u
`
`1‘
`
`is
`
`1-
`
`y %,’E:. ir".
`
`::
`
`u
`
`l! :v.,, 3' 15.1..
`
`1'1’
`
`is
`
`Le A 34 122-Foreivn Countries
`
`-24-
`
`represents one of the groups below:
`
`A-,
`
`A-M-.
`
`D-M-A-,
`
`B—M—A—,
`
`B—,
`
`B-M-,
`
`B—M~B-,
`
`D—M—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;
`
`-CH2—NH-, -OCH;-,
`-NH-CH2—,
`the radical “M” represents —NH-, -0-,
`-CI-I20-, -CONH-, —NHCO— 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 radical from the group consisting of halogen;
`trifluoromethyl; oxo; cyano; pyridyl; (C1-C3)-alkanoyl; (C6—C1o)-arylcarbonyl;
`(C5-C6)-heteroarylcarbonyl;
`(C.—C3)-alkanoyloxymethyloxy;
`-C(NR27R28)=NR2°; —CONR28R2°;
`-SO2NR23R29; -OH; —NR3°R3‘;
`(c,-c4)—__)
`alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
`
`where (C;-C4)—alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part
`may optionally be substituted by a radical from the group consisting of cyano;
`—OH; —OCH3; -NRZSR”; ~CO(NH)v(NR27R28) and —C(NR27R23)=NRz°,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`where:
`
`MYLAN - EXHIBIT 1006 - Part 13 of 14
`
`3862
`
`3862
`
`MYLAN - EXHIBIT 1006 - Part 13 of 14
`
`

`
`
`
`Le A 34 122-Foreivng Countries
`
`-25-
`
`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)-alkyl or
`else
`cyclopropyl,
`cyclopentyl or cyclohexyl
`and/or
`
`R27 and R28 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 heterocycle having up to two identical or different
`
`heteroatoms from the group consisting of N, O and S, and
`
`R30 and R3‘ are identical or different and independently of one another each
`represents
`hydrogen,
`(C,—C4)-alkyl,
`cyclopropyl,
`cyclopentyl,
`cyclohexyl,
`(C;-C4)-alkylsulphonyl,
`(C;—C4)—hydroxyalkyl,
`(C1-C4)-
`aminoalkyl, di-(C;—C4)—alkylamino-(C;—C4)-alkyl, (C1-C3)-alkanoyl or
`phenylcarbonyl.
`
`Likewise, in the compounds of the general formula (I), the radical
`
`R2
`
`may represent a group of the following formula:
`
`where
`
`R32
`
`represents hydrogen or (C.-C4)—alkyl, preferably hydrogen or methyl,
`and
`
`W
`
`represents S, NH or 0, preferably S.
`
`Moreover, in the compounds of the general formula (I), the radical
`
`7
`R-
`
`may be a group of the formula below
`
`3863
`
`10
`
`15
`
`20
`
`25
`
`30
`
`3863
`
`

`
`
`Le A 34 122-Foreicrn Countries
`
`-25-
`
`/
`
`rgc
`
`N
`
`3
`
`Finally, in the compounds of the general formula (I), the radical
`
`R2
`
`may be a group of the formula below
`
`NTNIZK
`
`0
`
`To date, oxazolidinones have essentially only been described as antibiotics, and in
`
`individual cases also as MAO inhibitors and fibrinogen antagonists (review: Riedl,
`
`B., Endermann, R., Exp. Opin. Ther. Patents 1999, 9 (5), 625), where a small 5-[acyl—
`aminomethyl] group (preferably 5—[acetylaminomethyl]) appears to be essential for
`the antibacterial activity.
`
`Substituted aryl— and heteroarylphenyloxazolidinones
`
`in which a mono— or
`
`polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone
`
`ring and which may have an unsubstituted N-methyl-2—thiopheneca.rboxamide radical
`in the 5-position of the oxazolidinone ring, and their use as antibacterial substances,
`
`are known from U.S- Patents US—A-5 929 248, 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.
`V
`p
`-
`4.1.5
`
`synthetic
`are known as
`addition, benzamidine-containing oxazolidinones
`In
`intermediates in the synthesis of factor Xa inhibitors and/or fibrinogen antagonists
`(WO—A-99/3 1092, EP-A-623615).
