Le A 35 490—Foreig countries
`
`CA 02451258 2003-12-1'7
`
`the radical "M" is —NH-, -0-, —NH-CH;-,
`
`-CH;-NI-1-, —OCH;—, —CH2O—,
`
`—CONH—, -NHCO— or a covalent bond;
`
`where
`
`the groups "A", "B" and "D" defined above may in each case optionally be
`
`substituted one or more times by a radical from the group of halogen;
`
`trifluoromethyl; oxo; cyano; pyridyl; (C 1—C3)-alkanoyl; (C5-Cm)-arylcarbonyl;
`
`(C5-C6)-heteroarylcarbony];
`
`(C1-C3)-alkanoyloxymethyloxy;
`
`_C(NRz7R2s)=NR29; _CONR2sR29; _SO2NR2sR29; _OH; _NR3oR31;
`
`(C‘_C4)_
`
`alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
`
`where (C;-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl may in turn
`
`optionally be substituted by a radical from the group of cyano; —OH; —OCH3;
`
`-NRRR”; -CO(NH)V(NR"R") and —c(NR“R“ =NR”,
`
`where:
`
`v
`
`is either 0 or 1, preferably 0, and
`
`R27, R28 and R29 are identical or different and are, independently of one
`
`another, hydrogen, (C,-C4)-alkyl or else cyclopropyl, cyclopentyl or
`
`cyclohexyl,
`and/or
`
`R27 and R28, or R27 and R29, may form together with the nitrogen atom to
`
`which they are bonded a saturated or partially unsaturated 5- to 7-
`
`membered heterocycle having up to two identical or different
`
`hetcroatoms from the group of N, O and S, and
`
`10
`
`20
`
`25
`
`30
`
`MYLAN - EXHIBIT 1006 - Part 10 of 14
`
`2820
`
`2820
`
`MYLAN - EXHIBIT 1006 - Part 10 of 14
`
`

`
`Le A 35 490-Foreig countries
`
`CA 02451258 2003-12-17
`
`- 1] _
`
`R30 and R3‘ are identical or different and are, independently of one another,
`
`hydrogen,
`
`(C1-C4)-alkyl,
`
`cyclopropyl,
`
`cyclopentyl,
`
`cyclohexyl,
`
`(C.-C4)-alkylsulfonyl, (C;-C4)-hydroxyalkyl, (C1-C4)-aminoalkyl, di-
`
`(C1-C4)-alkylamino-(C;-C4)-alkyl,
`
`(C1-C3)—a1kanoyl
`
`or
`
`phenylcarbonyl,
`
`R3, R4, R5, R6, R7 and R8 are identical or different and are hydrogen or (C1-C5)~a1kyl,
`
`and the pharmaceutically acceptable salts, hydrates and prodrugs thereof.
`
`Especial preference is given in this connection to compounds of the general
`formula (I)
`
`in which
`
`R‘
`
`is 2-thiophene which may optionally be substituted in position 5 by a radical
`
`from the group chlorine, bromine, methyl or trifluoromethyl,
`
`R2
`
`is one of the following groups:
`
`A-,
`
`A—M-,
`
`D-M-A-,
`
`where:
`
`the radical "A" is phenyl or naphthyl, in particular phenyl;
`
`10
`
`25
`
`30
`
`2821
`
`2821
`
`

`
`Le A 35 490-Foreig countries
`
`CA 02451258 2003-12-17
`
`-12-
`
`the radical "B" is a 5- or 6-membered aromatic heterocycle which comprises
`
`up to 2 heteroatorns from the series S, N, NO (N—oxide) and O;
`
`the radical "D" is a saturated or partially unsaturated 5- or 6-membered
`
`heterocycle which comprises a nitrogen atom and optionally a further
`
`heteroatom and/or hetero chain member from the series S, SO, SO; and O; or
`
`up to two heteroatoms and/or hetero chain members from the series S, SO,
`
`SO; and O;
`
`the radical "M" is —NH—, -0-,
`
`-N]-I—CH;—, —CHz—NH-, —OCH2—,
`
`-CHZO-,
`
`—CONH—, —N'HCO- or a covalent bond;
`
`where
`
`the groups "A", "B" and "D" defined above may in each case optionally be
`
`substituted one or more times by a radical from the group of halogen;
`
`trifluoromethyl; oxo; cyano; pyridyl; (C;-C3)-alkanoyl; (C5-Cm)-arylcarbonyl;
`
`(C5-C5)-heteroarylcarbonyl;
`
`(C;-C3)-alkanoyloxymethyloxy; —CONR28R29;
`
`-SO;NR28R29; -OH; -NR3°R3'; (C.-C4)-alkyl; and cyclopropyl, cyclopentyl or
`
`cyclohexyl,
`
`where (C,-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl may in turn
`
`optionally be substituted by a radical from the group of cyano; -OH; -OCH3;
`
