1191
`United States Patent
`4,613,610
`[11] Patent Number:
`[45] Date of Patent:
`Wareing
`Sep. 23, 1986
`
`
`
`wherein
`
`R1 is C1-5a1kyl not containing an asymmetric carbon
`atom,
`
`each of R2 and R5 is independently hydrogen, C1.3al-
`kyl, n-butyl, i-butyl, t-butyl, C1-3alkoxy, n-butoxy,
`i-butoxy, trifluoromethyl, fluoro, chloro, phenyl,
`phenoxy or benzyloxy,
`each of R3 and R5 is independently hydrogen, C1.3al—
`kyl, C1.3alkoxy,
`trifluoromethyl,
`fluoro, chloro,
`phenoxy or benzyloxy,
`each of R4 and R7 is independently hydrogen, C1.2al-
`kyl, C1.2alkoxy, fluoro or chloro, with the provisos
`that not more than one of R3 and R3 is trifluoro-
`methyl, not more than one of R2 and R3 is phenoxy,
`not more than one of R2 and R3 is benzyloxy, not
`more than one of R5 and R5 is trifluoromethyl, not
`more than one of R5 and R6 is phenoxy, and not
`more than one of R5 and R5 is benzyloxy,
`is —(CH2),,,—, —CH=CH—, —CH=
`CH——CH2— or —CH2--CHiH—, wherein m is
`0,1,2 or 3, and
`Z is
`
`X
`
`$10
`—C1-1—C1-1;--C—C1-12—COOR11or
`I
`I
`on
`on
`
`---CH
`I
`0
`
`C
`|\Rw.
`CH2
`
`wherein R10 is hydrogen or C1-3a1kyl, wherein
`R1; is a physiologically acceptable and hydrolyz-
`able ester group, and
`M is a pharmaceutically acceptable cation,
`with the provisos that (i) the—X—Z group is in the 4-
`or 5-position of the pyrazole ring, and (ii) the R1 group
`and the —-X-—Z group are ortho to each other,
`the use thereof for inhibiting cholesterol biosynthesis
`and lowering the blood cholesterol level and, therefore,
`in the treatment of hyperlipoproteinemia and athero-
`sclerosis, pharmaceutical compositions comprising such
`compounds and processes for and intermediates in the
`synthesis of such compounds.
`
`27 Claims, No Drawings
`
`Mylan Exhibit 1018, Page 1
`
`[54] CHOLESTEROL BIOSYNTHESIS
`INHIBITING PYRAZOLE ANALOGS OF
`MEVALONOLACTONE AND ITS
`DERIVATIVES
`
`[75]
`
`Inventor:
`
`James R. Wareing, Randolph, N.J.
`
`[73] Assignee:
`
`Sandoz Pharmaceuticals Corp., E.
`Hanover, N.J.
`
`[21] Appl. No.2 741,903
`
`[22] Filed:
`
`Jun. 6, 1985
`
`Related U.S. Application Data
`
`[63]
`
`Continuation-in-part of Ser. No. 623,393, Jun. 22, 1984,
`abandoned.
`
`[51]
`
`Int. cu ................ .. A61K 31/415; C07D 231/12;
`C07D 405/06
`[52] U.S. c1. .................................. .. 514/406; 548/374;
`548/378
`[58] Field of Search ............... .. 548/374, 378; 514/406
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`........................ .. 549/292
`3,983,140 9/1976 Endo et al.
`.
`549/292
`4,198,425
`4/1980 Mitsui et al.
`4,248,889
`2/1981 Oka et al.
`. . . ..
`. . . . .. 560/56
`4,255,444
`3/1981 Oka et al.
`.
`549/292
`4,308,378 12/1981 Stokker
`549/292
`4,351,844 9/1982 Patchett et al.
`549/292
`4,361,515 11/1982 Terahara et al.
`549/292
`4,375,475
`3/1983 Willard et al.
`549/292
`4,376,863
`3/1983 Lam .................
`549/292
`4,387,242
`6/1983 Lam
`.. 560/119
`4,440,927 4/1984 Prugh .......
