1 1987~O0030~US
`
`-139-
`
`R” and R28 or R27 and R29 together with the nitrogen atom to
`
`which they are attached form a saturated or partially
`
`unsaturated S to 7~membered heterocycle having up to
`
`three, preferabiy up to two,
`
`identical or different
`
`heteroatoms from the group consisting of N, O and S,
`
`and
`
`R30 and R31 are identical or different and independently of one
`
`another
`
`each
`
`represents
`
`hydrogen,
`
`(C2-C4)-elkyi,
`
`(C3—C7)—cycI0a1ky1,
`
`(C1-C4)-alkylsulphonyl,
`
`(C1-C4)-
`
`hydroxyalkyl,
`
`(C1—C4)—aminoa1ky1,
`
`di—(C1—C4)-
`
`a1ky1a1nino—(C1—C4)-aikyi,
`
`«CH-;,C(I\IR27R28)eNR29
`
`or
`
`—COR33,
`
`where
`
`R33
`
`represents
`
`(C1~C5)—a]koxy,
`
`(C}—C4)~
`
`aikoxy-(C1-C4)~a1ky1,
`
`(C1—C4)—a1koxycar’oenyI~
`
`(C;-C4)-alkyl,
`
`(C1-C¢)—a1ninoalky1,
`
`(C1~C4)—
`
`aikoxycatbonyl, (C1—C4)~alkanoy1~(C1-C4)—a1kyi,
`
`(C3~C7)-eycloalkyi,
`
`(C1-C5)-aikenyi,
`
`(C1-C3)~
`
`aikyl, which may optionally be substituted by
`
`phenyl
`
`or
`
`acetyl,
`
`(C5—C14)~ary1,
`
`(C5-C10)‘
`
`heteroaryl, trifluorornethyl, tetrahydrofinanyl or
`
`butyrolactone,
`
`R3, R4, R5, R6, R7 and R8 are identical or different and
`
`each represents hydrogen or represents (C1~C5)-alkyl
`
`and their pharmaceuticaliy acceptabie saits, hydrates and prodrugs,
`
`MYLAN - EXHIBIT 1006 - Palt 9 of 9
`
`2223
`
`2223
`
`MYLAN - EXHIBIT 1006 - Part 9 of 9
`
`

`
`1 198'/—00030—~US
`
`—140~
`
`except for compounds of the general formuia (I) in which the radical R1 is an
`
`unsubstituted 2—thiophene radical and the radical R2 is simultaneously a
`
`mono~ or polysubstituted phenyl radical and the radicals R3, R4, R5, R5, R7
`
`and R8 are each simultaneously hydrogen.
`
`Compounds of the general formula (1) according to Claim E, characterized in
`that
`
`10
`
`R1
`
`_ represents thiophene (thienyl), in particular 2—tl1iophene, which
`
`may optionally be mono— or polysabstituted by halogen, preferably
`
`chlorine or bromine, by amino, aminomethyl or
`
`(C1-Cg)—alky1,
`
`preferably methyl, where the (C;~Cg)~alky1 radical for its part may
`
`optionally be mono~ or polysubstituted by halogen, preferably fluorine,
`
`I5
`
`20
`
`25
`
`30
`
`R2
`
`represents one of the groups below:
`
`An
`
`A-M~,
`
`D—l\/I—A—,
`
`B-M—A—,
`
`3*,
`
`B~M—,
`
`B—1\/I-B—,
`
`D—M—B—,
`
`where:
`
`the radical “A” represents (C5~C14)~aryl, preferably (C5—C1o)'
`
`aryl,
`
`in particular phenyl or naphthyl, very particularly
`
`preferably phenyl;
`
`the radical “B” represents a 5- or 6—membercd aromatic
`
`heterocycle which contains up to 3 heteroatoms and/or hetero
`
`2224
`
`2224
`
`

`
`1198700030-US
`
`~ 141 —
`
`chain members, in particular up to 2 heteroatoms and/or hetero
`
`chain members, from the group consisting of S, N, NO (N-
`
`oxide) and O;
`
`the radicai “D” represents a saturated or partially unsaturated
`
`4~ to 7'—me1nbered heterocycle which contains up to three
`
`heteroatoms and/or hetero chain members from the group
`
`consisting of S, SO, S02, N, NO fl\I-oxide) and O;
`
`the radicai “M” represents —NIrI-, -CH2-, -CH2CH2~, -0-, —NH—
`
`CH2~,
`
`~CH2—NH-, —OCH2—,
`
`~CH2O—,
`
`-CONH-,
`
`-NHCO—,
`
`~COO-, —0OC-, -S- or represents a covalent bond;
`
`where
`
`the groups “A”, “B” and “D” defined above may in each case
`
`optionally be mono» or polysubstituted by a radicai from the
`
`group consisting of halogen; trifluoromethylg oxo; cyano; nitro;
`
`carbamoyl; pyridyi;
`
`(C1~C5)-alkanoyi; (C3-C7)-cycloalkanoyi;
`
`(C5—C;4)—ary3carbony§;
`
`(C5-C10)-heteroaryicarbonyl;
`
`(C1-C5)-
`
`aikanoyloxymethyloxy;
`
`—COOR27;
`
`-SOZRZ7;
`
`—c(NR”R2*):NR”;
`
`~CONR28R29; —so2NR23R”; —oR3“;
`
`~NR3°;a“, (C1-C5)—a1ky1and (C3-C7)—cycloa1ky1,
`
`where (C1-C5)-alkyi and (C3-C7)—eyc1oa1ky1 for their
`
`part may optionally be substituted by a radical from the
`
`group
`
`consisting
`
`of
`
`cyano;
`
`~OR27;
`
`-NRZSR29;
`
`-CO(NI~I)\.(NR27R28) and ~C(NR27R28)=NR29,
`
`where:
`
`v
`
`is either 0 or 1 and
`
`2225
`
`20
`
`25
`
`30
`
`2225
`
`

