
`(specific
`
`examples of the substituents include cyano, nitro,
`
`amino,
`
`lower (Cbé) alkoxycarbonyl (e.g.
`
`methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl),
`
`lower (Cbh) alkyl (e.g. methyl, ethyl, propyl),
`
`lower
`
`(Chg) alkoxy (e.g. methoxy, ethoxy, propoxy}, mono- and
`
`di- lower (Cbé) alkylamino (e.g. methylamino,
`
`ethylamino, propylamino, dimethylamino), hydroxy, amido
`
`and lower (an) alkylthio (e.g. methylthio, ethylthio),
`
`optionally substituted C642 aryl-carbonyl groups (e.g.
`
`phenylcarbonyl)
`
`(specific examples of the substituents
`
`include lower (CL4) alkyl (e.g. methyl, ethyl, propyl),
`
`lower (Cbé) alkenyl (e.g. vinyl, allyl) or lower
`
`(Cha)
`
`alkynyl (e.g. ethynyl), or optionally substituted
`
`carbamoyl groups (specific examples of the substituents
`
`include cyano, nitro, amino,
`
`lower (Cbh) alkoxy
`
`carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
`
`propoxycarbonyl),
`
`lower (Chg) alkyl (e.g. methyl,
`
`ethyl, propyl),
`
`lower (Cbfi) alkoxy (e.g. methoxy,
`
`ethoxy, propoxy), mono- and di- lower (Ch4) alkylamino
`
`(e.g. methylamino, ethylamino, propylamino,
`
`dimethylamino), hydroxy, amido and lower (Chg)
`
`alkylthio (e.g. methylthio, ethylthio), and optionally
`
`substituted oxadiazolyl or thiadiazolyl groups
`
`(examples of the substituents include oxo,
`
`thioxo,
`
`hydroxy, amino, mono— and di- lower (Ch4) alkylamino
`
`(e.g. methylamino, ethylamino, prOpylamino,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-13
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-13
`
`
`
`2186709
`
`13
`
`dimethylamino)r halogen (e.g. fluoro, bromo, chloro),
`
`cyano, azido,
`
`lower (CLA) alkyl optionally substituted
`
`with halogen (e.g.
`
`trifluoromethyl),
`
`lower (Cbé) alkoxy
`
`(CLA) alkylthio
`lower
`(e.g. methoxy, ethoxy, propoxy),
`(e.g. methylthio, ethylthio),
`lower (Cbé) alkoxy
`
`5
`
`carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
`
`propoxycarbonyl), mono— or di- lower (Cb4) alkylamino
`
`(e.g. methylamino, ethylamino, propylamino,
`
`dimethylamino),
`
`lower (C14) alkylcarbamoyl (e.g.
`
`10
`
`methylcarbamoyl, ethylcarbamoyl),
`
`(15_12 aryl (e.g.
`
`phenyl) groups optionally having a substituent
`
`(specific examples the substituents include cyano,
`
`nitro, amino,
`
`lower [Cb4) alkoxy carbonyl (e.g.
`
`methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl),
`lower (CL4) alkyl (e.g. methyl, ethyl, propyl),
`lower
`
`15
`
`(Chg) alkoxy (e.g. methoxy, ethoxy, propoxy), mono— and
`
`di— lower (Cbh) alkylamino (e.g. methylamino,
`
`ethylamino, propylamino, dimethylamino), hydroxy, amido
`
`and lower (Cb4) alkylthio (e.g. methylthio, ethylthio),
`
`20
`
`or CL“ aralkyl groups (e.g. benzyl) optionally having
`
`a substituent (specific examples of the substituents
`
`include cyano, nitro, amino,
`
`lower (CL4) alkoxy
`
`carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
`
`propoxycarbonyl},
`
`lower (th) alkyl (e.g. methyl,
`
`25
`
`ethyl, propyl),
`
`lower (Cba) alkoxy (e.g. methoxy,
`
`ethoxy, propoxy), mono— and di~ lower (Cry) alkylamino
`
`(e.g. methylamino, ethylamino, propylamino,
`
`dimethylamino), hydroxy, amido or lower (CLA) alkylthio
`
`(e.g. methylthio, ethylthio)), and among the optionally
`substituted oxadiazolyl or thiazolyl groups, 1,2,4—
`
`3O
`
`oxadiazol—3—yl or 1,2,4—thiadiazol—3-yl groups
`
`optionally having a substituent respectively are
`
`preferable. And,
`
`in the case where the substituent is
`
`35
`
`oxo or thioxo,
`enol—form.