`5... 549/292
`.. 549/214
`4,474,971 10/1984 Wareing ..... ..
`..
`.................. .. 514/529
`4,503,072
`3/1985 Hoffman et al.
`FOREIGN PATENT DOCUMENTS
`
`
`
`.
`
`4/1983 Belgium ............................ .. 549/292
`895445
`.. 549/292
`3806] 10/1981 European Pat. Off.
`.
`..
`
`.. 549/292
`68038
`1/1983 European Pat. Off.
`.
`..
`549/292
`56-7775
`1/1981
`Japan ..................... ..
`W084/02131
`6/1984 PCT Int’l Appl.
`..
`548/467
`W084/02903
`8/1984 PCT Int’l Appl.
`............... .. 549/292
`
`OTHER PUBLICATIONS
`
`Hulcher, Arch. Biochem. Biophys. 146, 422-427 (1971).
`Sato et al., Chem. Pharrn. Bull. 28, 1509-1525 (1980).
`Singer et al., Proc. Soc. Exp. Biol. Med. 102, 370-373
`(1959).
`
`Primary Examiner—-Richard A. Schwartz
`Assistant Exam1'ner—Kurt G. Briscoe
`Attorney, Agent, or Firm—-Gerald D. Sharkin; Richard
`E. Vila; Melvyn M. Kassenoff
`
`[57]
`
`ABSTRACT
`
`Compounds of the formula
`
`Mylan Exhibit 1018, Page 1
`
`

`
`1
`
`4,613,610
`
`2
`
`of Formula I and the use of the compounds of Formula
`I for inhibiting cholesterol biosynthesis and lowering
`the blood cholesterol level and, therefore, in the treat-
`ment of hyperlipoproteinemia and atherosclerosis.
`By the term “physiologically acceptable and hydro-
`lyzable ester group” is meant a group which, together
`with the —COO— radical to which it is attached, forms
`an ester group which is physiologically acceptable and
`hydrolyzable under physiological conditions to yield a
`compound of Formula I wherein R11 is hydrogen and
`an alcohol which itself is physiologically acceptable,
`i.e., non-toxic at the desired dosage level, and which,
`preferably, is free of centers of asymmetry. Examples of
`such groups are C1-3alkyl, n-butyl, i-butyl, t-butyl and
`benzyl, collectively referred to as R12’.
`For the avoidance of doubt, throughout this applica-
`tion it is the right-hand side of the X radical that is
`attached to the Z group.
`The compounds of Formula I may be divided into
`four groups, viz., those of Formulae IA, IB, IC and ID:
`
`(IA)
`
`(U3)
`
`(IC)
`
`
`
`R3
`
`R4
`
`R]
`
`\ N
`
`x-z
`
`R7
`
`x—z
`
`\ N
`
`R1
`
`I N
`
`R6
`
`l N
`
`R3
`
`R6
`
`R2
`
`R5
`
`Mylan Exhibit 1018, Page 2
`
`CHOLESTEROL BIOSYNTHESIS INHIBITING
`PYRAZOLE ANALOGS OF MEVALONOLACTONE
`AND ITS DERIVATIVES
`
`This application is a continuation—in-part of applica-
`tion Ser. No. 623,393, filed June 22, 1984 and now aban-
`doned.