`
`11987-00030~US
`
`— 142 —
`
`R27, R28 and R29 are identical or different and independently of
`
`one another each represents hydrogen, (C1—C4)~al1<y1 or
`
`(C3~C7)-cycloalkyl,
`
`and/or
`
`R27 and R28 or R27 and R29 together with the nitrogen atom to
`
`which they are attached form a saturated or partialiy
`
`unsaturated 5- to 7~n'1embered heterocycie having up to
`
`three, preferably up to two,
`
`identical or different
`
`lrereroatorns from the group consisting of N, O and S,
`
`and
`
`R30 and R31 are identical or different and independently of one
`
`another
`
`each
`
`represents
`
`hydrogen,
`
`(C1~C4)-alkyl,
`
`(C3—C7)—cyc1oalkyi,
`
`(C1-C4)-alkylsuiphonyl,
`
`(C;—Ca)-
`
`hydroxyalkyi,
`
`(C1-C4)-arninoalkyl,
`
`di-(C1-C4)~
`
`alky1a1nino—(C;—C4)~alky1,
`
`(C;—C4)—a1kanoyl,
`
`(c6—c14)-
`
`arylcarbonyl,
`
`(C5—CIo)-heteroarylcarbonyl,
`
`(C1-C4)-
`
`alkylarninocarbonyl or -CH2C(NR27R28)=NR.29,
`
`R3, R4, R5 , R6, R7 and R8 are identical or different and
`
`each represents hydrogen or represents (C;-C5)—alky1
`
`and their phannacentically acceptable salts, hydrates and prodrugs,
`
`except for compounds of the general formula (I) in which the radical R] is an
`
`unsubstituted 2—thiophene radical and the radical R2 is simultaneously a
`
`mono» or polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7
`
`and R8 are each simultaneously hydrogen.
`
`2226
`
`I0
`
`15
`
`20
`
`25
`
`30
`
`2226
`
`

`
`I l987~O0030~US
`
`-143-
`
`Compounds of the general formula (1) according to Claim 1, characterized in
`that
`
`R1
`
`I
`
`represents thiophene (thienyl), in particular 2—thiophene, which
`
`may optionally be mono- or polysubstituted by halogen, preferably
`
`chlorine or bromine, or by (C1~»Cg)~alky1, preferably methyl, where the
`
`(C1-Cg)—alky1 radical
`
`for
`
`its part may optionally be mono— or
`
`polysubstituted by halogen, preferably fluorine,
`
`10
`
`R2
`
`represents one of the groups below:
`
`is
`
`20
`
`25
`
`A-.
`
`A“M",
`
`D—M—A-,
`
`B—M—A—,
`
`13-,
`
`B—M—,
`
`B-M-B-,
`
`D—1\/I-B-,
`
`where:
`
`the radical “A.” represents phenyl or naphthyl, in particular
`
`phenyl;
`
`the radical “B” represents a 5- or 6—membered aromatic
`
`heterocycle which contains up to 2 heteroatoms from the group
`
`consisting of S, N, NO (N-oxide) and O;
`
`the radical “D” represents a saturated or partially unsaturated
`
`5— or 6~membered heterocycle which contains up to two
`
`heteroatoms and/or hetero chain members from the group
`
`consisting of S, SO, S02, N, NO (N—oxide) and O;
`
`2227
`
`2227
`
`

`
`I1987—00O30~US
`
`~ 144 ~
`
`the radical “M” represents —NH-, -0-, ~NH-CHg~, -CH2-NI-I—,
`
`—OCHg—, —CH2O—, -CONH~, -NHC-0- or represents a covalent
`
`bond;
`
`where
`
`the groups “A”, “B” and “D” defined above may in each case
`
`optionally be rnono~ or polysubstituted by a radical from the
`
`group consisting of halogen;
`
`tfifluoromethyl; oxo; cyano;
`
`pyridyl;
`
`(C1—C3)~a}kanoy1;
`
`(Cg.—C1o)~ary1carbony1;
`
`(C5-C5)~
`
`heteroarylcarbonylg
`
`(C 1~Cg.)-alkanoyioxymethyloxy;
`
`—c(NR”R2*)mNR”; —CONR23R29;
`
`-SOgNR28R29;
`
`-OH;
`
`-NR3°R3 1;
`
`(C1—C4)—a1kyl; and cyciopropyl, cyclopentyl or
`
`cyclohexyi,
`
`where (C;—C4)—a1ky1 and cyclopropyl, cyclopentyl or
`
`cyclohexyl for their part may optionally be substituted
`
`by a radicai from the group consisting of cyano; -OH;
`
`-OCH3;
`
`—
`
`“R”;
`
`-CO(NH)V(NR27R23)
`
`and
`
`_C(NR27R2s)=NR29’
`
`where:
`
`v
`
`is either 0 or 1, preferably 0, and
`
`R27, R28 and R29 are identical or different and independently of
`
`one another each represents hydrogen, (C1-C4)—a1ky1 or
`
`else cyclopropyi, cyclopentyl or cyclohexyl
`
`and./or
`
`R27 and R23 or R27 and R29 together with the nitrogen atom to
`
`which they are attached may form a saturated or
`
`2228
`
`15
`
`20
`
`25
`
`30
`
`2228
`
`