`
`the groups may take either keto— or
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-14
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-14
`
`
`
`2186709
`
`14
`
`Among the optionally substituted Cb”
`aryloxycarbonyl or CL“ aralkyloxycarbonyl groups,
`optionally substituted carbamoyl groups, optionally
`substituted Cfiu aryl groups or optionally substituted
`CL” aralkyl groups as the above substituent of the
`
`amidoxime, oxadiazolyl and thiadiazolyl group, are
`preferable those respectively substituted with cyano,
`nitro,
`lower (Cb4) alkoxy-carbonyl or lower (Cba)
`alkoxy.
`
`Among the optionally substituted Cfiu aryl—
`carbonyl groups as the above substituent of the
`
`amidoxime group, are preferable those substituted with
`hydrogen atom or lower (Cb4) alkyl.
`
`More specific examples of the groups convertible
`into protonraccepting groups include 5—oro-l,2,4—
`oxadiazol-3—yl group, 5-oxo-1,2,4-thiadiagol-3—yl
`group, 5—thioxo—l,2,4—oxadiazol—3—yl group, S—thioxo-
`1,2,4—thiadiazol-3-yl group, 4—methyl—5-oxo-l,2,4—
`oxadiazol-3nyl group, 4-ethyl-5-oxo—1,2,4—oxadiazol—3—
`yl group, 4-propyl—S-oxo—l,2,4woxadiazol—3—yl group,
`1,2,4—oxadiazol-3—yl group, Stethoxycarbonyl—l,2,4—
`oxadiazol-3—yl group, 5—carbamoyl-l,2,4—oxadiazol-3—yl
`group, 5-cyano—l,2,4-oxadiazol-3~yl group,
`5—
`trifluoromethyl—l,2,4—oxadiazol—3-yl group, 5—phenyl-
`1,2,4—oxadiazol—3-yl group, 5—amino—l,2,4~oxadiazol—3-
`yl group, 5—propylamino—1,2,4—oxadiazol—3—yl group, 5-
`methylthio—l,2,4—oxadiazol—3—yl group, 5—azido—1,2,4—
`oxadiazolw3—yl group, amino (hydroxy)
`imino group,
`amino (methoxycarbonyloxy)
`imino group, amino
`(ethoxycarbonyloxy)
`imino group, amino (n-
`propyloxycarbonyloxy)
`imino group, amino I
`(benzyloxycarbonyloxy)
`imino group, amino (p—
`nitrobenzyloxycarbonyloxy) imino group, amino (p-
`nitrophenyloxycarbonyloxy} imino group, amino (p—
`nitrobenzoyloxycarbonyloxy) imino group, amino
`(methoxy)
`imino group, amino {carbamoyloxy)
`imino
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`PETITIONER FORD MOTOR COMPANY EX .1006-15
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-15
`
`
`
`2186709
`
`15
`
`group, amino (methylcarbamoyloxy)
`
`imino group, amino
`
`(ethylcarbamoyloxy)
`
`imino group, amino (n—
`
`propylcarbamoyloxy)
`
`iminopgroup and amino (n-
`
`butylcarbamoyloxy)
`
`iminofgroup.