`—NR"R”; —co(NH),(NR”R”) and -C(NR27R28)=NR29,
`
`where:
`
`v
`
`is either 0 or 1, preferably 0, and
`
`R27, R28 and R29 are identical or different and are,
`
`independently of one
`
`another, hydrogen, (C1-C4)-alkyl or else cyclopropyl, cyclopentyl or
`
`cyclohexyl,
`and/or
`
`10
`
`15
`
`20
`
`25
`
`30
`
`2822
`
`2822
`
`

`
`Le A 35 490—Foreigr_1 countries
`
`CA 02451258 2003-12-17
`
`-13-
`
`R" and R23, or R27 and R29, may form together with the nitrogen atom to
`
`which they are bonded a saturated or partially unsaturated 5- to 7~
`
`membered heterocycle having up to two identical or difierent
`
`heteroatoms from the group of N, O and S, and
`
`R30 and R“ are identical or different and are, independently of one another,
`
`hydrogen,
`
`(C1-C4)-alkyl,
`
`cyclopropyl,
`
`cyclopentyl,
`
`cyclohexyl,
`
`(C;-C4)-alkylsulfonyl, (C;-C4)-hydroxyalkyl, (C;-C4)-aminoalkyl, di-
`
`(C1-C4)-alkylamino-(C;-C4)-alkyl,
`
`(C1-C3)-alkanoyl
`
`or
`
`phcnylcarbonyl,
`
`'
`
`R’, R‘, R’, R‘, R7 and R‘ are identical or different and are hydrogen or (C;-C4)-alkyl,
`
`and the pharmaceutically acceptable salts, hydrates and prodrugs thereof.
`
`Very particular preference is given in this connection to compounds of the general
`formula (I)
`
`in which
`
`R]
`
`is 2-thiophene which is substituted in position 5 by a radical from the group
`
`of chlorine, bromine, methyl or trifluoromethyl,
`
`is D-A-:
`
`where:
`
`the radical "A" is phenylene;
`
`the radical "D" is a saturated 5- or 6-membered heterocycle which
`
`is linked via a nitrogen atom to "A",
`
`which has a carbonyl group in direct vicinity to the linking nitrogen atom, and
`
`10
`
`15
`
`20
`
`25
`
`30
`
`2823
`
`2823
`
`

`
`cn_o24s125a 2oo3—12-17
`Le A 35 490-Foreign countries
`
`-14-
`
`in which a ring carbon member may be replaced by a heteroatom from the
`
`series S, N and 0;
`
`where
`
`the group "A" defined above may optionally be substituted once or twice in
`
`the meta position relative to the linkage to the oxazolidinone by a radical from
`
`the group of fluorine, chlorine, nitro, amino, trifluoromcthyl, methyl or cyano,
`
`R3, R‘, R5, R“, R7 and R‘ are hydrogen,
`
`and the pharmaceutically acceptable salts, hydrates and prodrugs thereof.
`
`Very particular preference is likewise given in this connection to the compound
`
`having the following formula
`
`°Q~@£Lo
`
`Cl
`
`and the pharmaceutically acceptable salts, hydrates and prodrugs thereof.
`
`To date, oxazolidinones have been described essentially only as antibiotics, and in a
`
`few cases also as MAO inhibitors and fibrinogcn antagonists (Review: Riedl, B.,
`
`Endermann, R., Exp. Opin. Ther. Patents 1999, 9(5), 625), and a small 5-
`
`[acylaminomethyl] group (preferably 5-[acetylaminomethyl]) appears to be essential
`for the antibacterial effect.
`
`10
`
`15
`
`20
`
`25
`
`2824'
`
`2824
`
`

`
`Le A 35 490-Foreiong countries
`
`cA 02451258 zoos-12-17
`
`-15-
`
`Substituted aryl- and heteroaiylphenyloxazolidinones in which a monosubstituted or
`
`polysubstituted phenyl radical may be bonded to the N atom of the oxazolidinone
`
`ring and which may have in position 5 of the oxazolidinone ring an unsubstituted N-
`
`methyl-2-thiophenecarboxamide
`
`residue,
`
`and
`
`their use
`
`as
`
`substances with
`
`antibacterial activity are disclosed in the U.S. patents US-A-5 929248, US—A-
`
`5 801 246, US-A-5 756 732, US-A-5 654 435, US-A-5 654 428
`
`and US-A-
`
`5 565 571.
`
`10
`
`15
`
`20
`
`25
`
`In
`
`addition, benzamidine-containing oxazolidinones
`
`are known as
`
`synthetic
`
`intermediates in the synthesis of factor Xa inhibitors or fibrinogen antagonists (WO-
`
`A-99/31092, EP-A-623615).