`
`l 1987-00030—US
`
`~ 145 ~
`
`partially unsaturated 5~ to 7—mernbered heterocycle
`
`having up to two identical or different heteroatoms
`
`from the group consisting of N, O and S, and
`
`R30 and R31 are identical or different and independently of one
`
`another
`
`each
`
`represents
`
`hydrogen,
`
`(C1—C4)—a1kyl,
`
`cyclopropyl,
`
`cyclopentyi,
`
`cyclohexyl,
`
`(C;~C4)-
`
`aikylsulphonyl,
`
`(C1-C4)—hydroxyalkyl,
`
`(C1—C4)~
`
`aminoalkyl,
`
`di—(C1~C4)—al1Qr1amino-(C1—C4)~alky1,
`
`(C;~C3)—al§:anoyl or phenylcarbonyl,
`
`R3, R4, R5, R“, R7 and R8 are identical or different and
`each represents hydrogen or represents (C1—C5)—alky1
`
`and their pharmaceutically acceptable salts, hydrates and prodrugs,
`
`10
`
`15
`
`except for compounds of the general formula (I) in which the radical R] is an
`
`unsubstituted 2-thiophene radical and the radical R2 is simultaneously a
`
`mono» or polysubstituted phenyi radical and the radicals R3, R4, R5, R6, R7
`
`20
`
`and R8 are each simultaneously hydrogen.
`
`Compounds of the general formula (1) according to Claim 1, characterized in
`that
`
`25
`
`R1
`
`represents 2»-thiophene which may optionally be substituted in
`
`the 5-position by a radical from the group consisting of chlorine,
`
`bromine, methyl or trifluoromethyl,
`
`R2
`
`represents one of the groups below:
`
`30
`
`A-,
`
`A~M-,
`
`D-M~—A~,
`
`2229
`
`2229
`
`

`
`1 1987-00030-US
`
`-146-
`
`B-M~A~,
`
`B":
`
`B~M—,
`
`B~M—B-,
`
`D-M-B-,
`
`where:
`
`the radical “A” represents phony} or naphthyi, in particuiar
`
`phenylg
`
`the radicai “B” represents a 5» or 6~n1embered aromatic
`
`heterocycle which contains up to 2 heteroatorns from the group
`
`consisting of S, N, NO (N—oxide) and O;
`
`the radical “D” represents a saturated or partially unsaturated
`
`5- or 6—mernbcred heterocycie which contains a nitrogen atom
`
`and optionafly a further heteroatorn and/or hetero chain
`
`member from the group consisting of S, SO, SO; and O; or
`
`contains up to two heteroatorns and/or hetero chain members
`
`from the group consisting of S, SO, S02 and O;
`
`the radical “M” represents WNH-, -0», —Ni~I—CH2—, -CI-I2—NH~,
`
`—OCH2—, -CH2O—, »-CONH-, -NHCO- or represents a covalent
`
`bond;
`
`where
`
`the groups “A”, “B” and “D” defined above may in each case
`
`optionaily be mono~ or polysubstituted by a radical from the
`
`group consisting of halogen;
`
`trifluoromethyig oxo; cyano;
`
`pyridyi;
`
`(C1—C3)—a1kanoyI;
`
`(C5~C;g)~ary1carbony1;
`
`(C5-C5)-
`
`heteroarylcarbonyl;
`
`(C1~C3)~a1ka.noy1oxyrnethy1oxy;
`
`—CONR28R”; —SO2NR28R29; —-OH; —NR3°:a~“;
`
`(C1—C4)—a1ky1;
`
`and cyclopropyl, cyclopentyi or cyclohexyl,
`
`2230
`
`15
`
`20
`
`25
`
`30
`
`2230
`
`

`
`1 1987—0()030—US
`
`—147«
`
`Where (C1-C4)—a1ky1 and cyciopropyl, cyclopentyl or
`
`cyclohexyl for their part may optionally be substituted
`
`by a radica} from the group consisting of cyano; —OH;
`
`—OCH3;
`
`—NR”8R”;
`
`—co(NH),(NR”R23)
`
`and
`
`_C(NR27R2s)wNR29,
`
`where:
`
`v
`
`is either 0 or 1, preferabiy 0, and
`
`R27, R28 and R29 are identicai or different and independentiy of
`
`one another each represents hydrogen, (C1~C,‘4)-aikyl or
`
`else cyclopropyl, cyclopentyl or cyclohexyl
`
`and/or
`
`R27 and R23 or R27 and R29 together with the nitrogen atom to
`
`which they are attached may form a saturated or
`
`partially unsaturated 5-
`
`to 7—membered heterocycie
`
`having up to two identical or different heteroatorns
`
`from the goup consisting of N, O and S, and
`
`R3” and R5” are identical or different and independently of one
`
`another
`
`each
`
`represents
`
`hydrogen,
`
`(C1-C4)-aikyl,
`
`cyciopropyi,
`
`cyclopentyl,
`
`cyciohexyl,
`
`(C1—C4)—
`
`aikylsulphonyi,
`
`(C1—C4)-hydroxyalkyl,
`
`(C1-C4)-
`
`arninoalkyi,
`
`di—(Cg—C4)—a1ky1arnino—(C1-C4)-alkyi,
`
`(C1-C3)—a1kanoyi or phenylcarbonyl,
`
`R3, R4, R5, R6, R7 and R8 are identical or different and
`
`each represents hydrogen or represents (C1—C4)—aIky1
`
`and their pharrnaceuticaily acceptable salts, hydrates and prodrugs,
`
`2231
`
`10
`
`E5
`
`20
`
`25
`
`2231
`
`

`
`I 1987-00030-US
`
`—l48~
`
`except for compounds of the general fonr1ula(I) in which the radical R1 is an
`
`unsubstituted 2—thiophene radical and the radical R2 is simultaneously a
`
`mono— or polysubstituted phenyl radical and the radicals R3, R4, R5, R6, R7
`
`and R8 are each simultaneously hydrogen.
`
`Compounds of the general formula (1) according to Claim 1, characterized in
`that
`
`10
`
`R2
`
`represents 2-thiophene which is substituted in the 5~positior1 by
`
`a radical from the group consisting of chlorine, bromine‘, methyl and
`
`15
`
`20
`
`25
`
`30
`
`trifluoromethyl,
`
`represents D~A~:
`
`where:
`
`i the radical “A” represents phenylene;
`
`the radical “D” represents a saturated 5- or
`
`6—membered
`
`heterocycle,
`
`which is attached to “A” via a nitrogen atom,
`
`which has a carbonyl group directly adjacent to the linking
`
`nitrogen atom and
`
`in which one carbon ring member may be replaced by a
`
`heteroatom from the group consisting of S, N and 0;
`
`where
`
`the group “A” defined above may optionally be mono— or
`
`disubstituted in the meta position with respect to the point of
`
`attachment to the oxazolidinone, by a radical from the group
`
`consisting of fluorine, chlorine, nitro, amino, trifluoromethyl,
`
`methyl and cyano,
`
`2232
`
`2232
`
`