`
`the compounds of the general formula (I)
`Depending on the substitution pattern,
`according to the invention may exist in stereoisomeric fonns which are either like
`
`image and mirror
`
`image (enantiomers) or not
`
`like image and mirror
`
`image
`
`3864
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`3864
`
`

`
`
` ..
`i
`
`r:
`
`,,
`w;
`.
`
`. ,,
`xx.
`2
`:.
`2:
`
`r;
`
`H
`:5’
`\
`
`.1
`2
`
`xi‘
`
`,
`
`,
`
`-1:
`2;
`
`V’
`
`U
`13
`.
`
`u,
`.l...
`=1.
`u x:—.
`
`.
`
`,
`.. u 4:
`n
`
`...
`1'
`'1
`
`I
`a»
`‘I
`
`,
`,
`.:
`1- 1/
`
`2:
`
`Le A 34 122-Foreigg Countries
`
`-27-
`
`(diastereomers). The invention relates both to the enantiomers or diastereomers and to
`
`their respective mixtures. The racernic forms, like the diastereomers, can be separated
`in a known manner into the stereoisomerically uniform components.
`
`in
`formula (I) can be present
`Furthermore, certain compounds of the general
`tautomeric forms. This is known to the person skilled in the art, and such compounds
`are likewise within the scope of the invention.
`
`Physiologically acceptable, i.e. pharmaceutically compatible, salts can be salts of the
`
`compounds according to the invention with inorganic or organic acids. Preference is
`
`given to salts with inorganic acids, such as,
`
`for example, hydrochloric acid,
`
`hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic
`carboxylic or sulphonic acids, such as, for example, acetic acid, trifluoroacetic acid,
`
`10
`
`15
`
`propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic
`acid,
`benzoic
`
`acid,
`
`or methanesulphonic
`
`acid,
`
`ethanesulphonic
`
`acid,
`
`benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
`
`Other pharmaceutically compatible salts which may be mentioned are salts with
`
`20
`
`customary bases, such as, for example, alkali metal salts (for example sodium or
`potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or
`
`ammonium salts, derived from ammonia or organic amines, such as, for example,
`diethylarnine,
`triethylamine,
`
`procaine,
`ethyldiisopropylamine,
`N—methylmorpholine, dihydroabietylarnine or methylpiperidine.
`
`dibenzylamine,
`
`25
`
`30
`
`35
`
`According to the invention, “hydrates” are fomis of the compounds of the general
`formula (1) above which form a molecule compound (solvate) in the solid or liquid
`state by hydration with water. In the hydrates, the water molecules are attached through
`secondary valencies by intermolecular forces,
`in particular hydrogen bridges. Solid‘
`hydrates contain water as so—called crystal water in stoichiometric ratios, where the If
`
`water molecules do not have to be equivalent with respect to their binding state.
`Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.
`Equally suitable are the hydrates of salts of the compounds according to the invention.
`
`According to the invention, “prodrugs” are forms of the compounds of the general
`formula (I) above which for their part can be biologically active or inactive, but which
`
`3865
`
`3865
`
`

`
`
`
`Le A 34 I22-Foreicrng Countries
`
`-23-
`
`can be converted into the corresponding biologically active form (for example
`metabolically, solvolytically or in another way).
`
`
`Halooen represents fluorine, chlorine, bromine and iodine. Preference is given to
`chlorine or fluorine.
`
`(Ql£§)—AIkyl represents 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, such as, for example, (C1-C6)-alkyl and (C;~C4)-alkyl, are derived
`analogously from this definition. In general, preference is given to (C1-C4)-alkyl.
`
`The meaning of the corresponding component of other more complex substituents,
`such as, for example, gljgylsulphonyl, hydroxyal§y_l, hydroxya_l_lgy1carbonyl, alkoxy-
`a_ll_<_vl, alkoxycarbonyl-ajlcfl, alkanoyl§fl<fl, aminofiyj or alkylarnino;a1l_kfl is likewise
`derived from this definition.
`
`radical having 3 to 7 carbon atoms.
