Européiisches Patentamt
`
`0)
`
`European Patent Office
`
`Office européen des brevets
`
`® Publication number:
`
`0 114027
`
`B1
`
`®
`
`EUROPEAN PATENT SPECIFICATION
`
`@ Date of publication of patent specification: 07.01.88
`(2) Application number: 83810548.4
`
`@ mt c|_4; C 07 D 209/18,
`C O7 D 405/04' A 61 K 31/405
`
`® Date offiling: 22.11.83
`
`
`
`® Analogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical
`compositions containing them and their use as pharmaceuticals.
`
` @ Priority: 22.11.82 us 443668
`® Proprietor: SANDOZ AG
`Lichtstrasse 35
`CH-4002 Basel (CH)
`BE CH FR GB IT LI LU NL SE
`® Proprietor: SANDOZ-PATENT-GMBH
`Humboldtstrasse 3
`D-7850 L6rrach (DE)
`DE
`
`04.1 1.33 us 548850
`
`® Date of publication of application:
`25.07.84 Bulletin 84/30
`
`Q5) Publication of the grant of the patent:
`07.01.88 Bulletin 88/01
`
`® Proprietor: SANDOZ-ERFINDUNGEN
`Verwaltungsgesellschaft m.b.H.
`Brunner Strasse 59
`
`A-1235 wien (AT)
`AT
`
`® Inventor: Kathawala, Faizulla Gulamhusein
`39 Woodland Avenue
`Mountain Lakes, N.J., 07946 (US)
`
`
`
`Designated Contracting States:
`AT BE CH DE FR GB IT LI LU NL SE
`
`References cited:
`
`TETRAHEDRON LETTERS, Vol.23, no. 42, 1982,
`Pergamon Press, Oxford, GB YUH-LIN YANG et
`aI.: ”Mevinic acids and analogues: preparation
`of a key chiral intermediate”, p. 4305, 4308
`
`
`
`‘ N
`
`ote: Within nine months from the publication of the mention of the grant of the European patent. any person may
`give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall
`be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1) European patent convention).
`
`Courier Press, Leamington Spa, England.
`
`Mylan Exhibit 1025, Page 1
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`EP0114027B1
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`Mylan Exhibit 1025, Page 1
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`Description
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`0 114 027
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`The invention concerns heterocyclic analogs of mevalono-lactone and derivatives thereof, process for
`their production, pharmaceutical compositions containing them and their use as pharmaceuticals,
`in
`particular as hypolipoproteinemic and antiatherosclerotic agents.
`The invention is especially concered with compounds of formula I
`
`wherein one of R and R4 is
`
`4
`
`7
`
`R2
`S
`
`5
`R
`
`3
`
`R
`
`3
`
`\ x -2
`
`l
`I
`R0
`
`R4
`
`R
`
`5
`
`R5a
`
`(I)
`
`and the other is primary or secondary C4_6a|ky|, C3_5cycloa|ky| or phenyl-(CH2),,,-,
`wherein
`
`R4 is hydrogen, C4_4alkyl, C,_4alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy,
`_
`R5 is hydrogen, C,_3a|kyl, C1_3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
`Rsa is hydrogen, C4_2alky|, C1_2a|koxy, fluoro or chloro, and
`m is 1, 2 or 3, with the provisos that both R5 and R53 must be hydrogen when R4 is hydrogen, R53 must
`be hydrogen when R5 is hydrogen, not more than one of R4 and R5 is trifluoromethyl, not more than one of
`R4 and R5 is phenoxy and not more than one of R4 and R5 is benzyloxy,
`R2 is hydrogen C4_4alkyl, C3_5cyc|oalkyl, C,_4alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro,
`phenoxy or benzyloxy,
`R3 is hydrogen, C1_3a|kyl, C,_3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the
`provisos that R3 must be hydrogen when R2 is hydrogen, not more than one of R2 and R3 is trifluoromethyl,
`not more than one of R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy,
`X is —(CH2),,— or —CH=CH—— (n=0, 1, 2 or 3), and
`
`Rs
`1
`2
`31
`4
`5
`2 is —CH——CH2— C——CH2——COOH
`I
`l
`OH
`OH
`
`n
`
`wherein R6 is hydrogen or C1_3alky| in free acid form or in the form of a physiological|y—hydrolysable and
`-acceptable ester of a 5-lactone thereof or in salt form.
`By the term ”physiologically-hydrolysable and -acceptable ester” is meant an ester of a compound in
`accordance with the invention in which the carboxyl moiety is esterified, and which is hydrolysable under
`physiological conditions to yield an alcohol which is itself physiologically acceptable, e.g. non-toxic at
`desired dosage levels. Preferred such esters as 2 can be represented together with the free acid by formula
`Ila
`
`Re
`l
`—CH—CH2-— C—CH2—-COOR7
`I
`I
`OH
`OH
`
`Ha
`
`wherein R7 is hydrogen, C,_4a|ky| or benzyl, preferably hydrogen, C1_.3alky|, n—buty|,
`benzyl and R5 is as defined above.
`When in salt form R7 represents a cation.