`
`1 1987-00030-US
`
`—i49—
`
`R3, R4, R5, R6, R7 and R8 each represent hydrogen
`
`and their pharmaeeuticaliy acceptable saits, hydrates and prodrugs.
`
`Compound according to Claim 1 having the following formuia
`
`Qfotfit
`
`CI
`
`O
`
`and its pharmaceutically acceptable salts, hydrates and prodrugs.
`
`Process for preparing substituted oxazolidinones according to Claim 1, Where
`either according to a process alternative
`
`[A]
`
`compounds of the general formula (i1)
`
`10
`
`15
`
`
`
`in which
`
`20
`
`the radicals R2, R3, R4, R5, R6 and R7 are each as defined in Claim 1
`
`2233
`
`2233
`
`

`
`1 1987300030-US
`
`— 150 —
`
`are reacted with carboxylic acids of the general formula (III)
`
`HO
`
`R‘
`
`\n/
`
`0
`
`(m),
`
`in which
`
`the radical R1 is as defined in Claim l,
`
`or else with the corresponding carbonyl halides, preferably carbonyl chlorides,
`
`or else with the corresponding symmetric or mixed carboxylic anhydrides of
`
`the carboxylic acids of the general formula (III) defined above
`
`in inert solvents, if appropriate in the presence of an activating or coupling
`
`agent andfor a base, to give compounds of the general formula (I)
`
`10
`
`15
`
`O
`
`RLN/U\
`
`
`
`in which
`
`20
`
`the radicals R‘, R2, R3, R4, R5, R6, R7 and R8 are each as defined in
`
`Claim 1,
`
`or else according to a process alternative
`
`2234
`
`2234
`
`

`
`E 1987-0003 0~US
`
`~ 151 —
`
`{B}
`
`compounds of the general formula (IV)
`
`R3
`
`R4
`“"lQ§T,:y<xN
`
`R5 R7 O
`JL
`it
`
`R5
`
`R1
`
`am
`)
`
`inwhich
`
`the radicals Ri, R3, R4, R5, R5, R7 and R8 are each as defined in
`
`Claim 1,
`
`10
`
`are converted, using a suitable selective oxidizing agent in an inert solvent,
`
`into the corresponding epoxide of the general formula (V)
`
`R3
`
`R5 R’ 0
`
`RL.’>8< /[L
`
`0
`
`R5
`
`N
`E-£8
`
`R‘
`
`(V),
`
`15
`
`inwhich
`
`the radicals R3, R3, R4, R5, R6, R7 and R8 are each as defined in
`
`Claim 1,
`
`20
`
`and, by reaction in an inert solvent, if appropriate in the presence of a catalyst,
`
`with an amine of the general formula (VI)
`
`R2—NH2
`
`(VI),
`
`25
`
`in which
`
`2235
`
`2235
`
`

`
`1 E987—00030—US
`
`-152-
`
`the radical R2 is as defined in Claim 1,
`
`the compounds of the general formula (VII)
`
`R2
`
`F?‘ R3 R6 R’ 0
`J-L (V11),
`pie
`
`HO R“
`
`in which
`
`10
`
`I5
`
`the radicals R‘, R2, R3, R4, R5, R“, R7 and R3 are each as defined in
`
`Claim 1,
`
`are initially prepared and,
`
`subsequently, in an inert solvent in the presence of phosgene or phesgene
`
`equivaients, such as, for example, oarbonyldiimidazole (CD1), cyclized to
`
`give the compounds of the general formu1a(I)
`
`0
`
`R“*N
`
`0
`
`20
`
`in which
`
`the radicals R’, R2, R3, Rfi’, R5, R6, R7 and R8 are each as defined in
`
`Claim 1,
`
`2236
`
`2236
`
`

`
`1 I987~O0030-US
`
`—153«
`
`where — both for process alternative {A] and for process alternative [B} «—
`
`in
`
`the case where R2 contains a 3~ to 7~rnernbered saturated or partiaiiy
`
`unsaturated cyciic hydrocarbon radical having one or more identical or
`
`different heteroatoms from the group consisting of N and S, an oxidation with
`
`a selective oxidizing agent to afford the corresponding sulphone, sulphoxide
`
`or N~oxide may follow
`
`and]or
`
`where ~ both for process alternative [A] and for process alternative {B} - in the
`
`case where the compound prepared in this manner has a cyano group in the
`
`molecule, an amidination of this cyano group by customary methods may
`
`follow
`
`and/or
`
`where ~ both for process alternative [A] and for process alternative [B} — in the
`
`case where the compound prepared in this manner has a BOC amino
`
`protective group in the niolecuie, removed of this BOC amino protective
`
`group by customary methods may follow
`
`andfor
`
`where -» both for process alternative [A] and for process alternative [B} — in the
`
`case where the compound prepared in this manner has an aniline or
`
`benzylamine radical in the molecule, a reaction of this amino group with
`
`various reagents such as carboxyiic acids, carboxylic anhydrides, carbonyl
`
`chiorides,
`
`isocyanates, sulphonyl chlorides or alkyl haiides to give the
`
`corresponding derivatives may follow
`
`2237
`
`10
`
`E5
`
`20
`
`25
`
`30
`
`2237
`
`

