`Koike et al.
`
`[54] TETRAHYDROTHIENOPYRIDINE
`DERIVATIVES, FURO AND PYRROLO
`ANALOGS THEREOF AND THEIR
`PREPARATION ‘AND USES FOR
`INHIBITING BLOOD PLATELET
`AGGREGATION
`
`[75] Inventors: Hiroyuki Koike; Fumitoshi Asai;
`Atsuhiro Sugidaclii, all of Tokyo;
`Tornio Kimura, Ube; Teruhiko Inoue,
`Ube; Shigeyoshi Nishino, Ube;
`Yasunori Tsuzaki, Ube, all of Japan
`
`||||l|lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`US005288726A
`Patent Number:
`5,288,726
`Feb. 22, 1994
`Date of Patent:
`
`[11]
`[45]
`
`FOREIGN PATENT DOCUMENTS
`
`421861 4/1991 European Pat. Off. .......... .. 546/114
`Primary Examiner-Alan L. Rotman
`Assistant Examiner—-Phyllis G. Spivack
`Attorney, Agent, or Firm-Frishauf, Holtz, Goodman &
`Woodward
`ABSTRACT
`[57]
`Compounds of formula (I):
`
`[73] Assignees: Ube Industries Limited, Ube; Sankyo
`Company, Limited, Tokyo, both of
`Japan
`
`R34
`
`[21] Appl. No.: 941,676
`
`[22] Filed:
`
`Sep. 8, 1992
`
`Foreign Application Priority Data
`[30]
`Sep. 9, 1991 [JP]
`Japan ................................ .. 3-227s75
`May 29, 1992 [JP]
`Japan
`.................... .. 4-138529
`
`[51] Int. Cl.5 .................... .. A01K 3/14; C07D 513/04
`[52] US. Cl. ................................... .. 514/301; 546/114
`[58] Field of Search .............. .. 546/114, 116; 514/301,
`514/302
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,051,141 9/1977 Castaigne ....................... ._ 260/2948
`4,075,215 2/1978 Castaigne .
`260/2948
`4,127,580 11/1978 Braye ......... ..
`546/114
`4,136,186 1/1979 Frehel et al. .................. .. 546/114
`4,458,074 7/1984 Bouscuet et al. ............. .. 546/114
`4,464,377 8/1984 Blanchard et al. ........... .. 424/256
`4,529,596 7/1985 Aubert et al. ................. .. 514/231
`4,740,510 4/1988 Badorc et al. .................... ., 514/291
`
`(111)"
`
`wherein: R‘ is hydrogen, alkyl, halogen, haloalkyl, hy
`droxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,
`amino, alkanoyl, haloalkanoyl, carboxy, alkoxycar
`bonyl, carbamoyl, cyano, nitro, alkanesulfonyl, haloalk
`anesulfonyl or sulfamoyl; R2 is optionally substituted
`alkanoyl, optionally substituted alkenoyl, optionally
`substituted cycloalkylcarbonyl, substituted benzoyl, or
`5,6-dihydro-1,4,2-dioxazin-3-yl; R3 is hydrogen, hy
`droxy, optionally substituted alkoxy, aralkyloxy, al
`kanoyloxy, alkenoyloxy, cycloalkylcarbonyloxy, aryl
`carbonyloxy, alkoxycarbonyloxy, aralkyloxycarbo
`nylxy, phthalidyloxy, (5-methyl-2-oxo-1,3-dioxolen-4
`yl)methoxy,
`(5-phenyl-2-ox0-l,3-dioxolcn-4-yl)me
`thoxy, optionally substituted amino or nitro; Y is
`-—NH— or oxygen or sulfur; n is l to 5; and tautomers
`and salts of said compounds of formula (I), have the
`ability to inhibit blood platelet aggregation, and can
`thus be used for treatment and prophylaxis of thrombo
`sis and embolisms.
`
`56 Claims, No Drawings
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1012, p. 1 of 43
`
`
`
`1
`
`5,288,726
`
`TETRAHYDROTHIENOPYRIDINE
`DERIVATIVES, FURO AND PYRROLO ANALOGS
`THEREOF AND THEIR PREPARATION AND
`USES FOR INHIBITING BLOOD PLATELET
`AGGREGATION
`
`5
`
`BACKGROUND OF THE INVENTION
`The present invention relates to a series of new tet
`rahydrothieno[3,2-c]pyridine derivatives and furo and
`pyrrolo analogs of these‘derivatives, and provides pro
`cesses for preparing these derivatives as well as meth
`ods and compositions using them for inhibiting blood
`platelet aggregation.
`A number of tetrahydrothienopyridine and tetrahy
`drofuropyridine derivatives is known, and some of
`these have been disclosed to have the ability to inhibit
`blood platelet aggregation. For example, US Pat. Nos.