`
`The compounds of the formula (I) may, depending on the substitution pattern, exist in
`
`stereoisomeric forms which either are related as image and mirror image (enantiomers)
`
`or are not related as image and mirror image (diastereomers). Both the enantiomers or
`
`diastereomers and respective mixtures thereof are included. The racernic forms can, just
`
`like the diastereomers, be separated in a known manner into the stereoisomerically pure
`constituents.
`
`Certain compounds of the formula (I) may also exist in tautomeric forms. This is
`
`known to the skilled worker, and such compounds are likewise included.
`
`Physiologically acceptable, i.e. pharmaceutically acceptable, salts may be salts of the
`
`compounds of the invention with inorganic or organic acids. Preferred salts are those
`
`with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid,
`
`phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids
`
`such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid,
`
`fumaric acid, malic acid, citric acid,
`
`tartaric acid,
`
`lactic acid, benzoic acid, or
`
`methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid
`
`30
`
`or naphthalnedisulfonic acid.
`
`2825
`
`2825
`
`

`
`cA_ 02451259 2oo3—12-17
`Le A 35 490-Foreign countries
`
`-15-
`
`Pharmaceutically acceptable salts which may also be mentioned are salts with
`
`conventional bases, such as, for example, alkali metal salts (e.g. sodium or potassium
`
`salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts
`
`derived from ammonia or organic amines such as,
`
`for example, diethylarnine,
`
`triethylarnine, ethyldiisopropylarnine, procaine, dibenzylamine, N—methylmorpholine,
`
`dihydroabietylamine or methylpiperidine.
`
`" " refers to those forms of the compounds of the above formula (I) which form
`
`a molecular compound (solvate) in the solid or liquid state through hydration with
`
`water. In the hydrates, the water molecules are attached through secondary valencies by
`
`intermolecular forces, in particular hydrogen bonds. Solid hydrates contain water as so-
`
`called water of crystallization in stoichiometric ratios, and the water molecules do not
`
`have to be equivalent
`
`in terms of their binding state. Examples of hydrates are
`
`sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are also the
`
`hydrates of salts of the compounds of the invention.
`
`10
`
`15
`
`"Prodrugs" refers to those forms of the compounds of the above formula (I) which may
`
`themselves be biologically active or
`
`inactive but can be convened into the
`
`corresponding biologically active fonn (for example metabolically, solvolytically or in
`
`20
`
`another way).
`
`Halogen is fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
`
`25
`
`30
`
`Q21gig is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms.
`
`Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n—butyl,
`
`isobutyl, tert-butyl, n—pentyl and n~hexyl. The corresponding alkyl groups with fewer
`
`carbon atoms are derived analogously from this definition, such as, for example,
`
`(C1—C(,)—alkyl and (C1-C4)-alkyl. It is generally true that (C1-C4)-alkyl is preferred.
`
`The meaning of the corresponding constituent of other more complex substituents is
`
`also derived from this definition, such as, for example, in the case of alkylsulfonyl,
`
`2826
`
`2826
`
`

`
`CA.02451258 2003-12-17
`Le A 35 490—Foreigr_z countries
`
`-17-
`
`hydroxyalgl, hydroxyalglcarbonyl, a1koxy—algl, alkoxycarbonyl-allgl, alkanoylglgd,
`
`aminoalgl or alkylaminoallgl.
`
`((_I;;§-_;)-Cycloalgl is a cyclic alkyl radical having 3 to 7 carbon atoms. Examples
`
`which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
`
`cycloheptyl. The corresponding cycloalkyl groups with fewer carbon atoms are derived
`
`analogously from this definition,
`
`such as,
`
`for example,
`
`(C;-C5)-cycloalkyl.
`
`Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
`
`The meaning of the corresponding constituent of other more complex substituents such
`
`as, for example, cycloalkanoyl is also derived from this definition.
`
`(C;-C§)~Alkenyl is a straight-chain or branched alkenyl radical having 2 to 6 carbon
`
`atoms. A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is
`
`preferred. Examples which may be mentioned are: vinyl, allyl, isopropenyl and n~but-2-
`
`en-1 —yl.
`
`(glfig)-Alkoxy is a straight-chain or branched alkoxy radical having 1
`
`to 8 carbon
`
`atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy,
`
`isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-
`
`octoxy. The corresponding alkoxy groups with fewer carbon atoms are derived
`
`analogously from this definition, such as, for example, (C;-C6)-alkoxy and (C1-C4)-
`
`alkoxy. It is generally true that (C.-C4)—alkoxy is preferred.
`
`The meaning of the corresponding constituent of other more complex constituents such
`
`as, for example, alkoxy-alkyl, alkoxycarbonyl-alkyl and alkoxvcarbonyl is also derived
`from this definition.