`(Q;;_C_3_Z)-Cycloalkyl represents a cyclic alkyl
`Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl,
`cyclohexyl or cycloheptyl. The corresponding cycloalkyl groups having fewer carbon
`atoms, such as, for example, (C3—C5)—cycloalkyl, are derived analogously from this
`definition. Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.
`
`The meaning of the corresponding component of other more complex substituents,
`such as, for example, cycloalkanoyl, is likewise derived from this definition.
`
`In the context of the invention, C3-Céralkenyl represents a straight—chain or branched
`alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight—chain_or_
`branched alkenyl
`radical having 2 to 4 carbon atoms. Examples which may be
`mentioned are: vinyl, allyl, isopropenyl and n-but—2—en-l—yl.
`
`fglfig)-Alkoxy represents 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 having fewer carbon atoms, such as, for
`
`10
`
`15
`
`25
`
`30
`
`35
`
`3866
`
`3866
`
`

`
`
`
`Le A 34 l22—Forei2n Countries
`
`-29-
`
`(C1—C6)—alkoxy and (C1-C4)-Alkoxy, are derived analogously from this
`example,
`definition. In general, preference is given to (C,-C4)-alkoxy.
`
`The meaning of the corresponding component of other more complex substituents,
`such as, for example alkoxy-alkyl, alkoxycarbonyl—alkyl and alkoxycarbonyl,
`is
`likewise derived from this definition.
`
`Mono— or di-(C1~C5)-alkylaminocaibonyl represents an amino group which is attached
`via a carbonyl group and which has a straight-chain or branched or two identical or
`
`different straight-chain or branched alkyl substitutents having in each case 1 to 4 carbon
`
`ethylamino,
`atoms. Examples which may be mentioned are: methylamino,
`n-propylamino, isopropylamino, t—butylamino, N,N-dimethylamino, N,N—diethylarnino,
`N-ethyl-N-methylamino, N-methyl—N-n-propylamino, N-isopropyl—N-n-propylamino
`and N-t-butyl-N—methylamino.
`
`(Q1—_C_§ )~A1kanoyl represents a st_raight—chain or branched alkyl radical having 1 to 6
`carbon atoms which carries a doubly attached oxygen atom in the 1-position and is
`attached via the l—position. Examples which may be mentioned are: formyl, acetyl,
`propionyl, n-butyryl,
`i—butyryl, pivaloyl, n—hexanoyl. The corresponding alkanoyl
`groups with fewer carbon atoms,
`such as,
`for example,
`(C;-C5)—alkanoyl,
`(C;—C4)~alkanoyl and (C.—C3)—alkanoyl, are derived analogously from this definition.
`In general, preference is given to (C;-C3)—alkanoyI.
`
`The meaning of the corresponding component of other more complex substituents,
`such as, for example, cycloalkanoyl and alkanoylalkyl, is likewise derived from this
`definition.
`
`(C3-C7 1-Cycloalkanoyl represents a cycloalkyl radical having 3 to 7 carbon atoms _as_
`defined above which is attached via a carbonyl group.
`
`(Q1—_C_I_§ )—Alkanoyloxu3ethyloxy
`
`represents
`a
`straight-chain
`or
`alkanoyloxymethyloxy radical having 1 to 6 carbon atoms. Examples which may be
`mentioned are:
`acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy,
`i-butyroxymethyloxy,
`pivaloyloxymethyloxy,
`n—hexanoyloxymethyloxy.
`The
`corresponding alkanoyloxymethyloxy groups having fewer carbon atoms, such as, for
`
`branched
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`3867
`
`3867
`
`

`
`
`
`Le A 34 122—Foreig1_1 Countries
`
`-30-
`
`are derived analogously from this
`(C;-C3)—alkanoyloxymethyloxy,
`example,
`definition. In general, preference is given to (C;-C3)-alkanoyloxymethyloxy.
`
`(§§_—_§J_j,);£fl represents 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, (C5—C1o)-aryl
`are derived analogously fi'om this definition.
`In general, preference is given to
`(C5-C10)-aryl.
`
`The meaning of the corresponding component of other more complex substituents,
`such as, for example, _a_rflcarbonyl, is likewise derived fi'om this definition.