`4,051,141, 4,075,215, 4,127,580, 4,464,377 and 4,529,596
`all disclose compounds of this type, although not all
`disclose them for the inhibition of blood platelet aggre
`gation. The closest prior art is believed to be US. Pat.
`No. 4,051,141, which discloses, inter alia, 5-(2
`chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
`and US Pat. No. 4,529,596, which discloses, inter alia,
`5-(2-chloro-a-methoxycarbonylbenzyl)-4,5,6,7-tetrahy
`drothieno[3,2-c]pyridine.
`However, there are problems with the prior art com
`pounds referred to above, especially in that many of
`them require a long time after administration before
`they manifest their activity. Accordingly, there is a
`need for new compounds of this type having improved
`activity and the ability to act faster.
`We have now discovered a series of new tetrahydro
`thieno[3,2-c]pyridine derivatives and furo and pyrrolo
`analogs of these derivatives which have an improved
`ability to inhibit the aggregation of blood platelets.
`
`30
`
`BRIEF SUMMARY OF INVENTION
`It is, therefore, an object of the present invention to
`provide a series of new compounds of this type.
`It is a further, and more speci?c object of the present
`invention to provide such compounds having valuable
`inhibitory activity against platelet aggregation.
`Other objects and advantages of the present invention
`will become apparent as the description proceeds.
`The compounds of the present invention are those
`compounds of formula (I):
`
`45
`
`R2
`
`50
`
`(I)
`
`(111)”
`
`wherein:
`R1 represents a hydrogen atom, an alkyl group hav
`ing from 1 to 4 carbon atoms, a halogen atom, a
`haloalkyl group having from 1 to 4 carbon atoms
`and at least one halogen atom, a hydroxy group, an
`alkoxy group having from 1 to 4 carbon atoms, a
`haloalkoxy group having from 1 to 4 carbon atoms
`and at least one halogen atom, an alkylthio group
`having from 1 to 4 carbon atoms, a haloalkylthio
`group having from 1 to 4 carbon atoms and at least
`one halogen atom, an amino group, an alkanoyl
`
`55
`
`65
`
`2
`group having from 1 to 5 carbon atoms, a haloal
`kanoyl group having from 2 to 5 carbon atoms and
`at least one halogen atom, a carboxy group, an
`alkoxycarbonyl group having from 2 to 5 carbon
`atoms, a carbamoyl group, a cyano group, a nitro
`group, an alkanesulfonyl group having from 1 to 4
`carbon atoms, a haloalkanesulfonyl group having
`from 1 to 4 carbon atoms and at least one halogen
`atom, or a sulfamoyl group;
`R2 represents an alkanoyl group having from 1 to 10
`carbon atoms, a substituted alkanoyl group which
`has from 2 to 10 carbon atoms and which is substi
`tuted by at least one substituent selected from the
`group consisting of substituents A, de?ned below,
`an alkenoyl group having from 3 to 6 carbon
`atoms, a substituted alkenoyl group which has from
`3 to 6 carbon atoms and which is substituted by at
`least one substituent selected from the group con
`sisting of substituents A, de?ned below, a cycloalk
`ylcarbonyl group having from 4 to 8 carbon atoms,
`a substituted cycloalkylcarbonyl group which has
`from 4 to 8 carbon atoms and which is substituted
`by at least one substituent selected from the group
`consisting of substituents A, de?ned below, a sub
`stituted benzoyl group having at least one substitu
`ent selected from the group consisting of substitu
`ents B, de?ned below, or a 5,6-dihydro 1,4,2-dioxa
`zin-3-yl group;
`R3 represents a hydrogen atom, a hydroxy group, an
`alkoxy group having from 1 to 4 carbon atoms, a
`substituted alkoxy ‘group which has from 1 to 4
`carbon atoms and which is substituted by at least
`one substituent selected from the group consisting
`of substituents C, de?ned below, an aralkylo'xy
`group in which the aralkyl part is as de?ned below,
`an alkanoyloxy group having from 1 to 18 carbon
`atoms, an alkenoyloxy group having from 3 to 6
`carbon atoms, a cycloalkyl carbonyloxy group
`having from 4 to 8 carbon atom, an arylcar
`bonyloxy group in which the aryl part is as de?ned
`below, an alkoxycarbonyloxy group having from 2
`to 5 carbon atoms, an aralkyloxycarbonyloxy
`group in which the aralkyl part is as de?ned below,
`a phthalidyloxy group, a (5-methyl-2-oxo-1,3-diox
`olen-4-yl)methoxy group, a (5-phenyl-2-oxo-1,3
`dioxolen-4-yl)methoxy group, a group of formula
`_NRaRb
`wherein RG and Rb are independently selected from
`the group consisting of hydrogen atoms, alkyl
`groups having from 1 to 4 carbon atoms and
`substituted alkyl groups which have from 1 to 4
`carbon atoms and which are substituted by at
`least one substituent selected from the group
`consisting of substituents C, de?ned below,
`an aralkylamino group in which the aralkyl part is as
`de?ned below, an alkanoylamino group having
`from 1 to 18 carbon atoms, an alkenoylamin group
`having from 3 to 6 carbon atoms, a cycloalkylcar
`bonylamino group having from 4 to 8 carbon
`atoms, an arylcarbonylamino group in which the
`aryl part is as de?ned below, an alkoxycar
`bonylamino group having from 2 to 5 carbon
`atoms, an aralkyloxycarbonylamino group in
`which the aralkyl part is as de?ned below, a
`phthalidylamino group, a (5-methy1-2-oxo-l,3
`dioxolen-4-yl)methylamino group, a (5-phenyl-2
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1012, p. 2 of 43
`
`
`
`3
`oxo-1,3-dioxolen-4-yl)methylamino group or a
`nitro group;
`Y represents a group of formula —Nl-l— or an oxy
`gen or sulfur atom; and
`n is an integer from 1 to 5, and, when n is an integer
`from 2 to 5, the groups represented by R1 may be
`the same as or different from each other;
`said substituents A are selected from the group con
`sisting of halogen atoms, hydroxy groups, alkoxy
`groups having from 1 to 4 carbon atoms and cyano
`
`5,288,726
`4
`The invention also provides processes for preparing
`these compounds, which are described in greater detail
`hereafter.