`When Z is in lactone form it forms a 6-lactone of formula llb
`
`i—butyl, t-butyl or ,
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`Mylan Exhibit 1025, Page 2
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`Mylan Exhibit 1025, Page 2
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`

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`0 114 027
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`-ca
`
`c
`
`‘*6
`
`rm
`
`and references to "|actone” hereinafter refer to 6-lactones.
`Salts ofthe compounds of the invention, e.g. of the compounds of formula I, include in partiuclar their
`pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include e.g. alkali metal salts
`such as the sodium and potassium salts and ammonium salts.
`References to compounds of formula I and sub-species thereof are intended to cover all forms unless
`otherwise stated.
`The compounds of formula I may be divided into two groups, the compounds of formulae IA and IB:
`
` R
`
`Sa
`
`(13)
`
`wherein
`R1 is primary or secondary C._6alky|, C3_6cycloa|ky| or phenyl-(CH2),,,—, and
`R2—R5a, X, Z and m are as defined above.
`The compounds of formula IA may be divided into a two sub-groups, the compounds wherein Z is a
`group of formula ll in other than lactone form (Group lAa) and those wherein Z is a group offormula (Group
`|Ab) llb. Likewise, the compounds of formula lB may be divided into two sub-groups, the compounds
`wherein Z is a group of formula ll in other than lactone form (Group |Ba) and those wherein Z is a group of
`formula llb (Group lBb).
`As is self~evident to those in the art, each compound of formula I (and every sub-scope and species
`thereof) has at least two centers of asymmetry (e.g. the two carbon atoms bearing the hydroxy groups in
`the group of formula lla and the carbon atom bearing the hydroxy group and the carbon atom having the
`free valence in the group of formula llb) and these lead to four stereoisomeric forms (enantiomers) of each
`compound (two racemates or pairs of diastereoisomers). These four stereoisomes may be designated as
`the R, R; R, S; S, R; and S, S enantiomers, all four stereoisomers being within the scope of this invention.
`Depending on the nature of substituents further asymmetric carbon atoms may be present and the
`resulting isomers and mixtures thereof also form part of the invention. Compounds containing only two
`centres of asymmetry (four mentioned stereoisomers) are preferred.
`R,
`is preferably primary or secondary C1_eaIkyl not containing an asymmetric carbon atom (e.g.
`methyl, ethyl, n—propy|, i-propyl, n-butyl, i-butyl, 1-ethylpropyl, neopentyl and n-hexyll, more preferably
`C1_3alkyl and most preferably methyl, ethyl or i-propyl, especially i-propyl.
`Alkyl as R2 is preferably C,_2 or n-, i- or t-butyl and alkoxy C1_2 or n- or i-butoxy. R2 is preferably R2’,
`where R2’ is hydrogen, C1_3a|ky|, C1_3a|koxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, more
`preferably R2”, where R2” is hydrogen, C1_3a|ky|,methoxy,f|uoro,chloro or 4-, 5- or 6-benzyloxy, and most
`preferably R2”’, where R2”’ is hydrogen, C,_3alky| or 4- or 6-benzyloxy, especially hydrogen or methyl and
`most especially hydrogen.
`.
`R2 is preferably R3’, where R3’ is hydrogen, C1_3alkyl, C1_2alkoxy, fluoro or chloro, more preferably R3",
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`Mylan Exhibit 1025, Page 3
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`Mylan Exhibit 1025, Page 3
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`O 114 027
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`where R3” is hydrogen or C4_3alkyl and most preferably R3”’, where R3”’ is hydrogen or methyl, especially
`hydrogen. R3 (R3’, etc.) must be hydrogen when R2 (R2’, etc.) is hydrogen.
`Preferably, when R2 (R2’, R2", etc.) is other than hydrogen and R3 (R3’, R3”, etc.) is hydrogen, R2 (R2’,
`etc.) is in the 4-, 5- or 6-position.
`Preferably, when both R2 (R2’, R2”, etc.) and R3 (R3’, R3”, etc.) are other than hydrogen, at least one of
`them is in the 5- or 6-position, neither of them is in the 7-position, and not more than one of them is a
`member of the group consisting of t-butyl, C3_5cycloalkyl, trifluoromethyl, phenoxy and benzyloxy; more
`preferably, they are not ortho to each other when neither of them is a member of the group consisting of
`methyl, methoxy, fluoro and chloro. Most preferably, one is in the 4-position and the other is in the 6-
`position.
`Except where otherwise indicated: (a) Any C1_4alky| or C3_5cyc|oalkyl group as R2, R2’, R3, R3’, etc. is
`more preferably in the 4- or 6-position. (b) Any C1_4alkoxy, fluoro or chloro substituent as R2, R2’, R3, R3’,
`etc. is more preferably in the 5-position. (c) Any benzyloxy as R2, R2’, R3, R3’, etc. is more preferably in the
`4-, 5- or 6-position and most preferably in the 4- or 6-position, especially the 6-position.