`
`@§;Q_l91—Heterog_ryl or a 5- to 10-membered aromatic heterocycle having up to 3
`
`heteroatoms and/or hetero chain members from the on consistin of S O N and NO
`(_l\_1—oxide) represents a mono- or bicyclic heteroaromatic which is attached via a carbon
`ring atom of the heteroaromatic or, if appropriate, via a nitrogen ring atom of the
`heteroaromatic. Examples which may be mentioned are: pyridyl, pyridyl N-oxide,
`pyiimidyl, pyridazinyl, pyrazinyl,
`thienyl,
`fiiryl, pyrrolyl, pyrazolyl,
`imidazolyl,
`thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]fu.ryl,
`indazolyl, quinolyl,
`isoquinolyl, naphthyridinyl, quinazolinyl. The corresponding
`heterocycles having a smaller ring size, such as, for example, 5- or 6-membered
`aromatic heterocycles, are derived analogously from this definifion.
`In general,
`preference is given to 5- or 6-membered aromatic heterocycles, such as, for example,
`pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl.
`
`The meaning of the corresponding component of other more complex substituents,
`such as,
`for example,
`L(_3§;(_3_1o)-heterogylcarbonyl,
`is likewise derived from this
`definition.
`
`A 3- to 9~membered saturated or artiall unsaturated mono- or bic clic o tionall
`___m_m
`benzo-fused heterocycle having up to 3 heteroatoms and/or hetero chain members
`fiom the group consisting of S, SO, SO_2, N, NO (§—oxide) and 0 represents a
`heterocycle which may contain one or more double bonds, which may be mono- or
`bicyclic, to which a benzene ring may be fl.1SCd to two adjacent carbon ring atoms and
`which is attached via a carbon ring atom or a nitrogen ring atom. Examples which
`may be mentioned are:
`tetrahydrofuryl, pyrrolidinyl, pyirolinyl, piperidinyl, 1,2-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`3868
`
`3868
`
`

`
`
`
`Le A 34 122-Foreicn Countries
`
`3869
`
`-31-
`
`dihydropyridinyl, 1,4-dihydropyiidinyl, piperazinyl, morpholinyl, morpholinyl N-oxide,
`
`thiomorpholinyl, azepinyl, 1,4-diazepinyl and cyclohexyl. Preference is given to
`
`piperidinyl, morpholinyl and pyrrolidinyl.
`
`The corresponding cycles having a smaller ring size, such as, for example, 5- to 7-
`
`membered cycles, are derived analogously from this definition.
`
`The present invention also provides a process for preparing the compounds of the
`
`g
`
`eneral formula (I) accordinv to the invention where either, accordinw to one rocess
`D
`D
`P
`
`10
`
`alternative
`
`[A]
`
`compounds of the general formula (II)
`
`0
`
`R2\NJl\
`
`
`
`in which
`
`the radicals R2, R3, R4, R5, R6 and R7 are each as defined above,
`
`are reacted with carboxylic acids of the general formula (111)
`
`R‘
`
`(HD,
`
`TO
`
`HO
`
`in which
`
`the radical R1 is as defined above,
`
`15
`
`20
`
`3869
`
`

`
`
`
`Le A 34 l22—Forei2n Countries
`
`.32.
`
`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 and/or a base, to give compounds of the general formula (I)
`
`O
`
`R3\N/JL\
`
`(I),
`
`in which
`
`the radicals R‘, R2, R3, R‘, R5, R6, R7 and R3 are each as defined
`above,
`
`or else according to a process alternative
`
`[B]
`
`compounds of the general formula (IV)
`
`R3
`
`(IV).