`
`Mono— or di—§C1£_5)-alglaminocarbonvl is an amino group which is linked via a
`
`carbonyl group and which has a straight-chain or branched or two identical or different
`
`straight-chain or branched alkyl substituents each having 1
`
`to 4 carbon atoms.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`2827
`
`2827
`
`

`
`ca. 02451258 2oo3-12-17
`Le A 35 490-Foreigg countries
`
`-13-
`
`Examples which may be mentioned are: methylamino, ethylarnino, n-propylamino,
`
`isopropylarnino,
`
`t—buty1a.mino, N,N-dirnethylamino, N,N-diethylarnino, N-ethyl-N-
`
`methylarnino, N-methyl-N~n—propylamino, N-isopropyl-N—n-propylamino and N—t-
`
`butyl-N-methylamino.
`
`(Ql£g)—Alkanoyl is a straight-chain or branched alkyl radical having 1 to 6 carbon
`
`atoms which has a double bonded oxygen atom in position 1 and is linked via position
`
`1. Examples which may be mentioned are: formyl, acetyl, propionyl, n—butyryl,
`
`i-
`
`_
`
`butyryl, pivaloyl, n-hexanoyl. The corresponding alkanoyl groups with fewer carbon
`
`atoms are derived analogously from this definition,
`
`such as,
`
`for example,
`
`(C.-C5)—alkanoy1, (C1-C4)-alkanoyl and (C1-C3)-alkanoyl. It
`
`is generaly true that
`
`(C;~C3)-alkanoyl is preferred.
`
`The meaning of the corresponding constituent of other more complex constituents such
`
`as, for example, cycloalkanoyl and alkanoylalkyl is also derived from this definition.
`
`(§;—_C_1)-Cycloalkanoyl is a cycloalkyl radical as defined above which has 3 to 7 carbon
`
`atoms and which is linked via a carbonyl group.
`
`(Q1;§§,)-Alkanoyloxyrnethyloxy is a straight-chain or branched alkanoyloxymethyloxy
`
`radical having 1
`
`to 6 carbon atoms. Examples which may be mentioned are:
`
`acetoxyrnethyloxy,
`
`propionoxymethyloxy,
`
`n-butyroxymethyloxy,
`
`i-
`
`butyroxymethyloxy,
`
`pivaloyloxymethyloxy,
`
`n-hexanoyloxymethyloxy.
`
`The
`
`corresponding alkanoyloxymethyloxy groups with fewer carbon atoms, such as, for
`
`example,
`
`(C;-C3)—alkanoyloxymethyloxy,
`
`are derived analogously from this
`
`definition. It is generally mic that (C 1—C3)—alkanoyloxymethyloxy is preferred.
`
`(§§;Qk)_~Ag/_l is an aromatic radical having 6 to 14 carbon atoms. Examples which may
`
`be mentioned are: phenyl, naphthyl, phenanthrenyl and anthracenyl. The corresponding
`
`aryl groups with fewer carbon atoms, such as, for example, (Cg,-C10)-aryl, are derived
`
`analogously from this definition. It is generally true that (C6—C;o)-aryl is preferred.
`
`10
`
`15
`
`20
`
`30
`
`2828
`
`2828
`
`

`
`Le A 35 490~Foreig countnes
`
`ca 02451253 2003-12-17
`
`-19-
`
`The meaning of the corresponding constituent of other more complex constituents such
`
`as, for example, glcarbonyl is also derived from this definition.
`
`(_C_Ié;Q]g[-Heterogfll or a 5- to l0-membered aromatic heterocycle having up to 3
`
`heteroatoms and/or hetero chain members from the series S, O, N and/or NO LN-oxide)
`
`is a mono- or bicyclic heteroaromatic system which is linked via a ring carbon atom of
`
`the heteroaromatic system, optionally also via a ring nitrogen atom of the
`
`heteroaromatic system. Examples which may be mentioned are: pyridyl, pyridyl N~
`
`oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,
`
`thiazoly], oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl,
`
`indazolyl, quinolyl,
`
`isoquinolyl, naphthyiidinyl, quinazolinyl. The corresponding
`
`heterocycles with a smaller ring size such as, for example, 5- or 6-membered
`
`aromatic heterocycles are derived analogously from this definition. It is generally true
`
`that 5- or 6-membered aromatic heterocycles such as, for example, pyridyl, pyridyl N-
`
`oxide, pyrimidyl, pyiidazinyl, fury] and thienyl are preferred.
`
`The meaning of the corresponding constituent of other more complex constituents such
`
`as, for example, (Q_5_-Q19)-heteroa_rylcarbonyl is also derived from this definition.