`Alkyl as R4 is preferably C1_3 or n-, i- or t—butyl and alkoxy C1_3 or n- or i-butoxy. R4 is preferably R4’,
`where R4’ is hydrogen, C,_3alkyl, C1_3a|koxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, more
`preferably R4”, where R4” is hydrogen, methyl, methoxy, fluoro or chloro, and most preferably R4”’, where
`R4”’ is hydrogen, methyl orfluoro, especially R4””, where R4”” is hydrogen, 3- or 4-methyl or 4-fluoro and
`most especially 4-fluoro.
`R5 is preferably R5’, where R5’ is hydrogen, C7_2alkyl, C1_2alkoxy, fluoro or chloro, more preferably R5”,
`where R5” is hydrogen, methyl, methoxy, fluoro or chloro, and most preferably R5”’, where R5”’
`is
`hydrogen or methyl, especially hydrogen. R5 (R5’, R5”, etc.) must be hydrogen when R4 (R4’, R4”, etc.) is
`hydrogen.
`_
`R55 is preferably R55’, where R55’ is hydrogen or methyl, and most preferably hydrogen. R55 (R55’, etc.)
`must be hydrogen when at least one of R4 (R4’, R4”, etc.) and R5 (R5’, R5”, etc.) is hydrogen.
`Preferably, when R4 (R4’, R4”, etc.) is other than hydrogen and R5 (R5’, R5", etc.) and R55 (R55’, etc.) are
`both hydrogen, R4 (R4’, etc.) is in a meta or para position, more preferably the para position. The most
`preferred monosubstituted phenyl group is 4-fluorophenyl.
`Preferably, when both R4 (R4’, R4”, etc.) and R5 (R5’, R5”, etc.) are other than hydrogen and R55 (R55’,
`etc.) is hydrogen, at least one of R4 (R4’, etc.) and R5 (R5’, etc.) is in a meta or para position (more preferably
`both are), and not more than one of them is a member of the group consisting of t-butyl, trifluoromethyl,
`phenoxy and benzyloxy; more preferably, R4 (R4’, etc.) and R5 (R5’, etc.) are not ortho to each other when
`neither of them is a member of the group consisting of methyl, methoxy, fluoro and chloro. The most
`preferred disubstituted phenyl groups are 3,4- and 3,5-dimethylphenyl and 4-fluoro-3-methylphenyl,
`especially 3,5-dimethylphenyl and 4-fluoro-3-methylphenyl.
`,—
`Preferably, when each of R4 (R4’, etc.), R5 (R5’, etc.) and R55 (R55’, etc.) is other than hydrogen, at least
`two of them (more preferably, all three) are in meta or para positions, and not more than one of them is a
`member of the group consisting of t-butyl, trifluoromethyl, phenoxy and benzyloxy; more preferably, no
`two fo them are ortho to each other unless at least one member of the or each pair of substituents that are
`ortho to each other is a member of the group consisting of methyl, methoxy, fluoro and chloro. The most
`preferred trisubsituted phenyl group is 3,5-dimethyl-4-fluorophenyl.
`R5 is preferably R5’, where R5’ is hydrogen or C1_2alkyl, more preferably R5”, where R5” is hydrogen or
`methyl, and most preferably hydrogen.
`R7 is preferably R7’, where R7’ is hydrogen or C1_3alkyl, more preferably R7”, where R7” is hydrogen or
`C1_2alkyl. Such compounds wherein Z is of formula ll or lla are most preferably in salt form. Preferred salt-
`forming cations are those free from centres of asymmetry, especially e.g. sodium, potassium or
`ammonium, most preferably sodium.
`X is preferably X’, where X is —(CH2),,,— or
`
`more preferably X”, where X” is ——CH2CH2— or
`
`H
`
`.
`, especially
`
`H
`
`c=c
`/\'
`
`H
`
`\
`
`c=c
`/\
`
`H
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`Z is preferably a group offormula lla wherein R5 is R5’ and R7 is R7’ or a group offormula llb where in R5 -
`is R5’, more preferably a group of formula lla wherein R5 is R5” and R7 is R7” or a group of formula llb
`
`4
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`Mylan Exhibit 1025, Page 4
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`Mylan Exhibit 1025, Page 4
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`

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`O 114 027
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`wherein R5 is R5” most preferably a group of formula Ila wherein R5 is hydrogen and R7 is R7” or a group of
`formula llb wherein R5 is hydrogen, especially a group of formula Ila wherein R5 is hydrogen in salt form,
`particularly in sodium salt form, or a group of formula llb wherein R5 is hydrogen.
`n is preferably m, where m is 1, 2 or 3, preferably 2 or 3 and most preferably 2.
`Insofar as the compounds of Groups |Aa and lBa are concerned, the erythro isomers are generally
`preferred over the threo isomers, erythro and three referring to the relative positions of the hydroxy groups
`in the 3- and 5-positions (of the group of formula II or Ila).
`As between compounds of formula I having identical R, R5, R2, R5, R5 and X groups, free acid, salt and
`ester forms are generally preferred to lactone forms.