`
`R6 R’ 0
`Fl ‘
`Jl\
` 'r R1
`
`R‘
`
`R‘
`
`in which
`
`the radicals R’, R3, R4, R5, R6, R7 and R8 are each as defined above,
`
`are converted, using a suitable selective oxidizing agent in an inert solvent,
`into the corresponding epoxide of the general formula (V)
`
`.L,,-,
`
`3870
`
`10
`
`15
`
`20
`
`3870
`
`

`
`
`
`1
`
`’»
`
`"‘
`
`*1
`
`Le A 34 122-Foreign Countries
`
`-33 _
`
`R’ R‘ R’ 0
`/U\ 1
`F‘
`
`‘T
`R“
`
`R5
`
`o
`
`R‘
`
`in which
`
`(V)’
`
`10
`
`15
`
`20
`
`25
`
`30
`
`the radicals R1, R3, R4, R5, R6, R7 and R8 are each as defined above,
`
`and, by reaction in an inert solvent, if appropriate in the presence of a catalyst,
`with an aznine of the general formula (VI)
`
`R2 — NH;
`
`(VI),
`
`in which
`
`the radical R2 is as defined above,
`
`the compounds of the general formula (VII)
`
`R4 R3 R6 R7 0
`
`R:N>SQL /“\,,. Wm.
`8T
`H
`
`Hc)R‘
`
`H
`
`in which
`
`the radicals R‘, R2, R3, R4, R5, R6, R7 and R8 are each as defined"
`
`above,
`
`are initially prepared and
`
`in an inert solvent in the presence of phosgene or phosgene
`subsequently,
`equivalents, such as, for example, carbonyldiimidazole (CD1), cyclized to
`give the compounds of the general formula (I)
`
`3871
`
`3871
`
`

`
`
`
`Le A 34 122—Forei9_n Countries
`
`W €i'1:%1i %??m %
`
`€fi%A:3
`
`~
`
`-34-
`
`G)
`
`in which
`
`the radicals R‘, R2, R3, R4, R5, R6, R7 and R8 are each as defined
`above,
`
`10
`
`in
`where - both for process alternative [A] and for process alternative [B] —
`the case where R2 contains a 3-
`to 7-membered saturated or partially
`unsaturated cyclic 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
`
`15
`
`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 altemative [A] and for process alternative [B] - in the
`case where the compound prepared in this manner has a BOC amino
`
`protective group in the molecule, removal of this BOC amino protective
`group by customary methods may follow
`
`and/or
`
`30
`
`3872
`
`3872
`
`

`
`
`
`Le A 34 122—Forei0n Countries
`
`-35-
`
`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
`
`benzylarnine radical in the molecule, a reaction of this amino group with
`various reagents such as carboxylic acids, carboxylic anhydrides, carbonyl
`chlorides,
`isocyanates, sulphonyl chlorides or alkyl halides to give the
`corresponding derivatives 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 phenyl ring in the
`molecule, a reaction with chlorosulphonic acid and subsequent reaction with
`amines to give the corresponding sulphonamides may follow.
`
`The processes according to the invention can be illustrated in an exemplary manner
`by the equations below:
`
`10
`
`15
`
`[A]
`F
`0
`/—\
`o N N)‘\O + H0
`\-—/
`\/H
`NH2
`
`0
`
`F
`
`CI
`
`S\\
`
`EDCI
`
`\N
`/
`HOBT
`(iso-Pr)2EtN \_/
`
`O
`
`N)\‘0
`\% C
`H o
`
`s
`
`F
`
`/-x
`°\
`/N
`
`0
`
`>~o
`
`on
`
`s \
`\
`
`+ 0'
`
`2
`
`F
`
`/‘W
`°\
`/N
`
`0
`
`>‘\o
`
`s
`
`on
`
`o
`
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`Le A 34 122-Foreign Countiies
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`[B]
`
`
`
` O
`(3/‘u’W”u \ 5/
`as
`
`CDI
`
` N 0
`S
`
`Cl
`S \
`
`The oxidation step described above, which is optional, can be illustrated in an
`
`exemplary manner by the equation below:
`
`8/
`\
`
`\
`/N
`
`O
`
`>Lo
`“ES
`
`F
`
`0
`
`
`
`NMo/oso. °\s\_//\,
`0:’
`
`Cl
`
`S \
`
`*0
`N28
`
`8
`
`Cl
`
`\
`
`O
`
`NalO4
`\
`
`F
`
`_ /—\
`O—S
`N
`
`O
`
`O
`>~o
`Nd»
`
`HN
`
`O
`
`Cl
`
`10
`
`15
`
`Suitable solvents for the processes described above are organic solvents which are
`inert under the reaction conditions. These include halogenated hydrocarbons, such as
`dichloromethane,
`tiichloromethane,
`carbon
`tetrachloride,
`l,2—dichloroethane,
`trichloroethane, tetrachloroethane,
`l,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 sulphoxide, acetonitiile, pyridine, hexa-
`methylphosphoric triamide or water.