`
`This invention relates to compounds of the formula
`
`(I)
`
`
`
`wherein
`R1 is C1.5alkyl not containing an asymmetric carbon
`atom,
`each of R2 and R5 is independently hydrogen, C1.3al-
`kyl, n-butyl, i-butyl, t-butyl, C1-3alkoxy, n-butoxy,
`i-butoxy, trifluoromethyl, fluoro, chloro, phenyl,
`phenoxy or benzyloxy,
`each of R3 and R6 is independently hydrogen, C1.3al-
`kyl, C1.3alkoxy,
`trifluoromethyl,
`fluoro, chloro,
`phenoxy or benzyloxy,
`each of R4 and R7 is independently hydrogen, C1.2al-
`kyl, C1-2alkoxy, fluoro or chloro, with the provisos
`that not more than one of R2 and R3 is trifluoro-
`methyl, not more than one of R2 and R3 is phenoxy,
`not more than one of R2 and R3 is benzyloxy, not
`more than one of R5 and R5 is trifluoromethyl, not
`more than one of R5 and R6 is phenoxy, and not
`more than one of R5 and R6 is benzyloxy,
`is —(CH2),,,—, —CH=CH—, —-CH:
`CH—CH2— or —CH2—CH=CH—, wherein m is
`0,1, 2 or 3, and
`
`X
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`R10
`5
`3 I
`z is —c|:H—cH2—<|:—cH3—cooR1,
`OH
`OH
`
`or
`
`OH
`
`CH;
`6/ \4/
`c
`-CH
`‘Rio
`I
`I‘
`0
`CH2
`
`\/c
`H0
`
`wherein R10 is hydrogen or C1.3alkyl, and R11 is
`hydrogen, R1; or M, wherein
`R12 is a physiologically acceptable and hydrolyz-
`able ester group, and
`M is a pharmaceutically acceptable cation,
`with the provisos that (i) the —X—Z group is in the 4-
`or 5-position of the pyrazole ring, and (ii) the R1 group
`and the —X—Z group are ortho to each other,
`processes for and intermediates in the synthesis thereof,
`pharmaceutical compositions comprising a compound
`
`(:1)
`
`45
`
`SO
`
`(b)
`
`55
`
`60
`
`65
`
`
`
`
`
`Mylan Exhibit 1018, Page 2
`
`

`
`4,613,610
`
`(ID)
`
`3
`-continued
`R5
`
`
`
`R3
`
`The compounds of each of Groups IA—ID may be
`divided into two subgroups based upon the significance
`of Z, viz., Group IAa (the compounds of Group IA
`wherein Z is a group of Formula a), Group IAb (the
`compounds of Group IA wherein Z is a group of For-
`mula b), Group IBa (the compounds of Group IB
`wherein Z is a group of Formula a), Group IBb (the
`compounds of Group IB wherein Z is a group of For-
`mula b), Group ICa (the compounds of Group IC
`wherein Z is a group of Formula a), Group ICb (the
`compounds of Group IC wherein Z is a group of For-
`mula b), Group IDa (the compounds of Group ID
`wherein Z is a group of Formula a) and Group ID}: (the
`compounds of Group ID wherein Z is a group of For-
`mula b).
`As is self-evident to those in the art, each compound
`_p of Formula I (and every subscope and species thereof)
`has two centers of asymmetry (the two carbon atoms
`bearing the hydroxy groups in the group of Formula a
`and the carbon atom bearing the hydroxy group and the
`carbon atom having the free valence in the group of
`Formula b) and, therefore, there are four stereoisomeric
`forms (enantiomers) of each compound (two racemates
`or pairs of diastereoisomers), provided that R11 does not
`contain any center of asymmetry. The four stereoiso-
`mers 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. When R11 contains one or more
`centers of asymmetry, there are eight or more stereoiso-
`mers. Since it is preferred that R11 not contain a center
`of asymmetry and for reasons of simplicity any addi-
`tional stereoisomers resulting from the presence of one
`or more centers of asymmetry in R11 usually will be
`ignored, it being assumed that R11 is free of centers of
`asymmetry.
`R1 is preferably R1’, where R1’ is C1-3alkyl, n-butyl or
`i-butyl, more preferably R1", where R1” is C1-3alkyl,
`and most preferably isopropyl.
`R2 is preferably R2’, where R2’ is hydrogen, C1-3alkyl,
`C1-3a1koxy,
`trifluoromethyl,
`fluoro or chloro, more
`preferably R2”, where R2” is hydrogen or fluoro, and
`most preferably hydrogen.
`R3 is preferably R3’, where R3’ is hydrogen, C1.2alkyl,
`C1-2alkoxy, fluoro or chloro, and most preferably hy-
`drogen.
`Is hydrogen or
`R4 is preferably R4’, where R4’
`methyl, and most preferably hydrogen.