`The preferred stereoisomers of the compounds having only two assymetric carbons wherein X is a
`direct bond or —CH=CH—, and Z is in other than lactone form are the 3R,5S and 3R,5R isomers and the
`racemate of which each is a constituent, i.e., the 3R,5S-3S,5R (erythro) and 3R,5R—3S,5S (threo) racemates,
`with the 3R,5S isomer and the racemate of which it is a constituent being more preferred and the 3R,5S
`isomer being most preferred.
`The preferred stereoisomers of the compounds having only two assymetric carbons wherein X is
`—(CH2),,,—, and Z is in other than lactone form are the 3R,5R and 3R,5S isomers and the racemate of which
`each is a constituent, i.e., the 3R,5R-38,58 (erythro) and 3R,5S-3S,5R (threo) racemates, with the 3R,5R
`isomer and the racemate of which it is a constituent being more preferred and the 3R,5R isomer being most
`preferred.
`The preferred stereoisomers of the compounds having only two assymetric carbons wherein X is a
`direct bond or —CH=CH—, and Z is a group of formula llb are the 4R,6S and 4R,6R isomers and the
`racemate of which each is a constituent, i.e., the 4R,6S-4S,6R (trans lactone) and 4R,6R-48,68 (cis lactone)
`racemates, with the 4R,6S isomer and the racemate of which it is a constituent being more preferred and
`the 4R,6S isomer being most preferred.
`The preferred stereoisomers of the compounds having only two assymetric carbons wherein X is
`—(CH2),,,——, and Z is a group of formula llb are the 4R,6R and 4R,6S isomers and the racemate of which each
`is a constituent, /'.e., the 4R,6R-4S,6S (trans lactone) and 4R,6S-4S,6R (cis lactone) racemates, with the
`4R,6R isomer and the racemate of which it is a constituent being more preferred and the 4R,6R isomer
`being most preferred.
`,
`Each of the preferences set forth above applies, not only to the compounds of formula I but also to the
`compounds of formulae IA and IB and those of Groups IAa,
`|Ab, lBa and lBb as well as to- every other
`subgroup thereof set forth infra, e.g., Groups (i)-(cxiv), unless otherwise indicated. When any preference
`contains a variable, the preferred significances of that variable apply to the preference in question, unless
`otherwise indicated.
`Preferred groups of compounds of formula I include the compounds
`X (i) of Group |Aa wherein R, is R1’, R2 is R2’, R5 is R5’, R4 is R4’, R5 is R5’, R55 is R55’, R5 is R5’, R7 is R7’, and
`is X’.
`(ii) of (i) wherein when R2’ is other than hydrogen and R5’ is hydrogen, R2’ is in the 4-, 5- or 6-position;
`when both R2’ and R5’ are other than hydrogen, at least one of them is in the 5- or 6-position and neither of
`them is in the 7-position; when both R4’ and R5’ are other than hydrogen and R55’ is hydrogen, at least one
`of R4’ and R5’ is in a meta or para position; and when each of R4’, R5’ and R55’ is other than hydrogen, at
`least two of them are in meta or para positions.
`(iii)—(iv) of (i) and (ii) wherein R5 is R5”, especially hydrogen,
`(v)-—(vi) of (i) and (ii) wherein R, is C1_2a|ky|, R2 is R2”, R5 is R3", R4 is R4”, R5 is R5”, R5 is R5”, especially
`hydrogen, R7 is R7”, and X is X”.
`(vii) of (i) wherein R, is C,_5alkyl, R2 is R2”, R5 is R5’”, R4 is R4”’, R5 is R5’”, R5, is hydrogen, R5 is
`hydrogen, R7 is R7”, and X is
`
`H
`
`,
`
`/
`
`\
`
`C=C
`
`\
`
`/
`
`H
`
`(viii)—-(xiii) of (i)—(vi) wherein any salt is a sodium, potassium or ammonium salt,
`(xiv) of Group lAb wherein R1 is R1’, R2 is R2’, R5 is R5’, R4 is R4’, R5 is R5’, R55 is R5,’, R5 is R5’ and X is X,
`(xv) of (xiv) wherein when R2’
`is other than hydrogen and R5’
`is hydrogen, R2’ is in the 4-, 5- or 6-
`position; when both R2’ and R5’ are other than hydrogen, at least one of them is in the 5- or 6—position and
`neither of them is in the 7-position; when both R4’ and R5’ are other than hydrogen and R55’ is hydrogen, at
`least one of R4’ and R5’
`is in a meta or para position; and when each of R4’, R5’ and R55 is other than
`hydrogen, at least two of them are in meta or para positions,
`(xvi)-—(xvii) of (xiv) and (xv) wherein R5 is R5”, especially hydrogen,
`(xviii)—(xix) of (xiv) and (xv) wherein R, is C,_5alky|, R2 is R2”, R5 is R5”, R4 is R4”, R5 is R5”, R5 is R5”,
`especially hydrogen, and X is X”,
`'
`
`5
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`Mylan Exhibit 1025, Page 5
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`Mylan Exhibit 1025, Page 5
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`(xx) of (xiv) wherein R1 is C1_5alkyl, R2 is R2”, R5 is R5”’, R4 is R4”’, R5 is R5”’, R55 is hydrogen, R5 is
`hydrogen, and X is
`
`0 114 027
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`(xxi) of Group |Ba wherein R1 is R1’, R2 is R2’, R5 is R5’, R4 is R4’, R5 is R5’, R55 is R55’, R5 is R5’, R7 is R7’,
`and X is X’.