`
`It is also possible to use solvent mixtures of the solvents mentioned above.
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`Le A 34 122-Foreion Countries
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`-37-
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`Suitable activating or coupling agents for the processes described above are the
`
`this
`for
`used
`customarily
`are
`reagents which
`N ’-(3-dimethylaminopropyl)-N-ethylcarbodiimide - HC1,
`diirnide, 1-hydroxy-1H—benzotriazole - H20 and the like-
`
`example
`for
`purpose,
`N,N’—dicyclohexylcarbo-
`
`Suitable bases are the customary inorganic or organic bases. These preferably include
`alkali metal hydroxides, such as, for example, sodium hydroxide or potassium
`hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium
`carbonate, or sodium methoxide or potassium methoxide or sodium ethoxide or
`
`potassium ethoxide or potassium-tert-butoxide, or amides, such as sodium amide,
`
`lithium bis-(t1imethy1silyl)amide or lithium diisopropylamide, or amines, such as
`
`diisopropylethylamine,
`triethylamine,
`pyridine or pyridine.
`
`diisopropylamine,
`
`4-N,N-dimethylamino—
`
`The base can be employed here 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).
`
`The reactions are generally canied out in a temperature range of from —78°C to
`
`reflux temperature, preferably in the range from 0°C to reflux temperature.
`
`The reactions can be carried out at atmospheric, elevated or reduced pressure (for
`
`example in the range from 0.5 to 5 bar). In general, the reactions are carried out at
`
`atmospheric pressure.
`
`Suitable selective oxidizing agents, both for the preparation of the epoxides and for
`
`the optional oxidation to give
`
`the
`
`sulphone,
`
`sulphoxide or N—oxide,
`
`are
`
`m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N—methylmorpholine
`
`N—oxide (NMO), monoperoxyphthalic acid or osmium tetroxide.
`
`With respect to the preparation of the epoxides, the preparation conditions which are
`
`customary for this purpose are employed.
`
`With respect to more detailed process conditions for the optional oxidation to give
`the sulphone, sulphoxide or N—oxide, reference is made to the following literature:
`M- R. Barbachyn et al., J. Med. Chem. 1996, 39, 680 and WO—A—97/10223.
`
`l0
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`15
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`20
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`25
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`30
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`Furthermore, reference is made to Examples 14 to 16 given in the experimental part.
`
`The optional amidation is carried out under customary conditions. For more details,
`reference is made to Examples 31 to 35 and 140 to 147.
`
`The compounds of the general formulae (H), (111), (IV) and (VI) are known per se to
`the person skilled in the art or can be prepared by customary methods. For
`oxazolidinones,
`in particular the 5-(aminomethyl)—2—oxooxazolidines required, cf.
`W0-A—98/01446; WO—A-93/23384; W0-A—97/03072; J. A. Tucker et al., J- Med-
`Chem. 1998, 41, 3727; S. J. Brickner et al.,
`J. Med. Chem. 1996, 39, 673;
`W. A. Gregory et al., J. Med. Chem. 1989, 32, 1673.
`
`The compounds of the general formula (I) according to the invention have an
`unforeseeable useful pharmacological activity spectrum and are therefore particularly
`suitable for the prophylaxis and/or treatment of disorders.
`
`The compounds of the general formula (I) according to the ivnention - including the
`compounds which are excluded by disclaimer
`from the chemical product
`protection - act
`in particular as anticoagulants and can therefore preferably be
`employed in medicaments for the prophylaxis and/or therapy of thromboembolic
`disorders. For the purpose of the present invention, “thromboembolic disorders”
`include, in particular, serious disorders such as myocardial infarct, angina pectoris
`(including unstable angina),
`reocclusions and restenoses after angioplasty or
`aortocoronary bypass,
`stroke,
`transitory ischaemic attacks, peripheral arterial
`occlusion disorders, pulmonary embolisms or deep venous thromboses.