`
`DETAILED DESCRIPTION OF INVENTION
`When the compounds of the present invention have
`an amino or hydroxy group at the 2- or 3- position (i.e.
`R3 represents an amino or hydroxy group at the 2- or 3
`position), they can exist as keto-enol tautomers, that is:
`
`0
`
`R2
`
`N
`
`(1')
`
`R2
`
`N
`
`(1")
`
`HZ
`
`Y
`
`HZ
`
`Y
`
`groups;
`said substituents B are selected from the group con
`sisting of alkyl groups having from 1 to 4 carbon
`atoms, halogen atoms and alkoxy groups having
`from 1 to 4 carbon atoms;
`said substituents C are selected from the group con
`sisting of alkoxy groups having from 1 to 4 carbon
`atoms, alkanoyloxy groups having from 1 to 6 car
`bon atoms and arylcarbonyloxy groups in which
`the aryl part is as de?ned below;
`said aralkyl parts of said aralkyloxy, aralkyloxy. car
`bonyloxy,
`aralkylamino and aralkyloxycar
`bonylamino groups are alkyl groups which have
`from 1 to 4 carbon atoms and which are substituted
`by at least one aryl group as de?ned below;
`said aryl groups and said aryl parts of said arylcar
`bonyloxy groups and of said arylcarbonylamino
`groups have from 6 to 10 carbon atoms in a carbo
`cyclic ring which is unsubstituted or is substituted
`by at least one substituent selected from the group
`consisting of substituents D, de?ned below; and
`said substituents D are selected from the group con
`sisting of the groups and atoms de?ned above in
`relation to R1, other than said hydrogen atom;
`and tautomers thereof and pharmaceutically accept
`able salts of said compounds of formula (I) and of
`said tautomers.
`The invention also provides a pharmaceutical compo
`sition for the treatment and prophylaxis of thrombosis
`or embolisms, comprising an effective amount of a
`blood platelet aggregation inhibitor in admixture with a
`pharmaceutically acceptable carrier or diluent, wherein
`said inhibitor is at least one compound of formula (I), or
`a tautomer or pharmaceutically acceptable salt thereof.
`The invention still further provides a method for the
`treatment or prophylaxis of thrombosis or embolisms,
`comprising administering to a mammal, which'may be
`human, an effective amount of a blood platelet aggrega
`tion inhibitor, wherein said inhibitor is at least one com
`pound of formula (I), or a tautomer or pharmaceutically
`acceptable salt thereof.
`
`40
`
`45
`
`50
`
`55
`
`wherein Y, R1, R2 and n are as de?ned above, and Z
`represents a group of formula =NI-I or an oxygen tom.
`These tautomers may or may not be readily separable,
`and, if separable, may be separated by methods well
`known in the art. In any event, the present invention
`embraces both the individual isolated tautomers, as well
`as mixtures thereof, and both the isolated tautomers and
`such mixtures may be used in the compositions and
`methods of the present invention. In particular, the
`tautomers of formula (Ia) are preferred.
`In the compounds of the present invention, where R1
`represents an alkyl group, this may be a straight or
`branched chain alkyl group having from 1 to 4 carbon
`atoms, and examples include the methyl, ethyl, propyl,
`isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups.
`Of these, we prefer those alkyl groups having from 1 to
`3 carbon atoms, more preferably the methyl and ethyl
`groups.
`Where Rl represents a halogen atom, this may be, for
`example, a ?uorine, chlorine, iodine or bromine atom,
`and is preferably a fluorine or chlorine atom.