`
`A 3- to 9—membered saturated or partially unsaturated, mono- or bicyclic, optionally
`
`benzo-fused heterocycle having up to 3 heteroatoms and/or hetero chain members
`
`from the series S, SO, SO_2, N, NO {E-oxide} and/or 0 is a heterocycle which may
`
`comprise one or more double bonds, which may be mono- or bicyclic, in which a
`
`benzene ring may be fused to two adjacent ring carbon atoms, and which is linked via a
`
`ring carbon atom or a ring nitrogen atom. Examples which may be mentioned are:
`
`tetrahydrofuryl,
`
`pyrrolidinyl,
`
`pyrrolinyl,
`
`piperidinyl,
`
`1,2-dihydropyridinyl,
`
`1,4-
`
`dihydropyiidinyl, piperazinyl, morpholinyl, morpholinyl N-oxide,
`
`thiomorpholinyl,
`
`azepinyl, 1,4-diazepinyl and cyclohexyl. Piperidinyl, morpholinyl and pyrrolidinyl are
`
`10
`
`15
`
`20
`
`25
`
`30
`
`preferred.
`
`2829
`
`2829
`
`

`
`2830
`
`Le A 35 490-Foreig countries
`
`CA 02451259 2oo3-12-17
`
`-20-
`
`The corresponding cyclic systems with a small ring size, such as, for example, 5- to
`
`7-membered cyclic systems are derived analogously from this definition.
`
`The compounds of the formula (I) can be prepared by either, in a process alternative,
`
`[A]
`
`reacting compounds of the general formula (II)
`
`
`
`10
`
`in which
`
`the radicals R2, R3, R4, R5, R6, R7 and R8 have the meanings indicated above,
`
`with carboxylic acids of the general formula (III)
`
`R‘
`
`(111),
`
`TO
`
`Ho
`
`in which
`
`the radical R] has the meaning indicated above,
`
`or else with the corresponding carbonyl halides, preferably carbonyl chlorides,
`
`or else with the corresponding symmetrical or mixed carboxylic anhydrides of
`
`the carboxylic acids of the general formula (III) defined above
`
`15
`
`20
`
`25
`
`2830
`
`

`
`Le A 35 490—ForeiQ countries
`
`CA 02451258 2003-12-17
`
`-21-
`
`in inert solvents, where appropriate in the presence of an activating or
`
`coupling reagent and/or of a base,
`
`to give compounds of the general
`
`formula (I)
`
`(I),
`
`in which
`
`the radicals R‘, R2, R3, R4, R5, R6, R7 and R8 have the meanings indicated
`
`above,
`
`or else in a process alternative
`
`[B]
`
`converting compounds of the general formula (IV)
`
`ER’ 0
`J\
`
`t‘
`
`R‘
`
`R‘
`
`W):
`
`‘
`
`R’
`R‘ \
`
`R5
`
`in which
`
`the radicals R‘, R3, R‘, R5, R6, R7 and R8 have the meanings indicated above,
`
`with a suitable selective oxidizing agent
`
`in an inert solvent
`
`into the
`
`corresponding epoxide of the general formula (V)
`
`2831
`
`15
`
`20
`
`2831
`
`

`
`Le A 35 490-ForeigI_1 countries
`
`up. 02451259 2003-12-17
`
`-22.
`
`in which
`
`the radicals R', R3, R4, R5, R6, R7 and R8 have the meanings indicated above,
`
`and are reacted in an inert solvent, where appropriate in the presence of a
`
`catalyst, with an amine of the general formula (VI)
`
`l0
`
`15
`
`RKNH2
`
`(VI),
`
`in which
`
`the radical R2 has the meaning indicated above,
`
`initially preparing the compounds of the general formula (VII)
`
`in which
`
`the radicals R', R2, R3, R4, R5, R6, R7 and R8 have the meanings indicated
`
`above,
`
`and
`
`2832
`
`2832
`
`

`
`CA 02451258 2003-12-17
`Le A 35 490-Foreivn countries
`
`-23-
`
`subsequently cyclizing in an inert solvent in the presence of phosgene or
`
`phosgene equivalents such as, for example, carbonyldiimidazole (CD1) to the
`
`compounds of the general formula (I)
`
`O
`2JL
`R\N
`R3
`
`R‘
`
`O 5
`ReR
`7
`R
`
`RLN\H,R'
`
`o
`
`(D
`
`in which
`
`the radicals R‘, R2, R3, R4, R5, R6, R7 and R8 have the meanings indicated
`
`above,
`
`where, both for process alternative [A] and for process alternative [B] in the
`
`case where R2 is a 3- to 7-membered saturated or partially unsaturated cyclic
`
`hydrocarbon radical having one or more identical or different heteroatoms
`
`from the group of N and S, it is possible for an oxidation with a selective
`
`oxidizing agent to the corresponding sulfone, sulfoxide or N—oxide to follow,
`
`and/or
`
`where, both for process alternative [A] and for process alternative [B] in the
`
`case where the compound prepared in this way has a cyano group in the
`
`molecule,
`
`it
`
`is possible for an amidination of this cyano group by
`
`conventional methods to follow,
`
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`15
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`
`and/or
`
`where, both for process alternative [A] and for process alternative [B] in the
`
`case where the compound prepared in this way has a BOC amino protective
`
`group in the molecule, it is possible for an elimination of this BOC amino
`
`protective group by conventional methods to follow,
`
`and/or
`
`where, both for process alternative [A] and for process alternative [B] in the
`
`case where the compound prepared in this way has an aniline or benzylamine
`
`residue in the molecule, it is possible for a reaction of this amino group with
`
`various reagents such as carboxylic acids, carboxylic anhydrides, carbonyl
`
`chlorides,
`
`isocyanates,
`
`sulfonyl chlorides or alkyl halides to give the
`
`corresponding derivatives to follow,
`
`and/or
`
`where, both for process alternative [A] and for process alternative [B] in the
`
`case where the compound prepared in this way has a phenyl ring in the
`
`molecule, it is possible for a reaction with chlorosulfonic acid and subsequent
`
`reaction with amines to give the corresponding sulfonamides to follow.