`
`(xxii) of (xxi) wherein R2’ is other than hydrogen and R5’ is hydrogen, R2’ is in the 4-, 5- or 6-position;
`when both R2’ and R5’ are other than hydrogen, at least one of them is in the 5- or 6-position and neither of
`them is in the 7-position; when both R4’ and R5’ are other than hydrogen and R55’ is hydrogen, at least one
`of R4’ and R5’ is in a meta or para position; and when each of R4’, R5’ and R55’ is other than hydrogen, at
`least two of them are in meta or para positions,
`(xxiii)—(xxiv) of (xxi) and (xxii) wherein R5 is R5”, especially hydrogen,
`(xxv)—(xxvi) of (xxi) and (xxii) wherein R1 is C1_5alkyl, R2 is R2”, R5 is R5”, R4 is R4”, R5 is R5”, R5 is R5”,
`especially hydrogen, R7 is R7”, and X is X”,
`(xxvii)—(xxxii) of (xxi)—(xxvi) wherein any salt is a sodium, potassium or ammonium salt,
`(xxxiii) of Group lBb wherein R1 is R1’, R2 is R2’, R2 is R5’, R4 is R4’, R5 is R5’, R55 is R55’, R5 is R5’ and X is
`
`X’,
`
`(xxxiv) of (xxxiii) wherein when R2’ is other than hydrogen and R5’ is hydrogen,'R2’ is in the 4-, 5- or 6-
`position; when both R2’ and R5’ are other than hydrogen, at least one of them is in the 5- or 6-position and
`neither ofthem is in the 7-position; when both R4’ and R5’ are other than hydrogen and R55’ is hydrogen, at
`least one of R4’ and R5’
`is in a meta or para position; and when each of R4’, R5’ and R55’ is other than
`hydrogen, at least two of them are in meta or para positions,
`(xxxv)—(xxxvi) of (xxxiii) and (xxxiv) wherein R5 is R5”, especially hydrogen,
`(xxxvii)—(xxxviii) of (xxxiii) and (xxxiv) wherein R1 is C1_5a|kyl, R2 is R2”, R5 is R5”, R4 is R4”, R5 is R5”,
`R5 is R5”, especially hydrogen, and X is X”,
`(xxxix)—(lxiii) of (i)—(xiii) and (xxi)—(xxxii) wherein the hydroxy groups in the 3- and 5—positions (of
`the group of formula Ila) have the erythro configuration,
`(lxiv)—-(|xxxviii) the 3R,5S enantiomers of the compounds of (xxxix)-(lxiii) wherein X is
`
`ll
`
`C
`
`0
`
`and the 3R,5R enantiomers of the compounds of these groups wherein X is —(CH2),,,—,
`(|xxxix)—(ci) of (xiv)—(xx) and (xxxiii)—(xxxviii) wherein the hydroxy group on the lactone ring llb is
`trans to X (/'.e., the trans lactones), and
`(cii)—(cxiv) the 4R,6S enantiomers of the compounds of (lxxxix)—-(ci) wherein X is
`
`ll
`
`C
`
`0
`
`and the 4R,6R enantiomers of the compounds of these groups wherein X is —(CH2),,,——.
`Groups (xxxix)—(lxiii) embrace the 3R,5S—-3S,5R racemate and the 3R,5S and 3S,5R enantiomers of
`the compounds wherein X is
`
`(the 3S,5R enantiomer being least preferred) and the 3R,5R———3S,5S racemate and the 3R,5R and 3S,5S
`enantiomers of the compounds wherein X is —(CH2),,,— (the 3S,5S enantiomer being least preferred).
`Groups (|xxxix)—(ci) embrace the 4R,6S—4S,6R racemate and the 4R,6S and 4S,6R enantiomers of the .
`compounds wherein X is
`
`5
`
`Mylan Exhibit 1025, Page 6
`
`70
`
`I5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`
`
`Mylan Exhibit 1025, Page 6
`
`

`
`o 114 027
`
`ll
`
`0
`
`C
`
`(the 4S,6R) enantiomer being least preferred) and the 4R,6R—4S,6S racemate and the 4R,6R and 48,68
`enantiomers of the compounds wherein X is —(CH2)m——— (the 43,68 enantiomer being least preferred).
`In the above-mentioned compound groups (i) to (cxiv)
`those containing a carboxyl group are
`preferably in salt form with a cation free from asymmetric carbon atoms e.g. sodium, potassium or
`ammonium, especially sodium.