`
`formula (1) according to the
`the general
`the compounds of
`Furthermore,
`invention —including the compounds which are excluded by disclaimer from the.,.,
`chemical product protection - are also suitable for treating disseminated intravascular
`coagulation (DIC).
`
`the
`to
`according
`(1)
`formula
`general
`the
`of
`compounds
`the
`Finally,
`invention —including the compounds which are excluded by disclaimer from the
`chemical product protection - are also suitable for the prophylaxis and/or treatment of
`atherosclerosis and arthritis, and additionally also for
`the prophylaxis and/or
`treatment of Alzheimer’s disease and cancer.
`
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`The compounds of the general formula (I) according to the invention - including the
`
`compounds excluded by disclaimer from the chemical product protection — act in
`
`particular as selective inhibitors of the blood coagulation factor Xa and ‘do not
`
`inhibit, or only inhibit at considerably higher concentrations, other serine proteases as
`
`well, such as thrombin, plasmin or trypsin.
`
`In the context of the present invention, inhibitors of the blood coagulation factor Xa
`
`in which the IC5o values for the factor Xa inhibition are lower by a factor of 100,
`
`preferably by a factor of 500, in particular by a factor of 1000, than the IC5o values
`
`for the inhibition of other serine proteases,
`
`in particular thrombin, plasmin and
`
`trypsin, are referred to as being ,,selective”, where with a view to the test methods for
`
`selectivity, reference is made to the test methods of Examples A-1) a.l) and a.2)
`described below.
`
`The compounds of the general formula (I) according to the invention — including the
`
`compounds which are excluded by disclaimer from the chemical product protection —
`
`can furthermore be used for preventing coagulation ex vivo, for example for banked
`
`blood or biological samples which contain factor Xa.
`
`The present invention thus provides oxazolidinones of the formula (I) effecting in
`
`particular an unexpected, strong and selective inhibition of factor Xa, and this also
`
`applies to the compounds excluded by disclaimer from the chemical product
`
`protection.
`
`The
`
`present
`
`invention
`
`further
`
`provides
`
`medicaments
`
`and
`
`pharmaceutical
`
`compositions comprising at least one compound of the general formula (I) according
`
`to the invention together with one or more pharmacologically acceptable auxiliar-i_es__‘
`or excipients, which medicaments and pharmaceutical compositions can be used for
`the indications mentioned above.
`
`Furthermore, the present invention relates to a method for the prophylaxis and/or
`
`treatment of disorders of
`
`the human or animal body,
`
`in particular of
`
`the
`
`abovementioned disorders, using the compounds of the general formula (I) according
`
`to the invention - including the compounds excluded by disclaimer from the chemical
`
`product protection.
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`Le A 34 122-Foreign Countries
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`Furthermore, the present invention also includes a method for preventing blood
`
`coagulation in vitro,
`
`in particular in banked blood or biological samples which
`
`contain factor Xa, which method is characterized in that compounds of the general
`
`formula (1) -including the compounds excluded by disclaimer from the chemical
`
`product protection — are added.
`
`All customary administration forms are suitable for administration of the compounds
`
`according to the invention. Administration is preferably canied out orally, lingually,
`
`sublingually, buccally, rectally or parenterally (i.e. bypassing the intestinal tract, that
`
`is
`
`intravenously,
`
`intraarterially,
`
`intracardially,
`
`intracutaneously,
`
`subcutaneously,
`
`transdermally, intraperitoneally or intramuscularly). Particularly suitable are oral and
`
`intravenous administration. Very particular preference is given to oral administration,
`
`this being a further advantage with respect to the prior—art therapy of thromboembolic
`disorders.
`
`The novel active compounds of the general formula (I) can be converted in a known
`
`manner into the customary formulations, such as tablets, sugar-coated tablets, pills,
`
`granules, aerosols, syrups, emulsions, suspensions and solutions, using inert non-
`
`toxic pharmaceutically suitable excipients or solvents. Here,
`
`the therapeutically
`
`active compound should in each case be present in a concentration of from about 0.1
`
`to 95% by weight, preferably from 0.5 to 90% by weight, in particular from 1 to 85%
`
`by weight, of the total mixture,
`
`i.e.