`
`The processes can be illustrated by way of example by the following formula
`
`diagrams:
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`CA 02451253 2oo3-12-17
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`[Al
`
`[Al
`
`F
`
`0
`}~
`
`WW
`
`—
`
`L/”\/“
`
`-25-
`
`(:1
`
`F
`P1 ‘-
`
`0
`
`,
`
`NH
`
`1
`
`5.
`
`EW
`
`c-
`“°,\\:.f.‘?:“I::°\/x/\)\:K
`S13
`0'
`ISA’
`I
`
`[B]
`
`\/\
`
`H
`
`S
`\ /
`
`C‘
`
`MCPBA
`_—--> (!»>/\P1
`
`S
`\ /
`
`o
`
`©\’NH’
`C‘ ————’
`0
`
`OH
`
`The oxidation step described above, which takes place where appropriate, can be
`
`illustrated by way of example by the following formula diagrams:
`
`2835
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`ca o245125e 2oo3—12-17
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`F
`2 >
`
`s/_\N
`\_/
`
`N&
`
`Cl
`
`~Mo/oso,
`
`F
`
`& ’
`
`°;‘5‘ N N\/K C,
`0’ L]
`
`0
`
`Nat
`X;0‘
`
`F
`
`o
`
`o=s
`
`N
`
`N
`
`“ e *
`x_/
`cg
`
`0
`
`cu
`
`\Yg0
`
`HN
`
`Solvents suitable for the processes described above are in these cases organic
`
`solvents which
`
`are
`
`inert
`
`under
`
`the
`
`reaction
`
`conditions. These
`
`include
`
`halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane,
`
`1,2-dichloroethane,
`
`trichloroethane,
`
`tetrachloroethane,
`
`1,2—dichloroethylene or
`
`trichloroethylene, ethers such as diethyl ether, dioxane,
`
`tetrahydrofuran, glycol
`
`dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol,
`
`ethanol, n-propanol,
`
`isopropanol, n-butanol or tert-butanol, hydrocarbons such as
`
`benzene, xylene,
`
`toluene, hexane or cyclohexane, dimethylformamide, dimethyl
`
`sulfoxide, acetonitnle, pyridine, hexamethylphosphoric triamide or water.
`
`It is likewise possible to employ solvent mixtures composed of the aforementioned
`solvents.
`
`Activating or coupling reagents suitable for the processes described above are in
`
`these cases the reagents normally used for these purposes, for example N'-(3-
`
`dimethylaminopropyl)-N-ethylcarbodiimide - HCI, N,N’-dicyclohexylcarbodiimide,
`
`1-hydroxy-1H-benzotriazole - H20 and the like.
`
`Suitable bases are the usual inorganic or organic bases. These preferably include
`
`alkali metal hydroxides such as, for example, sodium or potassium hydroxide or
`
`alkali metal carbonates such as sodium or potassium carbonate or sodium or
`
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`potassium methanolate or sodium or potassium ethanolate or potassium tert-butoxide
`
`or
`
`amides
`
`such
`
`as
`
`sodamide,
`
`lithium bis-(tn'methylsily1)amide or
`
`lithium
`
`diisopropylamide
`
`or
`
`amines
`
`such
`
`as
`
`triethylamine,
`
`diisopropylethylarnine,
`
`diisopropylarnine, 4-N,N-dimethylaminopyridine or pyridine.
`
`The base can be employed in these cases in an amount of from 1 to 5 mol, preferably
`
`from 1 to 2 mol, based on 1 mol of the compounds of the general formula (II).
`
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`
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`
`The reactions generally take place in a temperature range from —78°C to the reflux
`
`temperature, preferably in the range from 0°C to the reflux temperature.
`
`The reactions can be carried out under atmospheric, elevated or reduced pressure
`
`(e.g. in the range from 0.5 to 5 bar), generally under atmospheric pressure.