`
`Among them, are preferable 5-oxo—l,2,4-oxadiazol-
`
`3—yl group, 5—oxo—1,2,4—thiadiazol—3-yl group, 5-
`
`ethoxycarbonyl—1,2,4—oxadiagol-3-yl group, S—cyano—
`
`1,2,4-oxadiazol-3-yl grofip? 5—trifluoromethyl—l,2,4—
`
`oxadiazol—3—yl group, amino (methoxycarbonyloxy)
`
`imino
`
`group, amino (carbonyloxy) imino group, amino
`(methylcarbamoyloxy)
`iminélbroup and amino
`
`(ethylcarbamoyloxy)
`imino group.
`Preferable exampleroilh1 and A? include (1)
`
`amidino and guanidino grpups which may be substituted
`
`with CLB alkoxycarbonyloxy, and (2) amino‘groups which
`may be substituted with oxadiazolyl groupiwhich may be
`substituted with oxo or CL, alkyl which may be
`
`substituted with halogen, and are unsubstituted amino,
`
`10
`
`15
`
`20
`
`amidino or guanidino groups are more preferable.
`And,
`the compound (I), wherein A} or A? are a
`
`group convertible into a proton—accepting group, or a
`
`salt thereof can be advantageously used as an orally
`
`administrable preparation.
`
`In the above formula (I), D is a Spacer having a
`
`2- to S-atomic chain optionally bonded through a
`
`hetero—atom and/or a 5— or 6-membered ring (provided
`
`that the 5- or 6—membered ring is, depending on its
`
`bonding position, counted as 2- or 3—atomic chain).
`The spacer of D means a linear interval between A1
`
`O
`
`and C, and means having a interval which is lined with
`
`2 to 6 atoms between them in the present invention.
`
`In the above formula (I), examples of hetero—atoms
`
`in the spacer having a 2— to 6—atomic chain (2- to 6-
`
`membered chain) optionally bonded through a hetero—atom
`
`25
`
`30
`
`35
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-16
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-16
`
`
`
`2186709
`
`16
`
`and/or a 5— or 5-membered ring include N, O and S.
`And,
`the 5- or 6-membered ring may be carbocyclic one
`or a heterocyclic one containing 1 to 4 hetero—atoms
`
`selected from N, O and S or a saturated ring or an
`unsaturated ring such as aromatic ring.
`Examples of
`such 5— or 6—membered ring include the following;
`
`aQ aa:
`
`.9Q au is»
`
`the above-mentioned 5— or 6-membered ring is
`And,
`preferably such one as having no bond at the adjacent
`position on the ring.
`The above-mentioned 5- or 6-
`
`membered ring is preferably such one as having a bond
`at the second or third p0sition to one another on the
`
`ring. Usually, even the ring is saturated or
`
`unsaturated, it is regarded as 2- to 3—atomic chain (2-
`to 3-membered chain), and a group having a 2— to 6—
`atomic chain as D_itself is preferable. As the hetero—
`
`atom existing in the spacer shown by D, nitrogen is
`preferable above all, and, D bonded to a group shown by
`A}, such as amidino group existing through —NH— group,
`is especially preferable. And,
`the above-mentioned 5—
`or 6-membered ring may be bonded to the adjacent
`amidino group directly or to a group shown by A} such
`as amidino group through —NH— group, and further to a
`group shown by A} such as amidino group through
`methylene chain.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`And, D may be such one as the adjacent carbonyl
`group is bonded directly to the above-mentioned 5- or
`
`6-membered ring, or bonded through methylene chain or
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-17
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-17
`
`
`
`2186709
`
`17
`
`bonded through a hetero atom.
`
`The methylene chain in D
`
`pay be substituted with a group of the formula
`
`—+s4}~34
`l
`H
`830
`
`wherein R3 is a hydrogen atom or a lower (Cp4) alkyl
`
`group optionally substituted with an optionally
`substituted phenyl group; and R3 is a lower (Chg) alkyl
`
`group optionally substituted with an optionally
`
`substituted phenyl group, an optionally substituted
`
`phenyl group or benzyloxy group.
`
`Examples of substituents of the optionally
`
`substituted phenyl group as the substituent to the
`lower {CL4) alkyl group of R? or R4 include lower (Chg)
`
`alkyl (e.g. methyl, ethyl),
`
`lower (Cb4) alkoxy (e.g.