`The R2-bearing phenyl group is preferably unsubsti-
`tuted.
`
`R5 is preferably R5’, where R5’ is hydrogen, C1.3a.lkyl,
`C1.3alkoxy,
`trifluoromethyl,
`fluoro or chloro, more
`preferably R5”, where R5” is hydrogen or fluoro, and
`most preferably fluoro.
`R5 is preferably R5’, where R6’ is hydrogen, C1-2alkyl,
`C1-2all<oxy, fluoro or chloro, more preferably R5”,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`where R5" is hydrogen or methyl, and most preferably
`hydrogen.
`is hydrogen or
`R7 is preferably R7’, where R7’
`methyl, and most preferably hydrogen.
`Preferably, when two of R5 (R5’, etc.), R5 (R5’, etc.)
`and R7 (R7’, etc.) are other than hydrogen and one is
`hydrogen, at least one of the two that are other than
`hydrogen is in a meta or para position and not more
`than one of them is a member of the group consisting of
`t-butyl,
`trifluoromethyl, phenyl, phenoxy and ben-
`zyloxy; more preferably, the two that are other than
`hydrogen are not ortho to each other when neither of
`them is a member of the group consisting of methyl,
`methoxy, fluoro and chloro.
`Preferably, when each of R5 (R5’, etc.), R5 (R5’, etc.)
`and R7 (R7’, etc.) is other than hydrogen, at least two of
`them are in meta or para positions, and not more than
`one of them is a member of the group consisting of
`t-butyl,
`trifluoromethyl, phenyl, phenoxy and ben-
`zyloxy; more preferably, no two of them are ortho to
`each other unless at least one member of each pair of
`substituents that are ortho to each other is a member of
`the group consisting of methyl, methoxy, fluoro and
`chloro.
`
`is hydrogen or
`
`The R5-bearing phenyl group is preferably 4-
`fluorophenyl or 3,5-dimethylphenyl, preferably the
`former.
`R10 is preferably R10’, where R10’
`methyl, and most preferably hydrogen.
`R11 is preferably R11’, where R11’ is hydrogen, R12’ or
`M, more preferably R11”, where R11” is hydrogen,
`C1.3alkyl or M, even more preferably R11”’, where
`R11"’ is hydrogen, C1-2alkyl or M, and most preferably
`M, especially sodium.
`is C1.3alkyl, n-
`R12 is preferably R12’, where R12’
`butyl, i-butyl, t-butyl or benzyl, more preferably C1-3al-
`kyl, and most preferably C1-2alkyl, especially ethyl.
`Any —CH=CH—, ——CH=CH—CH2— or —CH-
`2—CH=CH— as X is preferably trans, ie., (E).
`X is preferably X’, where X’
`is —CH2CH2— or
`——CH—_—CH——, more preferably —CH:CH—, and
`most preferably
`
`(i.e., (E)—CH:CH—).
`Z is preferably a group of Formula a wherein R10 is
`R10’ (especially hydrogen), and R11 is R11’ or a group of
`Formula b, more preferably a group of Formula a
`wherein R10 is hydrogen, and R11 is R11” or a group of
`Formula b, even more preferably a group of Formula 21
`wherein R10 is hydrogen, and R11 is R11”’ or a group of
`Formula b, and most preferably a group of Formula a
`wherein R10 is hydrogen, and R11 is M (especially so-
`dium).
`m is preferably m’, where m’ is 2 or 3, most preferably
`
`2.
`
`M is preferably free from centers of asymmetry and is
`more preferably M’, i.e., sodium, potassium or ammo-
`nium, and most preferably sodium. For simplicity, each
`formula in which M appears has been written as if M
`were monovalent and, preferably, it is. However, it may
`also be divalent or trivalent and, when it is, balances the
`charge of two or three carboxy groups, respectively.
`
`Mylan Exhibit 1018, Page 3
`
`
`
`Mylan Exhibit 1018, Page 3
`
`

`
`5
`Thus, Formula "I and every other formula containing an
`M embraces compounds wherein M is divalent or triva-
`lent, i.e., compounds containing two or three carboxy-
`late-containing anions per cation M.