`
`5
`
`10
`
`9.
`
`10.
`
`1 1987~0003 O~US
`
`-154-
`
`and/or
`
`where - both for process alternative [A] and for process alternative {}3] - in the
`
`case where the compound prepared in this manner has a phenyl ring in the
`
`molecule, a reaction with chlorosulphonic acid and subsequent reaction with
`
`amines to give the corresponding sulphcnarnides may follow.
`
`Meciicaments, comprising at least one compound of the general formula (1)
`
`according to Claim 1
`
`and one or more pharmacologically acceptable
`
`auxiliaries or excipients.
`
`Use of compounds of the general formula (I)
`
`O
`
`2 Jk
`R‘*N
`R
`
`3
`
`R“
`
`0 R5
`
`Re
`R7’
`
`RLNYR‘
`
`O
`
`(1),
`
`15
`
`in which:
`
`R:
`
`R2
`
`represents optionally ben_zo—fused thiopliene (thienyl) which
`
`may optionally be mono— or polysubstituted;
`
`represents any organic radical;
`
`R3, R4, R5, R5, R7 and R8 are identical or different and
`
`each represents hydrogen or represents (C1-C5)-alkyl
`
`and their pharmaceutically acceptable salts, hydrates and prodrugs,
`
`20
`
`25
`
`2238
`
`2238
`
`

`
`1 1987—O0030~US
`
`~ 155 —
`
`for preparing medicarnents or
`
`pharmaceutical
`
`compositions
`
`for
`
`the
`
`prophylaxis and/or treatment of thromboembolic disorders,
`
`in particular
`
`myocardial infarct, angina pectoris (including unstable angina), reocclusions
`
`and restenoses after angioplasty or aorto-coronary bypass, stroke, transitory
`
`ischaemic
`
`attacks,
`
`peripheral
`
`arterial occlusive
`
`diseases, puirnonary
`
`emholisms or deep venous thrornboses.
`
`IO
`
`15
`
`11.
`
`12.
`
`13.
`
`Use of compounds of the general formuia (I) according to Claim 10 for-
`
`preparing medicarnents or -pharmaceutical compositions for the prophylaxis
`
`and/or treatment of disorders which are influenced positively by inhibition of
`
`factor Xa.
`
`Use of compounds of the general formula (1) according to Ciaim 10 for
`
`preparing medicarnents or pharmaceutical compositions for the treatment of
`
`disseminated intravascular coaguiation (DIC).
`
`Use of compounds of the general formula (1) according to Claim 10 for
`
`preparing medicarnents or pharmaceutical compositions for the prophylaxis
`
`and/or treatment of disorders such as atherosclerosis; arthritis; Alzl1eirner’s
`
`20
`
`disease or cancer.
`
`14.
`
`15.
`
`25
`
`30
`
`Use of compounds of the general formula (1) according to Claim 10 for
`
`preparing Inedicaments or pharmaceutical compositions for the inhibition of
`factor Xa.
`
`Method for preventing the coagulation of blood in vitro, in particular in the
`
`case of banked blood or biological
`
`samples
`
`containing factor Xa,
`
`characterized in that compounds of the general formula (1) according to Claim
`
`10 are added.
`
`2239
`
`2239
`
`

`
`11987-00O30~US
`
`-156-
`
`Substituted oxazolidinones and their use
`
`A b s tr a c t
`
`The invention relates to the field of blood coagulation. Novel oxazoiidinone
`
`derivatives of the general formula (I)
`
`0
`
`R‘“~N
`
`0
`
`processes for their preparation and their use as medicinally active compounds for the
`
`prophylaxis and/or treatment of disorders are described.
`
`s91os4W1.ooc
`
`2240
`
`2240
`
`

`
`COMBINED mic.
`
`Le A 34 122
`
`TION AND POWER OF ATTGRNEY
`
`DRNEY DOCKET NO
`
`As a below named inventor, I/we hereby declare that:
`
`My/our residence, post office address and citizenship are as stated below next to
`my/our name. E/we believe I am/we are the original, first and sole/joint
`inven-
`tor] s of the subject matter which is claimed and for which a patent is sought
`on the invention entitled
`
`SUBSTITUTED OXAZOLIDINONES AND THEIR USE IN THE FIELD OF BLOOD
`COAGULATION /
`
`the specification of" which is attached hereto,
`
`or was filed on December 11, 2000/
`
`as a PCT Application Serial No. PCT/fl’00l12492 /
`
`Ilwe have reviewed and understand the contents of the
`L/we hereby state that
`aboveddentified specification,
`including the claims.
`
`I/We acknowledge the duty to disclose information which is material to the patent-
`ability of
`this application in accordance with Title 3?, Code of Federal Regula-
`tions, §1.56.
`
`§i19
`Ifwe hereby claim priority benefits under Title 35, United States Code,
`and
`§ 119(c)(1) of any foreign andlor U.S. provisional application(s) for patent
`or inventor's certificate listed below and have also identified below any foreign
`application for patent or
`inventor-‘s certificate having a filing date before that
`of the application on which priority is claimed:
`
`199 62 924.2 ..
`(Number)
`
`Germany .z
`( Country)
`
`December 24, 1999.»
`(Month/Day/Year Filed)
`
`I/we hereby claim the benefit _under Title 35, United States Code, §l20 of any
`United States app1ication(s)
`listed below and,
`insofar as the subject matter of
`each of
`the claims of
`this application is not disclosed in the prior United
`States application in the manner provided by the first paragraph of Title 35,
`United States Code, §1l2, I/we acknowledge the duty to disclose the material in-
`formation as defined in Title 37, Code of Federal Regulations, §1.56 which oc-
`cured between the filing date of the prior application and the national or PCT
`international filing date of this application:
`
`(Application Serial No.)
`
`(Filing Date)
`
`(Application Serial No.)
`
`(Filing Date)
`
`(Status)
`(patented, pending, abandoned)
`
`(Status)
`( patented, pending , abndonad)
`
`statements made herein of my/our own l<nowl~
`all
`I/We hereby declare that
`edge are true and that all statements made on information and belief are believed
`to be true; and further that these statements were made with the knowledge that
`willful false statements and the like so made are punishable by fine or imprison-
`ment, or both, under Section 1001 of Title 18 of the United States Code and that
`such willful false statements may jeopardize the validity of
`the application or
`any patent issued thereon.
`
`Le A 34 122—US
`
`2241
`
`2241
`
`