`A particular compound group covers those of formula I wherein
`one of R and R0 is
`
` R
`
`5
`
`and the other is C1_3a|ky|, n-butyl or i-butyl,
`wherein
`
`i-butyl, C,_3alkoxy, n-butoxy,
`
`i-butoxy, trifluoromethyl, fluoro,
`
`R4 is hydrogen, C1_3alky|, n-butyl,
`chloro, phenoxy or benzyloxy, and
`R5 is hydrogen, C,_3a|kyl, C1_3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the
`provisos that not more than one of R4 and R5 is trifluoromethyl, not more than one of R4 and R5 is phenoxy,
`and not more than one of R4 and R5 is benzyloxy,
`R3 is hydrogen, C1_3alkyl, n-butyl,
`i-butyl, C,_3alkoxy, n-butoxy,
`chloro, phenoxy or benzyloxy,
`R3 is hydrogen, C,_3a|ky|, C,_3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the
`provisos that not more than one of R3 and R3 is trifluoromethyl, not more than one of R2 and R3 is phenoxy,
`and not more than one of R3 and R3 is benzyloxy,
`R
`X is —(CH3),,— or
`
`i-butoxy, trifluoromethyl, fluoro,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`wherein n is 0, 1, 2 or 3, and
`
`Rs
`.
`Zis —CH—CH3—— C—-CH3——COOR7’ or
`l
`.
`|
`I
`
`OH
`
`CH
`/ 2\
`- H
`
`OH
`
`OH
`
`50
`
`wherein
`
`55
`
`60
`
`R5 is hydrogen or C1_3alky|, and
`R7’
`is hydrogen, C,_3alkyl, n-butyl, i-butyl, t-butyl, benzyl or M, wherein M is a pharamceutically
`acceptable cation.
`The compounds of formula I can be prepared by
`a) when R5 is hydrogen, reducing a compound of formula V
`R
`
`R2
`
`R
`
`3
`
`\
`fit
`R0
`
`X-(‘SH-CH2-ti-CH2-COOR11
`on
`o
`
`V
`
`65
`
`wherein R1, is a radical forming a physiologically-hydrolysable and -acceptable ester and X, R, R0, R3 and R3
`are as defined above.
`
`7 Mylan Exhibit 1025, Page 7
`
`
`
`Mylan Exhibit 1025, Page 7
`
`

`
`b) when R6 = C,_3alkyl, hydrolysing a compound of formula Xll
`
`O 114 027
`
`R
`
`3
`
`R 3
`
`1
`
`R
`
`\
`
`N
`
`la
`
`0
`
`R
`‘6a
`X-(‘SH-CH2-(I3-CH2-COOR11
`E-0
`OH
`
`|-
`R12
`
`XII
`
`wherein R53 is C1_3alky|, R12 is an ester-forming group and X, R, R0, R3 and R11 are as defined above,
`c) when X is —-CH=CH— deprotecting a compound of formula XXV|ll
`
`R‘
`
`R3
`
`R
`
`i \
`N
`I
`R0
`
`0-Pro
`
`H
`
`CH=CH
`
`0
`
`0
`
`-
`
`xxvm
`
`wherein Pro is a protecting group and R, R0, R2 and R3 are as defined above,
`d) hydrolysing a compound of formula I in the form of a physiologically-hydrolysable ester or a lactone
`
`or
`
`e) esterifyig or lactonising a compound of formula l in free acid form, and when a free carboxyl group is
`present, recovering the compound obtained in free acid form or in the form of a salt. In processes a) and b)
`R1,
`is preferably C1_2alkyl, especially methyl, and R12 is preferably C1_3a|ky|, especially C1_2a|ky|,
`in
`particular methyl.
`It will readily be appreciated that the various forms of the compounds of formula I may interconverted
`as indicated in d) and e) above.
`In the same way compounds obtained according to a), b), and c) may be hydrolysed to free acid forms
`and free acids forms may be esterified or lactonised to produce a desired end-product. The invention thus
`also provides a process for preparing a compound of formula I which comprises hydrolysing a compound
`of formula I in ester or lactone form or esterifying or lactonising a compound of formula l in free acid form
`and when a free carboxyl group is present recovering the compound obtained in free acid form or in the
`form of a salt.
`Unless otherwise stated reactions are performed in a manner conventional for the type of reaction
`involved. Molar ratios and reaction times are as a rule conventional and non-critical and are chosen
`according to principles well established in the art on the basis of reactants and conditions employed.
`Solvents, alone or as mixtures, are generally chosen which remain inert and liquid during the reaction
`in question.
`Examples of inert atmospheres are carbon dioxide and-more _usua||y nitrogen or a nobel gas, nitrogen
`being preferred. Most reactions, including those wherein use of an inert atmosphere is not mentioned, are
`carried out under such for convenience.
`
`Reduction according to a) is preferably carried out using a mild reducing agent such as sodium
`borohydride or, preferably, a complex or t-butylamine and borane in an inert organic solvent such as a
`lower alkanol, preferably ethanol, conveniently at a temperature of -10“ to 30°, under an inert atmosphere.