`Where Rl represents a haloalkyl group, the alkyl part
`may be any one of the alkyl groups exempli?ed above
`and may be substituted by one or more halogen (for
`example ?uorine, chlorine, bromine or iodine) atoms.
`There is, in principle, no restriction on the number of
`halogen substituents on the alkyl group, this being lim
`ited only by the number of substitutable atoms. In gen
`eral, however, from 1 to 5 halogen substituents are
`preferred, from 1 to 3 substituents being more preferred.
`Speci?c examples of such groups include the ?uoro
`methyl, di?uoromethyl, trifluoromethyl, chloromethyl,
`dichlorornethyl, trichloromethyl, 2-tluoroethyl, 2
`chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trichloro
`ethyl, 2,2,2-tri?uoroethyl, 2-?uoropropyl, 3-?uoropro
`pyl, 3-chloropropyl, 2-fluorobutyl, 3-?uorobutyl, 4
`chlorobutyl and 4-iluorobutyl groups. The ?uorine-sub
`stituted and chlorine-substituted groups are preferred,
`the ?uorine-substituted groups being more preferred.
`The fluoromethyl, di?uoromethyl and trifluoromethyl
`
`60
`
`65
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1012, p. 3 of 43
`
`
`
`20
`
`5,288,726
`6
`5
`these, the ?uorine substituted alkanoyl groups are pre
`groups are most preferred, especially the tri?uoro
`ferred, the ?uoroacetyl, di?uoroacetyl and tri?uoroace
`methyl group.
`tyl groups being more preferred and the tri?uoroacetyl
`Where Rl represents an alkoxy group, this may be a
`group being most preferred.
`straight or branched chain alkoxy group having from 1
`Where Rl represents an alkoxycarbonyl group, this
`to 4 carbon atoms, and examples include the methoxy,
`may be a straight or branched chain alkoxycarbonyl
`ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec
`group having from 2 to 5 carbon atoms, that is the alk
`butoxy and t-butoxy groups. Of these, we prefer those
`oxy part has from 1 to 4 carbon atoms, and examples
`alkoxy groups having from 1 to 3 carbon atoms, more
`include the methoxycarbonyl, ethoxycarbonyl, propox
`preferably the methoxy and ethoxy groups.
`ycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobu
`Where R1 represents a haloalkoxy group, the alkoxy
`toxycarbonyl, sec-butoxycarbonyl and t-butoxycarbo
`part may be any one of the alkoxy groups exempli?ed
`nyl groups. Of these, we prefer those alkoxycarbonyl
`above and may be substituted by one or more halogen
`groups having from 1 to 3 carbon atoms, more prefera
`(for example ?uorine, chlorine, bromine or iodine)
`bly the methoxycarbonyl and ethoxycarbonyl groups._
`atoms. There is, in principle, no restriction on the num
`Where Rl represents an alkanesulfonyl group, this
`ber of halogen substituents on the alkoxy group, this
`may be a straight or branched chain alkanesulfonyl
`being limited only by the number of substitutable atoms.
`group having from 1 to 4 carbon atoms, and examples
`In general, however, from 1 to 5 halogen substituents
`include the methanesulfonyl, ethanesulfonyl, propane
`are preferred, from 1 to 3 substituents being more pre
`sulfonyl, isopropanesulfonyl, butanesulfonyl, isobutane
`ferred. Speci?c examples of such groups include the
`sulfonyl, sec butanesulfonyl and t-butanesulfonyl
`?uoromethoxy, di?uoromethoxy, tri?uoromethoxy,
`groups. Of these, we prefer those alkanesulfonyl groups
`2-?uoroethoxy, 2-chloroethoxy, 2-bromoethoxy, '2
`iodoethoxy,
`2,2,2-trichloroethoxy,
`2,2,2-tri?uoroe
`having from 1 to 3 carbon atoms, more preferably the
`methanesulfonyl and ethanesulfonyl groups.
`thoxy, 2-?uoropropoxy, 3-?uoropropoxy, 3-chloro
`Where Rl represents a haloalkanesulfonyl group, the
`propoxy,
`2-?uorobutoxy,
`3-?uorobutoxy,
`4
`alkanesulfonyl part may be any one of the alkanesulfo
`chlorobutoxy and 4-?uorobutoxy groups. The ?uo
`nyl groups exempli?ed above and may be substituted by
`roalkoxy groups are preferred. The ?uoromethoxy,
`one or more halogen (for example ?uorine, chlorine,
`di?uoromethoxy and tri?uoromethoxy groups are most
`preferred, especially the tri?uoromethoxy group.