`
`Suitable selective oxidizing agents both the preparing epoxides and for the oxidation
`
`which is optionally carred out to the sulfone, sulfoxide or N-oxide are, for example,
`
`m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N—methylmorpholine N-
`
`oxide (NMO), monoperoxyphthalic acid or osmium tetroxide.
`
`The conditions used for preparing the epoxides are those customary for these
`
`preparations .
`
`For detailed conditions for the process of oxidation, which is carried out where
`
`appropriate,
`
`to the sulfone, sulfoxide or N-oxide, reference may be made to the
`
`following literature: M. R. Barbachyn et al., J. Med. Chem. 1996, 39, 680 and
`
`W0-A-97/10223.
`
`Reference is further made to Examples 14 to 16 detailed in the experimental part.
`
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`
`The arnidination which is carried out where appropriate takes place under the usual
`
`conditions. For further details, reference may be made to Examples 31 to 35 and 140
`to 147.
`
`The compounds of the formulae (II), (III), (IV) and (VI) are known per se to the
`
`skilled worker or can be prepared by conventional methods. For oxazolidinones, in
`
`particular the 5—(aminornethyl)-2—oxooxazolidines required, cf. W0-A-98/01446;
`
`W0-A-93/23384; WO-A-97/03072; J. ‘A. Tucker et al., J. Med. Chem. 1998, 41,
`
`3727; S. J. Brickner etal., J. Med. Chem. 1996, 39, 673; W. A. Gregory eta1.,
`
`10
`
`J. Med. Chem. 1989, 32, 1673.
`
`A preferred compound A) of the formula (I) for use in combinations is 5-chloro-N-
`
`({(5S)-2-oxo—3-[4-(3 —oxo-4-morpholinyl)phenyl]- l ,3-oxazolidin-5-yl} methyl)-2-
`
`thiophenecarboxarnide, the compound of Example 44.
`
`The combinations of the invention are suitable in particular for the prophylaxis
`
`and/or treatment of arterial thromboses and embolisms associated with coronary heart
`
`disease, impairments of cerebrovascular blood flow and impairments of peripheral
`
`arterial blood flow. Combinations of oxazolidinones of the formula (I) with platelet
`
`aggregation inhibitors, anticoagulants and/or fibrinolytics are additionally suitable in
`
`particular for the prophylaxis and/or treatment of venous thromboses and pulmonary
`embolisms.
`
`The individual active ingredients of the combinations are known from the literature
`
`and for the most part commercially available. They may, where appropriate, just like
`
`the oxazolidinones of the formula (I), be employed in subtherapeutically effective
`doses.
`
`Suitable for the prophylaxis and/or treatment of arterial vascular disorders is a
`
`combination therapy of oxazolidinones of the formula (I) with lipid—lowering agents,
`
`in particular with HMG-CoA (3-hydroxy-3-methylglutaryhcoenzyme A) reductase
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`
`inhibitors such as, for example, cerivastatin (Rjvastatin, Baycol; US 5,177,080),
`
`lovastatin (Mevacor; US 4,231,938), simvastatin (Zocor, US 4,444,784), pravastatin
`
`(Pravachol; US 4,346,227), fluvastatin (Lescol; US 5,354,772), atorvastatin (Lipitor,
`
`US 5,273,995), or with coronary therapeutic agents/vasodilators, in particular ACE
`
`(angiotensin converting enzyme)
`
`inhibitors,
`
`such as,
`
`for example, captopril,
`
`lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril, perindopril;
`
`All (angiotensin II) receptor antagonists such as,
`
`for example, embusartan (US
`
`5,863,930),
`
`losartan, valsartan,
`
`irbesartan, candesartan, eprosartan,
`
`temisartan; B-i
`
`adrenoceptor antagonists such as, for example, carvedilol, alprenolol, bisoprolol,
`
`-acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol,
`
`propanolol, timolol; alpha-1-adrenoceptor antagonists such as, for example, prazosiri,
`
`bunazosin, doxazosin, terazosin; diuretics such as, for example, hydrochlorothiazide,
`
`_furosemide, bumetanide, piretanide, torasemide, amiloride; dihydralazine; calcium
`
`charmel blockers such as, for example, verapamil, diltiazem or dihydropyridine
`derivatives such as, for example, nifedipine (Adalat) or nitrendipine (Bayotensin);
`
`substances which bring about an increase in cyclic guanosine monophosphate
`
`(cGMP), such as,
`
`for example, stimulators of soluble guanylate cyclase (W0
`
`98/l6223, WO 98/16507, WO 98/23619, W0 O0/06567, WO 00/06568, WO
`
`00/06569, WO 00/21954, WO O0/66582, WO 01/17998, WO 01/19776, WO
`
`01/19355, WO 01/19780, WO 01/19778).