`Use of an optically pure starting material will lead to only two optical isomers (diastereoisomers) of the
`resulting end product. However, if stereospecificity is desired it is preferred to utilize a stereoselective
`reduction in order to maximize production of a mixture of the erythro stereoisomers (racemate) of which
`the preferred stereoisomer (as set forth above) is a constituent. Stereoselective reduction is preferably
`carried out in three steps. For example in the first step, the ketoester of formula V is treated with a
`trilprimary or secondary C2_4a|ky|)borane, preferably triethylborane or tri-n-butylborane, and air to form a
`complex. The reaction temperature is suitably 0° to 50°C, preferably 20° to 30°C. The first step is carried out
`in an anhydrous inert organic solvent, preferably an ether solvent such as tetrahydrofuran, diethyl ether,
`1,2-dimethoxyethane or 1,2-diethoxyethane, with tetrahydrofuran being the most preferred solvent. in the
`second step, for example, the complex is reduced with sodium borohydride, preferably in the same solvent
`as utilized for the first step, at —100° to -—40°C, preferably —90° to —70°C. in the third step, the product of the
`second step is, for example, treated with, preferably, anhydrous methanol at 20° to 40°C, preferably 20° to
`30°C. The amount of methanol is not critical. However, a large excess, e.g., 50—500 moles per mole of _
`ketoester of formula V, is typically utilized.
`
`8
`
`Mylan Exhibit 1025, Page 8
`
`10
`
`I5
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`55
`
`
`
`Mylan Exhibit 1025, Page 8
`
`

`
`O 114 027
`
`Hydrolysis according to b) or d) is carried out in a manner conventional for such reactions e.g.
`employing an inorganic hydroxide such as NaOH or KOH with, if desired, subsequent acidification to give
`the free acid form. Suitable solvents are mixtures of water and water-miscible solvents such as lower
`alkanols e.g. methanol or ethanol and reaction conveniently takes place at temperatures from 20°C to
`reflux, preferably not more than 80°C. If it is desired to recover the compound in a salt form corresponding
`to the cation of the hydroxide employed then slightly less than equivalent amounts of the latter may be
`employed. In b) R12 will conveniently be the same as R11 e.g. C1_3alkyl, especially C1_2alkyl, preferably
`methyl.
`Lactonisation according to e) is carried out in conventional manner e.g. by heating the corresponding
`acid in an anhydrous inert organic solvent e.g. a hydrocarbon such as benzene, toluene or a xylene or
`mixtures thereof, preferably at temperatures of 75°C to relfux although more preferably not above 150°C.
`Preferably, however, a lactonisation agent, e.g. a carbodiimide, preferably a water-soluble carbodiimide
`such as N-cyclohexyl-N’-[2-(N"-methylmorpholiniumlethyllcarbodiimide p-toluenesulfonate,
`in
`an
`anhydrous inert organic solvent, e.g., a halogenated lower alkane, preferably methylene chloride,
`is
`employed. Reaction temperatures then lie typically between 10° and 35°C, especially 20° to 30°C.
`As is evident to those in the art, a racemic threo 3,5-dihydroxycarboxylic acid yields a racemic cis
`lactone and a racemic erythro 3,5-dihydroxycarboxylic acid yields a racemic trans lactone. Use of a mixture
`of three and erythro 3,5-dicarboxylic acid yields a mixture of cis and trans lactones (all four possible
`diastereoisomers). Likewise, if a single enantiomer of the 3,5-dihydroxycarboxylic acid is utilized, a single
`enantiomer of the lactone is obtained. For example,
`lactonisation of a 3R,5S erythro-3,5-dihydroxy-
`carboxylic acid yields a 4R,6S lactone.
`Esterification according to e) is conventional employing e.g. a large excess of a compound RHOH,
`wherein R1, is as defined above, at 20°C to 40°C in the presence of a catalytic amount of an acid such as p-
`toluenesulfonic acid. Where methyl esters are required these can also be obtained e.g. using diazomethane
`in an anhydrous inert ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or 1,2-diethoxyethane
`and especially diethylether at e.g. 0° to 30°C, preferably 20° to 30°C.
`Examples of protecting groups in reaction c) are diphenyl-t-butylsilyl, tri-isopropylsilyl, dimethy|-t-
`butylsilyl, C,_5n-alkyl, benzyl,
`triphenylmethyl,
`tetrahydrofuran-2-yl,
`tetrahydropyran-2-yl, 4-methoxy-
`tetrahydorpyran-2-yl and C,_6n-alkanoyloxy. Especially preferred are trisubstituted silyl
`radicals,
`in
`particular diphenyl-t-butylsilyl.
`Deprotection is carried out in conventional manner e.g. by cleavage under mild conditions such as
`employing e.g. for removal of a silyl group such as diphenyl-t—butylsily| a fluoride reagent e.g. tetra-n-
`butylammonium fluoride in an anhydrous inert organic medium, preferably tetrahydrofuran containing
`glacial acetic acid at temperatures of 20° to 60°C, especially 20° to 30°C. Preferably 1-4 moles of fluoride
`are used per mole of silyl group with 1.2 to 1.8 moles of glacial acetic acid to each mole of fluoride.