`As between otherwise identical compounds of For-
`mula 1, those wherein Z is a group of Formula a are
`generally preferred over those wherein Z is a group of
`Formula b.
`
`5
`
`15
`
`Insofar as the compounds of Groups IAa, IBa, ICa 10
`and IDa and each of the subgroups thereof are con-
`cerned, the erythro isomers are preferred over the threo
`isomers, erythro and threo referring to the relative posi-
`tions of the hydroxy groups in the 3- and 5-positions of
`the group of Formula a.
`Insofar as the compounds of Groups IAb, IBb, ICb
`and IDb and each of the subgroups thereof are con-
`cerned, the trans lactones are generally preferred over
`the cis lactones, cis and trans referring to the relative 20
`positions of R10 and the hydrogen atom in the 6-position
`of the group of Formula b.
`The preferred stereoisomers of the compounds of
`Formula I having only two centers of asymmetry
`wherein X is a direct bond, —CH=CH— or —-CH-
`2-—CH=CH——, and Z is a group of Formula a are the
`3R,5S isomer and the racemate of which it is a constitu-
`ent, i.e., the 3R,5S-3S,5R (erythro) racemate.
`The preferred stereoisomers of the compounds of 30
`Formula I having only two centers of asymmetry
`wherein X is —CH2—, —CH2CH2—, —CH2CH2C—
`H2— or -—CH=CI-I-—CH2—, and Z is a group of For-
`mula a are the 3R,5R isomer and the racemate of which
`it is a constituent, i.e., the 3R,5R-3S,5S (erythro) race- 35
`mate.
`
`25
`
`The preferences set forth in the preceding two para-
`graphs also apply to the compounds of Formula I hav-
`ing more than two centers of asymmetry and represent 40
`the preferred configurations of the indicated positions.
`The preferred stereoisomers of the compounds of
`Formula I wherein X is a direct bond, —CH=CH— or
`—CH2—CH=CH—, and Z is a group of Formula b are
`the 4R,6S and 4R,6R isomers and the racemate of 45
`which each is a constituent, i.e., the 4R,6S-4S,6R (trans
`lactone) and 4R,6R-4S,6S (cis lactone) racemates, with
`the 4R,6S isomer and the racemate of which it is a con-
`stituent being more preferred and the 4R,6S isomer
`being most preferred.
`The preferred stereoisomers of the compounds of
`Formula I wherein X is —CH2—, ——CH2CH2——,
`—CH2CH2CH2—- or -—-CH=CH-—CH2—, and Z is a
`group of Formula b are the 4R,6R and 4R,6S isomers
`and the racemate of which each is a constituent, i.e., the
`4R,6R-4S,6S (trans lactone) and 4R,6S-4S,6R (cis lac-
`tone) racemates, with the 4R,6R isomer and the race-
`mate 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, 1B, 1C and ID and those of
`Groups IAa, IAb, IBa, IBb, ICa, ICb, IDa and IDb as 65
`well as to every other subgroup thereof set forth in the
`specification, e.g., Groups (i) et seq., unless otherwise
`indicated. When any preference or group contains a
`
`55
`
`60
`
`50
`
`4,613,610
`
`6
`the preferred significances of that variable
`variable,
`apply to the preference in question, unless otherwise
`indicated.
`
`Preferred groups of compounds of Formulae IAa and
`IAb include the compounds
`(i) of Group IAa wherein R1 is R1’, R2 is R2’, R3 is R3’,
`R4 is R4’, R5 is R5’, R6 is R6’, R7 is R7’, R1ois R10’,
`R11 is R11’, and X is X’,
`(ii) of (i) wherein R2 is R2", R3 is hydrogen, R4 is
`hydrogen, R5 is R5", R6 is R6", R10 is hydrogen,
`R11 is R11”, and X is (E)——CH:CH—,
`(iii) of (ii) wherein R1 is R1”,
`(iv)—(vi) of (i)—(iii) wherein R11 is M, especially so-
`dium,
`(vii)—(xii) of (i)—(vi) wherein the hydrogen groups in
`the 3- and 5-positions of the group of Formula a
`have the erythro configuration.