`
`The pharmacotherapeutic aim of treatment of a pre-existing coronary heart disease is
`
`to eliminate the inbalance between oxygen supply and oxygen demand in the areas of
`
`myocardium affected by the ischemia. Suitable for the treatment of a pre-existing
`
`coronary heart disease is therefore in particular combination therapy of an
`
`oxazolidinone of the formula (I) with coronary therapeutic agents, in particular with
`
`B-adrenoceptor antagonists; ACE (angiotensin converting enzyme) inhibitors; A-II
`
`(angiotensin II) receptor antagonists; nitrates such as, for example,
`
`isosorbide 5—
`
`mononitrate, isosorbide dinitrate, glycerol trinitrate; substances which bring about an
`
`increase in cyclic guanosine monophosphate (cGMP); calcium channel blockers.
`
`Most of these compounds are also employed for therapy of hypertension.
`
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`
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`
`Thrombolytic
`
`therapy with plasminogen acktivators
`
`(thrombolytic/fibrinolytic
`
`agents) such as, for example, tissue plasminogen activator (t-PA), streptokinase,
`
`reteplase or urokinase has proved effective for reopening thrombotically occluded
`
`vessels. However, administration of plasminogen activators on their own does not
`
`prevent further growth of the thrombus. High doses of plasminogen activators may
`
`additionally mean an increased risk of bleeding. Combined administration of a
`
`thrombolytic agent with an oxazolidinone of the formula (I)
`
`for opening
`
`thrombotically occluded vessels associated with coronary heart disease,
`transient
`ischemic attacks, stroke, peripheral arterial occlusive diseases and pulmonary
`
`embolisms prevents further growth of the thrombus through inhibition of thrombin
`
`fonnation and thus reduces the risk of reocclusion. In addition, on combination
`
`therapy with a thrombolytic agent and an oxazolidinone of the formula (I) it
`
`is
`
`possible to reduce the dose of thrombolytic agent necessary for therapy, which leads
`
`to a reduction in the bleeding complications and thus represents a considerable
`
`advantage over monotherapy.
`
`Oxazolidinones of the formula (I) can also be given in combination with other
`
`substances with anticoagulant activity (anticoagulants) for the prophylaxis and/or
`
`treatment of
`
`arterial,
`
`intracardiac
`
`and
`
`venous
`
`thromboembolic
`
`disorders.
`
`Combination therapy of oxazolidinones of the formula (I) in particular with heparin
`
`(UFH), lower molecular weight heparins (LMWH) such as, for example, tinzaparin,
`
`certoparin, pamaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin or
`
`10
`
`15
`
`20
`
`thrombin inhibitors such as, for example, hirudin leads to an enhanced
`direct
`antithrombotic effect.
`
`25
`
`Oxazolidinones of the formula (I) can additionally also be given in combination with
`
`platelet aggregation-inhibiting substances (platelet aggregation inhibitors) for the
`
`prophylaxis and/or treatment of arterial, intracardiac and venous thromboembolic
`disorders. An endothelial lesion is associated with adhesion to the wall and activation
`
`30
`
`of blood platelets and simultaneous stimulation of coagulation. This leads to the
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`
`formation of platelet- and fibrin-containing thrombi, and the platelets contribute to
`
`stabilizing the fibrin matrix (J. Hirsh, E. W. Salzman, V. J. Marder, R W. Colman,
`
`Overview of the Thrombotic Process and its Therapy, pages 1151-1163 in
`
`Hemostasis and Thrombosis: Basic Principles and Clinical Practice, Third Edition,
`
`edited by R. W. Colman, J. Hirsh, V. J. Marder, E. W. Salzman. J. B. Lippincott
`
`Company, Philadelphia, 1994). Simultaneous inhibition of coagulation and of platelet
`
`aggregation therefore leads to an enhanced antithrombotic effect. Particularly suitable
`
`for combination therapy are combinations of an oxazolidinone of the formula (I) with
`
`platelet aggregation inhibitors such as, for example, aspirin,
`
`ticlopidin (Ticlid),
`
`clopidogrel
`
`(Plavix);
`
`fibrinogen
`
`receptor
`
`antagonists;
`
`(glycoprotein Hb/Illa
`
`antagonists) such as,
`lefradafiban.
`
`for example, abciximab, eptifrbatide,
`
`tirofiban,
`
`lamifiban,
`
`All usual administration forms are suitable for administering the combinations of the
`
`invention. Administration preferably takes place orally,
`
`lingually, sublingually,
`
`buccally, rectally,
`
`topically or parenterally (i.e. avoiding the intestinal
`
`tract,
`
`i.e.
`
`intravenous,
`
`intraa.rteria1,
`
`intracardiac,
`
`intracutaneous, subcutaneous,
`
`transderrnal,
`
`intraperitoneal or intramuscular).
`
`The present
`
`invention includes pharmaceutical preparations which, besides non-
`
`toxic,
`
`inert pharmaceutically suitable excipients and/or carriers, comprise one or
`
`mor