`
`‘POWER OF ATTORNEY: As a Mmefwanwr, I hereby appoint the foliowing attori
`this appiication and to transact all has.
`=in the Patent and Trademark Office connected
`
`‘dlor agent(s) to prosecute
`ewith:
`
`Jeffrey M. Greenman.g
`Barbara A. Shimei, Reg. No, 29,3562
`William F. Gray, Reg. No. 3I,![]fi
`"' Mice A. Brewer, Reg. No. Jzflfi
`Jerrie L. Chin, §_e;g.__I\_lg,_g§1,fi1£)_
`Susan M. Pellegrino, Reg. No. 55,272
`
`all of Bayer Corporatian, 490 Merger: Lane, West Haven. Connecticut 06516
`
`Send Correspondence To:
`MLhfi
`gagencnxznnratinn
`gm Mergan Lam
`West Haven, Cunngctigut Qfifilfi
`
`FULL mute or SOLE OR FIRST Imrezrme
`Alexa d
`.
`-
`RESIDENCE
`
`_
`
`I
`
`poem orrxce ADDRESS
`
`r
`
`-
`
`-
`
`',-.u'&--
`‘
`
`dfl_u’
`
`‘
`
`-
`
`
`
`Birec1Teiephene Calls To:
`
`(
`
`1
`
`
`
`r V.
`er-
`_-/0/Cs.
`CITIZEN
`e Germ
`
`SHIP
`an /’
`
`'
`
`3/0 Ba er Aktienesellschaft,‘ D 51368 Leverkusen, German
`
`Ev
`
`Fem. smug or seconn INVENTOR
`omas u--
`zmsznnnce
`
`_
`
`INV'ENTOR‘S szsnnwnfix
`_
`é7“"1
`
`"'
`<
`
`__...
`
`aw .
`2'
`at
`
`D 42105 _,--
`POST OFFICE ADDRESS
`
`.
`
`German
`
`£16-‘)r
`
`German.-
`
`clo Ba er Aktienesellschaft. D 51368 Leverkusen, German
`rum emu: or srzmun mvewron
`raven -e '5 sx
`
`been
`
`Jens Pohlman
`anszn-was
`
`D 42285 _--~ .
`pose orrzcs ADDRESS
`
`. German Qt,"-"X
`
`.
`
`/6%.?
`
`/v’{ C—-»--—..
`cxrrzewsnn»
`
`German.»
`
`c/o Ba er Aktienesellschaft, D 51368 Leverkusen, German
`
`,1;-’-‘-:9 ‘.
`RESEDENCE
`
`‘
`
`at
`
`/
`
`1.4L...-..
`(:1
`
`.
`
`- 4».
`
`D 45276 Essen, German D1?-X.
`POST OFFICE ADDRESS
`
`German ,«
`
`Clo Ba er Aktieneseilschaft. D 51368 Leverkusen, German
`FULL NAME or FIFTH xnvenroa
`
`
`
`Elisabezh Per u.
`
`RESIDENCE
`
`D 42327 upaergeg German
`poem orrzce ADDRESS
`
`‘V }
`,
`
`IL?’I.- R
`
`c/o Ba er Aktien;ese12schaft. 9 51368 Leverkusen, German
`
`FULL mum or sure rmrszarosz
`5 , [p 1Heinz Schlmmer
`RESIDENCE
`
`' ‘
`
`IK iIR(‘A '
`
`CITIZENSHIP
`Ge rmar: /
`
`.-:1“, 1“
`cxarxzmzsaxp
`
`DATE
`
`3”’ {ML
`
`2/42
`
`D 42113 \iy.nne';:.a.L. German
`9os'r orrrce mzmuass
`
`15
`
`A‘
`
`German (/
`
`clo Ba er Aktienesellschaft. D 51368 Leverkusen, German
`FULL muse or srvearrra rmremma
`. C 2?
`L4 0
`*U i\-.=
`_
`,__
`RESIDENCE
`L’
`I
`CITIZEWSHIP
`D #2109 , German QSX
`Austrian
`POST OFFICE ADDRESS
`
`
`
`C-
`
`1
`
`Clo Ba er Aktienesellschaft, D 51368 Leverkusen. German
`
`Le A 34 122-—US
`
`'“°""
`
`2242
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Docket No.: 1 I987-00030—US
`
`(PATENT)
`
`In re Patent Application of:
`Alexander Straub et al.
`
`Application No.: Not Yet Assigned
`
`Confinnation No.: N/A
`
`Filed: Concurrently Herewith
`
`Art Unit: WA
`
`For: SUBSTITUTED OXAZOLIDINONES AND
`TI~IEIR USE IN THE FIELD OF BLOOD
`
`Examiner: Not Yet Assigned
`
`COAGULATION
`
`FIRST PRELIMINARY AMENDMENT
`
`MS Amendment
`
`Commissioner for Patents
`
`PO. Box 1450
`
`.
`
`Alexandria, VA 223134450
`
`Dear Sir:
`
`INTRODUCTORY COMMENTS
`
`Prior to examilmtion on the merits, please amend the above-captioned U.S. patent
`
`application as follows:
`
`Amendments to the Claims are reflected in the listing of cEaims which begins on page 2
`
`of this paper.
`
`Remarks/Arguments begin on page 3 of this paper.
`
`5910934
`
`2243
`
`2243
`
`

`
`Application No; Not Yet Assigned
`Preliminary Amendment dated Feivruary 7, 2008
`First Preliminary Amendment
`
`Docket No; 1 E987-00030-US
`
`AMENDMENTS TO THE CLAIMS
`
`Claims l~lS (Cancelled)
`
`16.
`
`(New) A compound of formula:
`
`0/‘
`N
`
`O
`N)l\O
`
`\“No
`
`HN
`
`or 3. prodrug or hydrate thereof.
`
`17.
`
`(New) The compound of claim 16, wherein said compound is a hydrate of the compound
`
`of formula:
`
`0/\\
`"‘
`
`0
`HR
`
`\“Q
`
`HN
`
`591093-1
`
`2244
`
`2244
`
`