`(xiii)—(xviii) the 3R,5S enantiomers of the compounds
`of (vii)—(xii) wherein X is -—CH=CH— and the
`3R,5R enantiomers of those wherein X is ——CH2C-
`H2—,
`(xix) of Group IAb wherein R1 is R1’, R2 is R2’, R3 is
`R3’, R4 is R4’, R5 is R5’, R6 is R6’, R7 is R7’, R10 is
`R10’, and X is X’,
`(xx) of (xix) wherein R2 is R2”, R3 is hydrogen, R4 is
`hydrogen, R5 is R5”, R6 is R6”, R10 is hydrogen,
`and X is (E)—CH=CH—,
`(xxi) of (xx) wherein R1 is R1”,
`(xxii)—(xxiv) of (xix)—(xxi) wherein R10 and the hydro-
`gen atom in the 6-position of the group of Formula
`b are trans to each other (i.e., the trans lactones),
`and
`
`the 4R,6S enantiomers of the com-
`(xxv)—(xxvii)
`pounds of (xxii)—(xxiv) wherein X is -—CH=CH—
`and the 4R,6R enantiomers of those wherein X is
`—CH2CH2-—.
`Groups (viii)-(xii) embrace the 3R,5S-3S,5R race-
`mate and the 3R,5S and 3S,5R enantiomers, the 3S,5R
`enantiomer being least preferred.
`Groups (xxiii) and (xxiv) embrace the 4R,6S-4S,6R
`racemate and the 4R,6S and 4S,6R enantiomers, the
`4S,6R enantiomer being least preferred.
`Insofar as Groups IBa, IBb, ICa, ICb, IDa and IDb
`are concerned, the preferred subgroups are those that
`correspond to Groups (i)—(xxvii). As should be self-evi-
`dent,
`the preferred groups of compounds of Groups
`IBa, ICa and IDa are those that correspond to Groups
`(i)—(xviii),
`i.e., Groups (xxviii)—(xlv), (lv)-(lxxii) and
`(lxxxii)—(xcix), respectively, and the preferred groups of
`compounds of Groups IBb, ICb and IDb are those that
`correspond to Groups (xix)—(xxvii), i.e., Groups (xlvi-
`)—(liv), (lxxiii)—(1xxxi) and (c)—(cviii), respectively.
`The compounds of Formula I may be synthesized as
`follows:
`
`Reaction Scheme I
`
`The compounds of Formula I wherein X is —CH=
`CH— and Z is a group of Formula b having the 4R,6S
`configuration or X is —CH2CH2—— and Z is a group of
`Formula b having the 4R,6R configuration may be
`synthesized by the following series of reactions:
`
`Mylan Exhibit 1018, Page 4
`
`
`
`Mylan Exhibit 1018, Page 4
`
`
`
`
`
`

`
`4,613,610
`
`_
`Py CH2Y + (CeH5)3P
`(II)
`
`A
`
`_
`>Py CH2
`
`e________I3____.\
`_@
`P(C6H5)3Y msmg Base
`/
`2
`(III)
`‘
`)
`
`c(,H5
`
`H,/0
`
`OR-—?i"'§-C4H9
`C6H5(1v)
`
`H
`5 °
`HC
`
`-o
`
`('3aH5
`OR—*Sl3i—§-C4H9
`C5H5
`
`H’,/0
`
`-0
`
`0
`
`(V)
`
`D H
`.
`
`2
`
`H
`Py—CH=CI-i“ s
`
`
`
`Desilylation
`reagent
`
`#
`
`H/////
`
`OH
`
`$6115
`R
`H’//,/ Oj?i—L-C4H9
`C5H5
`
`H
`Py—CH=cH“\ s
`
`o
`
`-0
`
`H
`Py—CH2CH2“\\\R 0
`
`-o
`
`(VII)
`
`E
`
`Desilylation reagent
`
`#
`
`H'/,// OHR
`
`H
`Py—CHgCHg>\\\\R
`
`-0
`
`(VIII)
`
`H
`S h
`.