`
`methoxy, ethoxy), halogen (e.g. fluoro, chloro, bromo),
`
`and hydroxyl group.
`
`Example of the lower (Chg) alkyl group of R? or R4
`
`include methyl and ethyl.
`
`Preferable typical groups shown by D include those
`of the.formula
`
`*{NHBE—£CH2}E—{E}T-€CH23E-
`
`wherein h and i each is 0 or 1; m and k each is 0,
`
`1 or
`
`2; and E is the above-mentioned 5— or 6—membered ring,
`
`especially cyclohexane ring, benzene ring, piperidine
`
`or a group of the formula
`
`As E,
`
`5— or 6-membered ring is especially
`
`preferable. And, as h,
`
`0 or 1, as m, 0,
`
`l or 2, and as
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-18
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-18
`
`
`
`2186709
`
`18
`
`k,
`
`0 are respectively preferable. Among 5- or 6—
`
`membered rings shown by E, benzene ring and cyclohexane
`
`ring are preferable, and benzene ring is especially
`preferable.
`
`In the above‘mentioned formula (I), groups of the
`formula
`
`HN
`
`H,”
`
`>—NH—-(CH;) —CH—
`m I
`N-C-R‘
`Ml
`
`3
`.
`wherein R,
`
`.
`.
`lo
`I1 and m are of the same meaning as defined
`
`above, are substituted groups derived from arginine or
`
`homoarginine.
`
`As D, groups of the formula
`
`—@—'
`
`.
`
`--NH-—CHrO-, —NH-@—. —(Cflz)2‘@‘
`
`(among others, above all
`especially
`“(3% )
`
`dCJF
`
`and
`
`-(CHfl2 *C)”
`
`,
`
`are especially preferable.
`
`(in these groups, either of the bonds may be bonded to
`A1)
`
`In the above formula (I), R1 is a hydrogen atom or
`
`a hydrocarbon group.
`
`As the hydrocarbon shown by R}, mention is made of
`
`chain-like or cyclic hydrocarbon groups including C1_6
`
`alkyl groups (e.g. methyl, ethyl, propyl,
`
`isopropyl,
`
`butyl, sec—butyl,
`
`tert—butyl, pentyl and hexyl), Che
`
`alkenyl groups (e.g. vinyl, allyl,
`
`isopropenyl,
`
`butenyl,
`
`isobutenyl and sec—butenyl), CLE alkynyl
`
`groups (e.g.propargyl, ethynyl, butynyl and 1—hexynyl),
`
`C}, cycloalkyl groups (e.g. cyclopropyl, cyclobutyl,
`
`cyclopentyl and cyclohexyl), Cb“ aryl groups (e.g.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-19
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-19
`
`
`
`
`
`~.
`
`2186709
`
`19
`
`phenyl, tolyl, xylyl,
`l-naphthyl, 2—naphthyl,
`biphenyl, 2-indenyl andEZ—anthryl, especially phenyl
`
`group), and CLM aralkyl groups (e.g. benzyl,
`
`phenethyl, diphenylmethyl,
`
`triphenylmethyl,
`
`lw
`
`5
`
`naphthylmethyl, 2-naphthylmethyl, 2—diphenylethyl,
`
`3—
`
`phenylpropyl, 4—phenylbutyl and 5—phenylpentyl,
`especially benzyl groupj, and as R1, are preferable
`
`hydrogen,
`
`lower (Cbé) alkyl or benzyl (especially
`
`hydrogen).
`In the above formula (I), R2 is a hydrogen atom or
`
`a residual group formed by removing -CH(NH2)COOH from
`an a-amino acid.