`bromine or iodine) atoms. There is, in principle, no
`restriction on the number of halogen substituents on the
`Where R1 represents an alkylthio group, this may be
`alkanesulfonyl group, this being limited only by the
`a straight or branched chain alkylthio group having
`number of substitutable atoms. In general, however,
`from 1 to 4 carbon atoms, and examples include the
`methylthio, ethylthio, propylthio, isopropylthio, bu
`from 1 to 5 halogen substituents are preferred, from 1 to
`3 substituents being more preferred. Speci?c examples
`tylthio, isobutylthio, sec-butylthio and t-butylthio
`of such groups include the ?uoromethanesulfonyl, di
`groups. Of these, we prefer those alkylthio groups hav
`?uoromethanesulfonyl, tri?uoromethanesulfonyl, di
`ing from 1 to 3 carbon atoms, more preferably the meth
`chloromethanesulfonyl, trichloromethanesulfonyl, 2
`ylthio and ethylthio groups.
`fluoroethanesulfonyl, 2-chloroethanesulfonyl 2-bromo
`Where R1 represents a haloalkylthio group, the alkyl
`ethanesulfonyl, 2-iodoethanesulfonyl, 2,2,2-trichloroe
`thio part may be any one of the alkylthio groups exem
`thanesulfonyl, 2,2,Z-tri?uoroethanesulfonyl, 2-?uoro
`plified above and may be substituted by one or more
`propanesulfonyl, 3-?uoropropanesulfonyl, 3-chloro
`halogen (for example ?uorine, chlorine, bromine or
`propanesulfonyl,
`2-?uorobutanesulfonyl,
`3
`iodine) atoms. There is, in principle, no restriction on
`?uorobutanesulfonyl, 4-chlorobutanesulfonyl and 4
`the number of halogen substituents on the alkylthio
`?uorobutanesulfonyl groups. The ?uorine-substituted
`group, this being limited only by the number of substi
`alkanesulfonyl and chlorine substituted alkanesulfonyl
`tutable atoms. In general, however, from 1 to 5 halogen
`groups are preferred, the ?uorine-substituted alkanesul
`substituents are preferred, from 1 to 3 substituents being
`fonyl groups being more preferred. The ?uorome
`more preferred. Speci?c examples of such groups in
`thanesulfonyl,
`di?uoromethanesulfonyl
`and
`tri
`clude the ?uoromethylthio, di?uoromethio, tri
`?uoromethylthio, 2-?uoroethylthio, 2-chloroethylthio,
`?uoromethanesulfonyl groups are most preferred, espe
`cially the tri?uoromethanesulfonyl group.
`2-bromoethylthio, 2-iodoethylthio, 2,2,2-trichloroeth
`ylthio, 2,2,2-tri?uoroethylthio, 2-?uoropropylthio, 3
`Of the above groups and atoms, we especially prefer
`?uoropropylthio,
`3-chloropropylthio,
`2-fluorobu
`that R1 should represent: a hydrogen atom; an alkyl
`tylthio, 3-?uorobutylthio, 4-chlorobutylthio and 4
`group having from 1 to 4 carbon atoms; a halogen atom;
`a ?uorine substituted alkyl group having from 1 to 4
`?uorobutylthio groups. The ?uorine substituted groups
`carbon atoms; a hydroxy group; an alkoxy group hav
`are preferred. The ?uoromethylthio, di?uorometh
`ing from 1 to 4 carbon atoms; a ?uorine-substituted
`ylthio and tri?uoromethylthio groups are most pre
`alkoxy group having from 1 to 4 carbon atoms; an alkyl
`ferred, especially the tri?uoromethylthio group.
`thio group having from 1 to 4 carbon atoms; a ?uorine
`Where R1 represents an alkanoyl group, this has from
`substituted alkylthio group having from 1 to 4 carbon
`1 to 5 carbon atoms and may be a straight or branched
`atoms; an amino group; an alkanoyl group having from
`chain group. Examples include the formyl, acetyl, pro
`pionyl, butyryl, isobutyryl, valeryl, isovaleryl and pi
`1 to 5 carbon atoms; a ?uorine-substituted alkanoyl
`group having from 2 to 5 carbon atoms; an alkoxycar
`valoyl groups, of which the formyl and acetyl groups
`bonyl group having from 2 to 5 carbon atoms; a carbam
`are preferred.
`oyl group; a cyano group; a nitro group; an alkanesulfo
`Where R1 represents a haloalkanoyl group, this has
`nyl group having from 1 to 4 carbon atoms; a ?uorine
`from 2 to 5 carbon atoms and may be a straight or
`substituted alkanesulfonyl group having from 1 to 4
`branched chain group. Examples include the fluoroa
`cetyl, di?uoroacetyl, tri?uoroacetyl, chloroacetyl, tri
`carbon atoms; or a sulfamoyl group.
`chloroacetyl, bromoacetyl, iodoacetyl, 3-?uoropropio
`More preferably R1 represents: a hydrogen atom; a
`methyl group; an ethyl group; a halogen atom; a ?uo
`nyl, 4-?uorobutyryl and S-?uorovaleryl groups. Of
`
`55
`
`60
`
`65
`
`25
`
`45
`
`50
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1012, p. 4 of 43
`
`
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`5,288,726
`8
`7
`acetyl, chloroacetyl, 3-?uoropropionyl, hydroxyacetyl,
`tine-substituted methyl group; a hydroxy group; a me
`methoxyacetyl, ethoxyacetyl and cyanoacetyl groups.