`R
`C ems
`Cacao“
`The compounds of Formula I wherein X is —CH2C-
`H2—, —CH2CH2CH2—, —CH:CH—, —CH:
`
`CH—CH2— or -CH2—CH=CH—, and Z is a group
`45 of Formula a wherein R11 is R12’ may be synthesized by
`the following series of reactions:
`
`F
`99
`PY"X1-P(C6Hs)3Ye
`(IX)
`W
`$10
`(2) H—C-X2-(IIH
`CH2—lC—CHg—C00R'12
`O
`O
`|_
`I‘
`C5H5-S1—C5H5 C5}-I5-S1-C5H5
`I
`I
`L-C4H9
`t.-C4H9
`
`(X)
`
`Py—X3—(|3H
`0
`I
`C5H5—?i—C5H5
`I.~C4H9
`
`Ilho
`$10
`,
`G
`.
`CH2'——(II—CHz—COOR12 Py—X3—$H—CH2"—$"'CH2"’COOR12
`0
`reagent
`OH
`on
`I
`C(,H5—Si—C(~,H5
`L-C4H9
`
`(X11)
`
`(XI)
`H H2
`
`V
`
`Mylan Exhibit 1018, Page 5
`
`
`
`
`
`Mylan Exhibit 1018, Page 5
`
`

`
`9
`
`4,613,610
`
`-continued
`
`10
`
`Illio
`Py-X4-CH—Cl-I2-C-CH2-COORIZ
`I
`I
`'
`OH
`OH
`
`(XIV)
`
`Py-X4—CI-I
`I
`‘I’
`C6!-I5-Si—C5H5
`I-C4H9
`
`RIO
`I
`CH2--C-CH2—COOR'I2
`I
`‘I’
`C61-I5—Si—Cg,H5
`I
`L-C4H9
`
`
`
`D°5“>"““°"
`reagent
`
`(XIII)
`
`Reaction Scheme III
`
`15
`
`Reaction Scheme IV
`
`The compounds of Formula I wherein X is —(CI-I2.
`),,,- or (E)-CH:CH——, and Z is a group of Formula
`a wherein Rmis hydrogen, and R11 is R12’ or R10 is R101,
`and R11 is M239 may be synthesized by the following
`series of reactions:
`
`The compounds of Formula I wherein Z is a group of
`Formula a wherein R11 is R12’ or a group of Formula b
`may be converted into the corresponding compounds of
`Formula I wherein Z has a different significance by the
`20 following series of reactions:
`
`Py—X5—CHO Py—x5—CH—CH2—C—CH2—cOOR32
`(1) CI-l3COCH2COORI2 (XIX) +
`|
`[|
`(XV)
`Strong base
`OH
`0 (xx)
`(2) Aldehyde Of Formula XV
`
`L
`
`(1) CH3COR1o,, (XVI) +
`Strong base
`(2) Aldehyde of
`Formula XV
`
`K Mild reducing
`agent
`
`P)!‘X5—$H’CH2“?H“'CH2‘C00RI2
`OH
`OH
`(XXI)
`
`N
`M
`.