`The required starting materials may be prepared for example as illustrated in the following reaction
`schemes. The symbols used are defined as follows:
`R, R0, R1, R2, R3, R4, R5, R53, R6, Rea, R11, R12, X = as defined above,
`Rm = C,_3a|kyl, preferably C,_2alkyl
`Y = halogen, preferably chloro or bromo, more preferably chloro
`Ac = acetyl
`q: = phenyl
`+ = t-butyl
`lac =
`
`?§“5
`O-%1- t-C4H9
`°5”s
`
`H
`
`o
`
`H
`
`on
`
`[on=OCH3(XXVl), OH(XXVl|) or =O(XXVl||)]
`
`10
`
`75
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`9
`
`Mylan Exhibit 1025, Page 9
`
`
`
`Mylan Exhibit 1025, Page 9
`
`

`
`32::e.<x_x.c:u-:uuamAm=euv+
`
`0 114 027
`
`x_xmaace;x
`
`xxmm-=uu=u-uxzmgx
`
`ax_xxmumA~=u.uxgmgz
`
`
`ux_xxmuN.~mu.uxcog:
`mx_xxwezunxgag:.
`
`Au__xxVo:uz~.~_z.
`
`+.m__xx.m>o¢+
`
`ozu=Ag__xx./unux
`
`:\/z~A-.¢.
`
`
`
`+.m__xx.>o;+
`
`«mm
`
`mg.1
`
`2~_¢oou//_
`
`_xx=mm
`
`mg
`
`
`
`_—zuom:w;zVTK+@
`
`
`
`uzuzumzo_pu<u¢
`
`2.x_xmax“.me=c~=,/
`
`z
`
`___>x
`
`2~_zoou//_
`
`om__>x_ma.
`
`Nzz
`
`10
`
`Mylan Exhi
`
`it 1025, Page 10
`
`
`
`Mylan Exhibit 1025, Page 10
`
`
`
`
`

`
`.;.c..N81=3._.cn.53..:ou.3£5uu._¢
`
`
`:8...£+\n.wmLmuT®‘_815_N:5.
`
`
`mN2.33.
`N3.81:3N2:NNNNN23,.W.N«II;NNNN@3..N3@._.5/_
`NN
`>5.o
`
`o.2;
`
`N
`
`:~.cou-~:o-u:~:ou:u-x/_
`wNoN
`
`NNN
`
`Oz>M_N
`
`0 114 027
`
`._NNnN_+|I|1_.=aN.NN$_as.N3/mg/NNzz
`o..NNxcc.Ne..NN
`NN_¢|.®I.25.5/
`
`N_N
`
`O
`
`Ne.:.N_N.
`
`N.
`
`.....N:N
`
`..No8NNN-N-NNN-Nu-N/_..No8..NN+
`N......NAullllll...
`nm..-m..-N=u-:w-x/_so.8N?
`...N:.NN%N“..._NN.N..NNALBIFNN.
`
`N...
`
`SNN<:.NN
`
`Nz¢
`
`5.
`
`N
`
`NN
`
`N_..N...NNN-N-NNN-NN-N/_
`
`aN
`
`
`
`:uzurumN.:5<NN
`
`“
`
`Mylan Exhibit 1025, Page 11
`
`
`
`Mylan Exhibit 1025, Page 11
`
`
`
`
`

`
`Two isomers of the compound of formula XXV may be synthesized by the following series of
`reactions:
`
`0 114 027
`
`Reaction Scheme lll
`
`H
`
`ACO
`AC H
`
`(CUH
`
`3 e..___’‘5
`
`H
`
`H
`
`(CV)
`H
`
`”
`
`0/
`
`AF
`
`ca
`
`H
`OCH3
`W
`
`H
`
`0”
`(CV1)
`
`H
`OCH3
`
`AB
`Ac "" Ho
`
`H
`
`0
`
`C93
`«fl.
`
`H
`
`”
`A‘
`H0 H
`
`H Hg)/WDH
`H
`H0
`locH3
`H
`
`H
`OCH3
`OH
`
`H
`OCH3
`
`(CII)
`
`(CH1)
`
`(cvm
`
`)
`
`3
`
`AG
`_‘—_’
`
`H
`
`(cIv)°°“3
`W3
`————>A“
`H
`H.
`0 :
`zzsio
`92510
`4’ (CVII) C 3
`
`(CXI)
`
`H0
`
`H
`
`OCH3
`
`AG‘
`
`
`gc¢3
`'
`(cm) fl2SiO
`4
`H
`OCH3
`
`W3
`
`+
`
`H
`
`0H
`
`3
`
`oca
`
`o
`H
`CH3
`
`(CV1)
`
`AH‘
`“9
`
`-
`
`+
`
`0
`
`OH
`”25‘°% (CXIII‘
`H
`OCH3
`Ari
`
`)
`
`CHO
`
`9S1‘0
`
`2;
`
`H
`
`06:3
`
`(cxxv)
`
`Unless othen/vise stated reactions are performed in a manner conventional for the type of reaction
`involved. Mol ratios and reaction times are as a rule conventional and non-critical and are chosen
`according to principles well established in the art on the basis of reactants and conditions employed.
`Solvents, alone or as mixtures, are generally chosen which remain inert and lqiuid during the reaction
`in question. i
`Examples of inert atmospheres are carbon dioxide and more usually nitrogen, helium, neon, argon or
`krypton, nitrogen being preferred. Most reactions, including those wherein