`thoxy group; an ethoxy group; a ?uorine-substituted
`The most preferred groups are the ?uoroacetyl, di
`methoxy group; a methylthio group; a ?uorine-sub
`fluoroacetyl, tri?uoroacetyl, chloroacetyl, 3-fluoropro
`stituted methylthio group; a formyl group; an acetyl
`pionyl, hydroxyacetyl, methoxyacetyl and cyanoacetyl
`group; a ?uorine-substituted acetyl group; a methoxy
`groups, especially the 'fluoroacetyl, di?uoroacetyl and
`carbonyl group; an ethoxycarbonyl group; a propox
`tri?uoroacetyl groups.
`ycarbonyl group; a carbamoyl group; a cyano group; a
`Where R2 represents an alkenoyl group having from
`nitro group; a methanesulfonyl group; an ethanesulfo
`nyl group; a ?uorine-substituted methanesulfonyl
`3 to 6 carbon atoms, this may be a straight or branched
`chain group, and examples include the acryloyl, meth
`group; or a sulfamoyl group.
`acryloyl, Z-butenoyl, Z-pentenoyl and Z-hexenoyl
`Still more preferably R1 represents: a halogen atom; a
`groups, of which the acryloyl and methacryloyl groups
`tri?uoromethyl group; a hydroxy group; a di?uorome
`are preferred.
`thoxy group; a tri?uoromethoxy group; a di?uorometh
`These alkenoyl groups may also be substituted by one
`ylthio group; a tri?uoromethylthio group; a formyl
`or more of substituents A, de?ned and exempli?ed
`group; an acetyl group; a trifluoroacetyl group; a cyano
`above. Speci?c examples of such substituted groups
`group or a nitro group.
`include the B-fluoroacryloyl, 3-chloroacryloyl and 3
`Most preferably Rl represents: a ?uorine atom, a
`cyanoacryloyl groups, of which the 3-?uoroacryloyl
`chlorine atom or a tri?uoromethyl group; especially a
`group is particularly preferred.
`?uorine atom or a chlorine atom.
`-
`Where R2 represents a cycloalkylcarbonyl group, this
`The number of the substituents, n, represented by R1
`has from 4 to 8 carbon atoms, that is the cycloalkyl
`is from 1 to 5, although the maximum may be lower
`group itself has from 3 to 7 ring carbon atoms. Exam
`than 5 in some cases if there is a problem of steric hin
`ples of such groups include the cyclopropylcarbonyl,
`drance. Preferably n is from 1 to 3, and more preferably
`cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexyl
`1 or 2. The position of substitution by R1 on the phenyl
`carbonyl and cycloheptylcarbonyl groups, of which the
`group is preferably para or ortho, more preferably or
`cyclopropylcarbonyl and cyclobutylcarbonyl groups
`tho.
`are particularly preferred.
`Where R2 represents an alkanoyl group having from
`These cycloalkylcarbonyl groups may also be substi
`1 to 10 carbon atoms, this may be a straight or branched
`chain group, and examples include the formyl, acetyl,
`tuted by one or more of substituents A, de?ned and
`propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pi
`exempli?ed above. Speci?c examples of such substi
`valoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl and
`tuted groups include the 2-?uorocyclopropylcarbonyl,
`2,2-difluorocyclopropylcarbonyl, Z-chlorocyclopropyl
`decanoyl groups, of which those groups having from 2
`carbonyl, 2-bromocyclopropylcarbonyl, 2-?uorocy
`to 6 carbon atoms are preferred, especially the acetyl,
`clobutylcarbonyl,
`2-chlorocyclobutylcarbonyl,
`2
`propionyl and isobutyryl groups, of which the acetyl
`fluorocyclopentylcarbonyl, Z-chlorocyclopentyl car
`and propionyl groups are most preferred.
`bonyl, 2-?uorocyclohexylcarbonyl, 2-chlorocyclohex
`Those alkanoyl groups represented by R2 and having
`ylcarbonyl, Z-hydroxycyclopropylcarbonyl, Z-hydrox
`from 2 to 10 carbon atoms may be substituted by one or
`ycyclobutylcarbonyl, 2-hydroxycyclopentylcarbonyl,
`more of substituents A, defined above. Examples of
`2-hydroxycyclohexylcarbonyl, Z-methoxycyclopropyl
`such substituents A include:
`carbonyl, Z-methoxycyclobutylcarbonyl, 2-methoxycy
`halogen atoms, such as the ?uorine, chlorine, bro
`clopentylcarbonyl, Z-methoxycyclohexylcarbonyl, 2
`mine and iodine atoms;
`ethoxycyclopropylcarbonyl, Z-ethoxycyclobutylcarbo
`hydroxy groups;
`nyl, 2-ethoxycyclopentylcarbonyl, 2-ethoxycyclohexyl
`alkoxy groups having from 1 to 4 carbon atoms, such
`carbonyl, 2-cyanocyclopropylcarbonyl, 2-cyanocy
`as those exempli?ed above in relation to R1; and
`clobutylcarbonyl, 2-cyanocyclopentylcarbonyl and 2
`cyano groups.