`
`Application No; Not Yet Assigned
`Preliminary Amendment dated February 7, 2008
`First Preliminary Amendment
`
`Docket No.: 11987«O0030—US
`
`REMARKS
`
`Claims 1-15 are cancelled without prejudice or disclaimer and new claims l6 and 37 are
`
`presented. Support for new claims 16 and l7 is found, for example, in the specification at page
`
`14, line 34 to page 15, line 2; page 27, line 26 to page 28, line 2; and claim 7 as originally filed.
`
`No new matter has been added.
`
`In View of the foregoing amendment and remarks, Applicants believe the pending
`
`application is in condition for allowance.
`
`Applicants believe no fee is due with this Preliminary Amendment. However, if a fee is
`
`due, please charge our Deposit Account No. 03~27’7S, under Order No. 1 1987-0003015S from
`
`which the undersigned is authorized to draw.
`
`Dated: February 7, 2008
`
`Respectfully submitted,
`
`Electronic signature:
`Earnonn Morrison
`
`/Earnonn Morrison/'
`
`Registration No.: 55,841
`CONNOLLY BOVE LODGE & HUTZ LLP
`
`1007 North Orange Street
`P. O. Box 2207
`
`Wilmington, Delaware l9899~2207
`(302) 658—9l4l
`_
`(302) 658-56l4 (Fax)
`Attorney for Applicants
`
`59109134
`
`2245
`
`2245
`
`

`
`PTOISBIGS (0?-6?)
`Approved for use ilirough G6i3Gi2D10. OMB D651-0032
`L}.S. Patent and Trademark Office. US. DEPARTMENT OF COMMERCE
`Under the Pa e:wod< Reduction Act of 1995, no persons are reuired to zesond to a collection of inionnalioiz unless it disla s a valid OMB comic; number.
`
`
`
`
`
`
`
`11987-00030-US
`
`
`
`
`
`Wmiigg-;f{WON
`8UBS"l"i"¥’UTE£) OXAZOLIDINONES AND THEIR
`TRANSMITTAL
`
` ESE IN THE FIELD OF BLOOD COAGUL/1\TiON
`(ONL Y FOR NEW NONPROVISION/U. APPUCA TIONS‘ UNDER
`37 cm 153(3))
`Express Mail Label No.
`
`APPLECATEON ELEMENTS
`ADDRESS TO:
`See MPEP chapter 600 conceming utility patent appiicaiiori coriieriis,
`
`Commissioner for Patents
`i‘-‘.0. Box 1450
`Aiexandria, VA 22313-1450
`ACCOMPANYING APPLlCA“E'!ON PARTS
`
`
`
`1‘
`
`2_
`3.
`
`Fee Transmittal Form (e.g., PTOISB/1?)
`{Submfl an original and a dupficafe for fee processing)
`Applicant claims sm-ail entity status,
`See 37 CFR 12?.
`157
`Specification
`$1.-Dfajpages
`Both the claims and absiraci must start on a new page
`{Foriniormalion on the preferred arrangement, sea MPEF lS08.01(i2)}
`
`
`
`c. [:1 Statements veriiying identity of above copies
`if a CONTWUENG A¥>i'-’LlCAT|ON. check appropriate box, and suppiy the requisite information below and in the first seriience ofihe
`specificaiion foi‘iowi'ng the iiiie, oriri an Appiicaiiori Data Sheet i.Incler37 CFR 1.76:
`D Continuation
`Divislona§ E] Continuation-Ea-part (curs)
`of prior appiication No.:
`Prior appiicalion information.‘ Examiner
`NOT Yet AS$_i_giiECi
`Ari Unit.‘
`19. CORRESPONDENCE ADDRESS
`
`18.
`
`1 1 14
`
`N/A
`
`
`
`The address associated with Gusiomer Number:
`
`23416
`
`0R E] C°"e5P°”de"5e 3"-W955 b9‘°W
`
`—__
`———
`/Eamonn Morrison.’
`February 7, 2008
`-
`Eamorin Morrison
`55,841
`
`
`Name
`PFWT E
`
`R ‘t
`
`t’
`
`N ,
`
`
`
`
`5910924
`
`2246
`
`
`
`
`
`
`
`
`
`
`h
`{P
`3
`9 El A
`apers (covers ee
`es gnmeri
`.
`Name of Assignee
`
`1
`
`18‘ d
`
`I
`ocumen {s))
`
`Power of
`“:| 37 CFR 3.'i'3(b) Statement
`10
`Attorney
`{when there is an assignee)
`11. El English Transfiation Document (ifappiicablej
`_
`E]
`12.
`Information Dlsciosure Statement (PTOISBIGS or PTO 1449}
`Copies oi citations aliached
`
`Prefimmary Amendment
`
`Return Receipt Postcard (MFEP 503)
`(Sliouid be specificaiiy itemized}
`
`Certified COPY 0? PFIGVFW Documfifliisi
`(i?'i‘0i’9l'£T" .0fl'0-’-‘Ti’ is Giaimedf
`Nonpufnlicailon Request under 35 U.S.C.%22 {b)(2){B)(i).
`Applicant must altacii form PTOi'SBi‘35 or equivalent.
`
`
`
`
`
`i
`
`‘
`
`]
`§Totai Sheets
`4‘ B Drawi:1g(s){35 U. SVC. 113)
`t
`J
`h
`5‘ O Eh
`D I
`N
`[To 3 S ears m...m.....m._ 1
`3
`or 9° am on
`a, D Newly executed (original or copy)
`A copy from 5: prior application ('37 CFR 1.63(d))
`b,
`(Wconmuaucwdwmonafwith Box 18 commmd)
`DE;-ETION OF |NVEN~{OR 3
`Signed siaiemeni ailached deleting iiwenior(s) name in lhe
`pdorappilcaiion, see 37 CFR 1.e3(ci)i2) and 1.339;).
`Application Data Sheet‘ See 37 {3FR1.76
`CD-ROM or CD»R ii; duplicate, large iainie or
`Computer Program (Appendix)
`E Landscape Table on CD
`3_ Nucleotide andior Amino Acid Sequence Submission
`(if appifcabie, items a. — c. are required;
`
`6.
`7.
`
`ii. [:1 Faper
`
`11
`
`14‘
`
`15_
`
`13
`
`
`
`
`
`
`
`
`a. I: Computer Readable Form (CERF)
`l“
`b.
`Specification Sequence Listiag on:
`1?. __J Oiher:
`
`
`
`L :l CD-ROM or CD-R (2 copies); or
`
`
`
`
`
`
`
`
`2246
`
`