`_
`
`As the group shown by R2, any of the residual
`
`groups formed by removigg'—CH(NH2)COOH from an a—amino
`acid can be mentioned. LAnd, R1 and R? may be combined
`
`to form a 5— or 6—membered ring. Preferable examples
`
`of such 5— or 6—membered ring include rings as shown
`
`below,
`
`(W
`
`-N—-C- ,
`
`,,
`
`O
`
`.... —C-
`
`Usually, preferable'examples of R2 include.
`
`residual groups of essential amino acids. Especially
`preferable examples of R? include a hydrogen atom,
`
`lower (CL4) alkyl groups,
`
`lower (CLq) alkyl groups
`
`substituted with an optionally substituted phenyl
`
`group,
`
`lower,(Cb4) alkyl groups substituted with
`
`10
`
`15
`
`20
`
`25
`
`hydroxyl group and lower (Cb4) alkyl groups substituted
`
`30
`
`with carbamoyl group. More specifically, hydrogen,
`
`methyl,
`
`isopropyl, sec—butyl,
`
`isobutyl, hydroxylmethyl,
`
`benzyl, p-hydroxybenzyl, p-methoxybenzyl,
`
`carbamoylmethyl and carbamoylethyl are mentioned as
`
`typical examples.
`
`35
`
`As substituents optionally substituted on the
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-20
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-20
`
`
`
`2186709
`
`20
`
`benzene ring of Optionally substituted phenyl group as
`
`the substitutent of the lower (CLJ) alkyl of the above
`
`RF, mention is made of, for example,
`
`lower (Chg) alkyl"'
`
`groups (e.g. methyl, ethyl, propyl,
`
`isopropyl, n-butyl
`
`and sec—butyl),
`
`lower (Cb4) alkoxy groups (e.g. methoxy
`
`and ethoxy), halogen (e.g. chlorine, fluorine and
`
`bromine) and hydroxyl group, and the lower (Cbh) alkoxy
`
`group is preferable.
`As the group or atom shown by R2, hydrogen atom or
`
`Chg alkyl group substituted with phenyl group
`
`optionally Substituted with CPA alkoxy are preferable,
`
`pwhydroxybenzyl, p—methoxybenzyl or hydrogen atom (more
`
`preferably p—methoxybenzyl or hydrogen atoms especially
`
`hydrogen atom) are more preferable.
`
`In the above—mentioned formula (I), n is an
`
`integer of O to 8 (preferably 1 to 4 especially 2 or
`
`3).
`
`In the above formula (I), P is a spacer_having a
`
`1- to lO—atomic chain optionally bonded through a
`
`hetero—atom and/or a 5- or 6-membered ring (provided
`
`that the 5— or 6-membered ring is, depending on its
`
`bonding position, counted as 2- or 3—atomic chain).
`
`The spacer of P means a linear interval between (CH2)n
`
`and AF, and means having a interval which is lined with
`
`1 to 10 atoms between them in the present invention.
`
`As the spacer having 1— to lO-atomic chains (1— to 10—
`
`membered chain) optionally bonded through hetero—atoms
`
`and/or a 5— or 6-membered ring, mention is made of a
`
`divalent hydrocarbon group optionally bonded through 1
`
`to 4 (preferable l or 2) groups selected from
`
`s l
`
`[I
`l
`—N-, —C~, —0—, -S- and —C-
`H
`
`o
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`and/or a 5— or Swmembered ring (the 5— or 6—membered
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-21
`
`PETITIONER FORD MOTOR COMPANY EX. 1006-21
`
`
`
`21
`
`2i86709
`
`ring may be a carbocyclic one or a heterocyclic one
`
`containing 1 to 4 hetero-atoms selected from N, O and
`
`S, which may be saturated ring or unsaturated one such
`
`as aromatic ring; as the’carbocyclic one, for example,
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`are mentioned, and benzgne ring and cyclohexane ring
`are preferable, and especially benzene ring is
`
`preferable; as the heterocyclic ring, a 5—membered
`
`cyclic group containing, besides carbon atoms,
`
`1 to 4
`
`hetero-atoms selected from, for example, oxygen atom,
`
`sulfur atom and nitrogen’atom, as exemplified by 2— or
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