`cyanocyclohexylcarbonyl groups, of which the 2
`In the case of these substituted groups, and all substi
`fluorocyclopropylcarbonyl, 2,2-di?uorocyclopropyl
`tuted groups referred to herein, there is no speci?c
`carbonyl, 2-chlorocyclopropylcarbonyl, 2-?uorocy
`limitation on the number of the substituents, except such
`clobutylcarbonyl,
`2-chlorocyclobutylcarbonyl,
`2
`as may be imposed by the number of substitutable posi
`fluorocyclopentylcarbonyl,
`2-fluorocyclohexylcar
`tions and possibly also by steric constraints. However,
`bony, 2-hydroxycyclopropylcarbonyl, 2-methoxycy
`in general, from 1 to 3 such substituents are preferred.
`clopropylcarbonyl, Z-ethoxycyclopropyl. carbonyl and
`Specific examples of such substituted alkanoyl groups
`include the fluoroacetyl, di?uoroacetyl, tri?uoroacetyl,
`Z-cyanocyclopropylcarbonyl groups are preferred.
`chloroacetyl, trichloroacetyl, bromoacetyl, iodoacetyl,
`More preferred groups are the 2-?uorocyclopropylcar
`bonyl,
`Z-chlorocyclopropylcarbonyl,
`2-?uorocy
`3-?uoropropiony1, 3-cloropropionyl, 3-bromopropio
`clobutylcarbonyl and Z-methoxycyclopropyl carbonyl
`nyl, 3-iodopropionyl, 4-fluorobutyryl, 4-chlorobutyryl,
`S-?uorovaleryl, hydroxyacetyl, 3-hydroxypropionyl,
`groups, and the most preferred is the Z-?uorocyclo
`4-hydroxybutyryl, S-hydroxyvaleryl, methoxyacetyl,
`propylcarbonyl group.
`3-methoxypropionyl, 4-methoxybutyryl, 5-methox.
`Where R2 represents a substituted benzoyl group, this
`yvaleryl, ethoxyacetyl, 3-ethoxypropionyl, 4-ethoxybu
`is substituted by at least one of substituents B, which are
`tyryl, 5-ethoxyvaleryl, cyanoacetyl, 3-cyanopropionyl,
`selected from the group consisting of alkyl groups hav
`ing from 1 to 4 carbon atoms, halogen atoms and alkoxy
`4-cyanobutyryl and S-cyanovaleryl groups, of which
`the fluoroacetyl, di?uoroacetyl, tri?uoroacetyl, chloro
`groups having from 1 to 4 carbon atoms, all of which
`acetyl, 3-?uoropropionyl, 3-chloropropionyl, hydrox
`may be as exempli?ed in relation to the same groups and
`yacetyl,
`3-hydroxypropionyl,
`methoxyacetyl,
`3
`atoms represented by R‘. The number of the substitu
`methoxypropionyl, ethoxyacetyl, cyanoacetyl and 3
`ents may be from 1 to 5, provided that there is no prob
`lem of steric hindrance; preferably, however, are from 1
`cyanopropionyl groups are more preferred. Still more
`preferred are the ?uoroacetyl, di?uoroacetyl, trifluoro
`to 3 substituents, more preferably 1 or Speci?c exam»
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1012, p. 5 of 43
`
`
`
`20
`
`25
`
`30
`
`35
`
`5,288,726
`10
`ples of such substituted benzoyl groups include the
`Where R3 represents an alkanoyloxy group, this may
`2-?uorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2,4
`be a straight or branched chain group and has from 1 to
`di?uorobenzoyl, 2,4,6-trifluorobenzoyl, 2,3,4,5,6-penta
`18 carbon atoms. Examples of such groups include the
`formyloxy,
`acetoxy,
`propionyloxy,
`butyryloxy,
`?uorobenzoyl, 4-chl0robenzoyl, 2,4-dichlorobenzoyl,
`isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy,
`4-methylbenzoyl, 2,4-dimethylbenzoyl, 4-ethylbenzoyl,
`2,4-diethylbenzoyl, 4-methoxybenzoyl, 2,4-dimethoxy
`hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoy
`loxy, decanoyloxy, lauroyloxy, myristoyloxy, pal
`benzoyl, 4-ethoxybenzoyl and 2,4-diethoxybenzoyl
`mitoyloxy and stearoyloxy groups, of which those
`groups, of which the 4-tluorobenzoyl and 2,4-di?uoro~
`groups having from 1 to 12 carbon atoms are preferred,
`benzoyl groups are preferred.