`
`in amounts which are sufficient in order to
`
`achieve the dosage range indicated.
`
`In spite of this, if appropriate, it may be necessary to depart from the amounts
`
`mentioned, namely depending on the body weight or on the type of administration
`
`route, on the individual response to the medicament, on the manner of its formulation _
`
`and the time or interval at which administration takes place. Thus, in some cases it
`
`may be adequate to manage with less than the abovementioned minimum amount,
`
`while in other cases the upper limit mentioned must be exceeded. In the case of the
`
`administration of relatively large amounts, it may be advisable to divide these into
`
`several individual administrations over the course of the day.
`
`The formulations are prepared, for example, by extending the active compounds with
`
`solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it
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`Le A 34 122-Foreigg Countries
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`-41-
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`being possible, for example if the diluent used is water, optionally to use organic
`solvents as auxiliary solvents.
`
`In general it has proved advantageous in the case of intravenous administration to
`administer amounts from approximately 0.001 to 10 mg/kg, preferably approximately
`0.01 to 10 mg/kg, in particular approximately 0-1 to 8 mg/kg, of body weight to
`achieve effective results.
`
`In general, it has proved advantageous in the case of oral administration to administer
`amounts from approximately 0.01 to 50 mg/kg, preferably approximately 0.1 to
`10mg/kg, in particular approximately 0-5 to 8 mg/kg, of body weight to achieve
`effective results.
`
`In spite of this, if appropriate, it may be necessary in the case of intravenous or oral
`administration to depart from the amounts mentioned, namely depending on the body
`weight or on the type of administration route, on the individual response to the
`medicament, on the manner of its formulation and the time or interval at which
`administration takes place. Thus, in some cases it may be adequate to manage with
`less than the abovementioned minimum amount, while in other cases the upper limit
`mentioned must be exceeded. In the case of the administration of relatively large
`amounts, it may be advisable to divide these over the course of the day, namely into
`several individual doses or as a continuous infusion.
`
`Compared to the conventional preparations for treating thromboembolic disorders,
`the compounds of the general formula (1) according to the invention — including the
`compounds excluded by disclaimer from the chemical product protection - are
`distinguished in particular by the fact that a greater therapeutic range is achieved by
`the selective inhibition of factor Xa. For the patient, this means a lower risk-oft
`bleeding, and for the treating physician, this means that the patient is easier to adjust.
`Moreover — owing to the mechanism - the onset of action is more rapid. Above all,
`however, the compounds according to the invention permit an oral administration
`form, which is a further advantage of the therapy with the compounds according to
`the invention.
`
`The present invention is illustrated by the examples below; however, these examples
`are not meant to restrict the invention in any way.
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`-42-
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`Examples
`
`A
`
`1.
`
`Evaluation of the physiological activi_t_v_
`
`General test methods
`
`The particularly advantageous biological properties of the compounds
`according to the invention can be determined by the following methods.
`
`at Test description gin vitrol
`
`a.1) Determination of the factor Xa inhibition
`
`The enzymatic activity of human factor Xa (I-'Xa) was measured using the conversion
`
`of a chromogenic substrate specific for FXa. Factor Xa cleaves p—nitroaniline from
`
`the chromogenic substrate. The determinations were carried out in microtitre plates
`as follows.
`
`The test substances,
`
`in various concentrations, were dissolved in DMSO and
`
`incubated at 25°C with human FXa (0.5 nmol/1 dissolved in 50 mmol/l of tris buffer
`
`[C,C,C—tris(hydroxymethyl)—aminomethane],
`
`150 mmol/l of NaCl, 0.1% BSA
`
`(bovine serum albumin), pH 2 8.3) for 10 minutes. Pure DMSO was used as control.
`
`The chromogenic substrate (150 p.mol/1 of Pefachrome® FXa from Pentapharm) was
`then added. After an incubation time of 20 minutes at 25°C, the extinction at 405 nm
`
`was determined. The extinctions of the test mixtures containing test substance were
`
`compared with the control mixtures without test substance, and the IC5o values were
`calculated from these data.
`
`a.2) Determination of the selectivity
`
`To assess selective FXa inhibition,
`
`the test substances were examined for their
`
`inhibition of other human serine proteases s