`
`Application Data Sheet
`
`Apptication information
`
`Appiication Type::
`
`Subject Matter::
`
`Suggested Group Art Unit:
`
`CD—ROM or CD—R?::
`
`Sequence subrnission?::
`
`Computer Readable Form (CRF)?::
`
`Regular
`
`Utility
`
`1626
`
`None
`
`None
`
`No
`
`Titie:
`
`SUBSTITUTED OXAZOUDINONES AND
`
`Attorney Docket Number:
`
`Request for Early Pub|ication?::
`
`Request for Non—Pubiication?::
`
`Small Entity?::
`
`Petition inciuded?::
`
`Secrecy Order in Parent Appl.'?::
`
`Applicant information
`
`Applécant Authority Type:
`
`Primary Citizenship Country:
`
`Status:
`
`Given Name:
`
`Family Name:
`
`THEIR USE IN THE FiELD OF BLOOD
`
`COAGULATION
`
`1198'/—00G30—US
`
`No
`
`No
`
`No
`
`No
`
`No
`
`Inventor
`
`US
`
`Full Capacity
`
`Alexander
`
`Straub
`
`Applicant Authority Type:
`
`inventor
`
`Primary Citizenship Ccuntryiz
`
`Germany
`
`Status:
`
`Given Name:
`
`59109691
`
`Full Capacity
`
`Thomas
`
`Page # 1
`
`Enitiai 02107108
`
`2247
`
`2247
`
`

`
`Family Name:
`
`Applicant Authority Type:
`
`Lampe
`
`inventor
`
`Primary Citizenship Country:
`
`Germany
`
`Status::
`
`Given Narnez:
`
`Family Name::
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`
`Status:
`
`Given Name::
`
`Farnity Namez:
`
`Fuit Capacity
`
`Jens
`
`Pohimanri
`
`Inventor
`Germany
`
`Pull Capacity
`
`Susanne
`
`Rohrig
`
`Appticant Authority Typez:
`
`inventor
`
`Primary Citizenship Country:
`
`Germany
`
`Status:
`
`Given Name:
`
`Family Name:
`
`Fuil Capacity
`
`Elisabeth
`
`Perzborn
`
`Applicant Authority Type:
`
`Enventor
`
`Primary Citizenship Country::
`
`Germany
`
`Status::
`
`Given Name:
`
`Famiiy Namez:
`
`Fuii Capacity
`
`KarI—i-ieinz
`
`Schiernmer
`
`Appiicant Authority Type:
`
`Inventor
`
`Primary Citizenship Country:
`
`Germany
`
`Status::
`
`Given Name:
`
`Fuil Capacity
`
`Joseph
`
`Page # 2
`
`Initial 02/07lO8
`
`2248
`
`2248
`
`

`
`Family Name:
`
`Pernerstorfer
`
`Correspondence Information
`
`Name:
`
`Connoliy Bove Lodge & Hutz LLP
`
`Street of mailing acldresszz
`
`1007 North Orange Street
`
`P. O. Box 2207
`
`City of mailing address::
`
`Wilmington
`
`State or province of maiting addressz:
`
`Country of mailing address:
`
`DE
`
`US
`
`Postal or Zip Code of maiiing address:
`
`198992207
`
`Phone number:
`
`Fax number::
`
`E—i\/iail addressz:
`
`(302) 65843141
`
`(302) 6586614
`
`emorrison@cblh.com
`
`Representative Information
`
`Representative Customer Number:
`
`23416
`
`Domestic Priority Information
`
`This Application
`11/460529
`1 O/181051
`
`Continuity Typezz
`
`Nationai Stage of
`
`
`
`Parent App|icaiion::
`111460529
`30/181051
`PCTIEPOO/12492
`
`Parent Fiiing Date::
`06/27/08
`06/24/02
`12/11/00
`
`Foreign Priority Information
`
`Filing Date::
`Priorit Claimed: “E ‘Q9 62 9242
`‘W99
`
`Application number::
`
`Page # 3
`
`Initial 92107108
`
`2249
`
`2249
`
`

`
`Assignee information
`
`Assignee name:
`
`Bayer Healthcare Aktiengesellschaft
`
`City of mailing address:
`
`Country of mailing address:
`
`Leverkusen
`
`Germany
`
`Postai or Zip Code of maiiing address:
`
`51368
`
`Page # 4
`
`Initial 02/07/08
`
`2250
`
`2250
`
`

`
`P'$”0.'SB:'0Bafb (07505)
`Approved for use through 0?n'31:'2006. OMB 0651-0031
`U.S. Patent and Trademark Office; US, DEFARTMENT 0%”-” COMMERCE
`Under the Papemrorét Reduction Act of ‘£995, no persons are required to respond to a coileciion of information uniess it contains a valid OMB control number.
`
`Substitute for form 1t$49A!B.'PTO
`
`C°‘'"p‘'°‘° '7 K"°“'"
`
`INFORMATION DISCLOSURE
`
`STATEMENT BY APPLICANT
`
`(Use as