`’
`those having from 2 to 10 carbon atoms are more pre
`Where R3 represents an alkoxy group, this may be a
`ferred, and those having from 2 to 5 carbon atoms are
`straight or branched chain group having from 1 to 4
`most preferred, especially the acetoxy, propionyloxy,
`carbon atoms and may be any of the alkoxy groups
`butyryloxy, pivaloyloxy, nonanoyloxy and decanoy
`exempli?ed above in relation to R1. Such a group may
`loxy groups, of which the acetoxy, propionyloxy,
`be unsubstituted or it may have one or more substituents
`butyryloxy and pivaloyloxy groups are most preferred.
`selected from the group consisting ofssubstituents C,
`Where R3 represents an alkenoyloxy group, this may
`de?ned above, and examples of which are as follows:
`be a straight or branched chain group and has from 3 to
`alkoxy groups having from 1 to 4 carbon atoms, such
`6, more preferably 3 or 4, carbon atoms. Examples of
`as those exempli?ed above in relation to R1;
`such groups include the acryloyloxy, methacryloyloxy,
`alkanoyloxy groups having from 1 to 6 carbon atoms,
`Z-butenoyloxy, 2-pentenoyloxy and Z-hexenoyloxy
`which may be a straight or branched chain group,
`groups, of which the acryloyloxy and methacryloyloxy
`for example the formyloxy, acetoxy, propionyloxy,
`groups are preferred.
`butyryloxy, isobutyryloxy, valeryloxy, isovalery
`Where R3 represents a cycloalkylcarbonyloxy group,
`loxy, pivaloyloxy or hexanoyloxy groups, of which
`this has from 4 to 8, more preferably from 4 to 7, carbon
`those groups having from 1 to 5 carbon atoms are
`preferred, and the acetoxy, propionyloxy, butyry
`atoms, that is the cycloalkyl group itself has from 3 to 7
`ring carbon atoms. Examples of such groups include the
`loxy and pivaloyloxy groups are most preferred;
`cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cy
`and
`clopentylcarbonyloxy, cyclohexylcabonyloxy and cy
`arylcarbonyloxy groups in which the aryl part is as
`cloheptylcarbonyloxy groups, of which the cyclo
`de?ned above, for example the arylcarbonyloxy
`propylcarbonyloxy and cyclobutylcarbonyloxy groups
`groups exempli?ed below in relation to R3.
`are particularly preferred.
`Speci?c examples of such substituted alkoxy groups
`Where R3 represents arylcarbonyloxy group, the aryl
`include the methoxymethoxy, ethoxymethoxy, propox
`ymethoxy, butoxymethoxy, 2-methoxyethoxy, 2-ethox
`part is as de?ned above, and examples of such groups
`include the benzoyloxy, l-naphthoyloxy, 2-naph
`yethoxy, formyloxymethoxy, acetoxymethoxy, pro
`pionyloxymethoxy, 2-formyloxyethoxy, 2-acetoxye
`thoyloxy, o-, m- and p-toluoyloxy, 0-, m- and p
`thoxy, Z-propionyloxyethoxy, 3-acetoxypropoxy, 4
`chlorobenzoyloxy, o-, m- and p-?uorobenzoyloxy, 0-,
`acetoxybutoxy, valeryloxymethoxy, pivaloyloxyme
`m- and p-methoxybenzoyloxy, 2,3-, 2,4-, 2,5-, 2,6-, 3,4
`and 3,5-dichlorobenzoyloxy, 2,4-di?uorobenzoyloxy
`thoxy, benzoyloxymethoxy, naphthoyloxymethoxy,
`p-toluoyloxymethoxy,
`p-chlorobenzoyloxymethoxy,
`and 2,4,6-tri?uorobenzoyloxy groups, preferably the
`benzoyloxy group.
`2-benzoyloxyethoxy, 3-benzoyloxypropoxy and 4-ben
`Where R3 represents an alkoxycarbonyloxy group,
`zoyloxybutoxy groups, of which the pivaloyloxyme
`this may be a straight or branched chain alkoxycar
`thoxy group is most preferred.
`bonyloxy group having from 2 to 5 carbon atoms, that
`Where R3 represents an aralkyloxy group, the alkoxy
`is the alkoxy part has from 1 to 4 carbon atoms, and
`part is an alkoxy group having from 1 to 4, preferably
`examples include the methoxycarbonyloxy, ethoxycar
`from 1 to 3,
![](/site_media/img/document_icon.png)
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ ChargeStill Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
![](/site_media/img/error_icon.png)
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
![](/site_media/img/error_icon.png)
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
![](/site_media/img/error_icon.png)
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
![](/site_media/img/document_icon.png)
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
![](/site_media/img/document_icon.png)
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
![](/site_media/img/error_icon.png)
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site