`Py-X5-CH-CH2-C-R100 ——————————->Py—x5-cH—cH2—C—R1o,, ———-—————-———9
`|
`u
`(R13-C0)2O (XVIIA)
`1
`||
`(1) CH3—COOR14(XVIID) +
`OH
`0
`or R13-CO—Y (XVIIB)
`CI’
`0
`Strong base
`__
`(2) Compound of
`$"'° (XVUC)
`Formula XVIIC
`R13
`
`(XVII)
`
`lliloa
`lllioa
`I=y—x5—cH-—cHg—c—cH1—cOOR14 Py—X5—CH—CH2—C—CH2-C009 M369
`I
`I
`I
`M2
`0“
`I
`‘O
`OH
`(XXIII)
`OH
`OH
`O=O
`(XVIIE)
`R13
`
`(XVIII)
`
`I|{1o
`lilo
`Py—X—CH-CH2-C-CH2-C00R'12 Py—X—CH—CH2—C--CH2-COO9M2@ —P—9
`I
`I
`I
`M2$9OH (XXIII)
`I
`Has
`OH
`OH
`OH
`OH
`
`(XXII)
`
`(XXIV)
`
`lilio
`Fliio
`I=y—x—<|:H-cH2—<l:—cH2—cooH Py—x—cH—cH;—c—cH2—cOOeM<B
`OH
`OH
`(XXVI)
`OH
`OH (xxvn)
`(XXV)
`
`S
`
`A or
`Lactonization
`agent
`
`P
`
`H93
`
`Mylan Exhibit 1018, Page 6
`
`Mylan Exhibit 1018, Page 6
`
`
`
`

`
`M
`
`4,613,610
`
`-continued
`
`112
`
`R10
`
`H
`Py—X
`
`OH
`
`0
`(Xxx)
`
`R10
`—le——->I>y—x—cII—cII;-C-—cH2—coo6M2€9
`=0 M293 0“
`I
`I
`(XXIII)
`OH
`OH
`(XXIV)
`
`Q M29eOR1;
`
`(XXVIII)
`
`V
`
`Ilho
`Py—X—Cl3H—CH2—(|:—CH2—COOR12
`OH
`OH
`(XXIX)
`
`Reaction Scheme V
`
`The compounds of Formulae II and CCI wherein Py
`is PyA may be synthesized by the following series of
`25 reactions:
`
`R6
`
`R7
`
`R5
`
`R4
`
`R2
`
`cHg—c
`II
`0
`
`(XXXIII)
`
`R3
`
`——”=L-——>
`R1—NHNH2
`
`(XXXIV)
`
`CH2Y ———i——-——>
`(1) Mg
`R
`
`R4
`
`3
`
`(2)
`
`CN
`(XXXII)
`
`(3) H59
`
`R2
`
`R4
`
`R7
`
`Re
`
`R5
`
`(XXXI)
`
`R7
`
`R5
`
`R5
`
`R3
`
`CH —C
`2
`1|
`If
`N
`/ \
`
`H
`
`R:
`
`R;
`
`(XXXV)
`
`AC
`j-————
`CH3COCl + >
`Base
`
`R3
`
`AD
`GoH,A >
`
`R7
`
`R5
`
`CH —C
`2
`u
`If
`N
`\ / \
`C
`/
`
`(XXXVI)
`
`R5
`
`0
`
`CH3
`
`R3
`
`R6
`
`R2
`
`R1
`
`NBS, NCS or NIS N\
`
`R7 ——jj—-
`AH
`> R2
`
`[
`R1
`
`(XXXVII)
`
`AE
`
`Pb(OAc)4
`
`N
`[
`R1
`
`CHzY = PyA-'CH2Y
`(XLIII)
`(XLIV)
`
`Mylan Exhibit 1018, Page 7
`
`
`
`Mylan Exhibit 1018, Page 7
`
`

`
`13
`
`4,613,610
`
`-continued
`
`14
`
`la’
`CH2O'-C—CH3
`
`(xxxvm)
`
`
`
`AG
`
`soy‘: (XLI) or
`PY’3(XLII)
`
`
`
`\N
`I
`R1
`
`AF
`
`90},
`
`N 1
`
`R1
`
`CH2OH = PyA—CHzOH
`
`(XXXIX)
`
`(XL)
`
`Reaction Scheme VI
`
`The compounds of Formulae II and CCI wherein Py ‘
`is PyB may be synthesized by the following series of
`reactions:
`
`R4
`
`R2
`R4
`
`2
`
`R
`
`R3
`
`R3
`
`5
`
`R
`
`R5
`
`R7
`
`R5
`
`fi—CH2—R; +
`0
`
`NHNH2 E9
`
`(LI)
`
`Rs
`
`(LII)
`
`fi—C”2'RI *cT,c*o3—l3+—aT.s:'>
`N
`l
`N
`
`\
`
`H (LIII)
`
`R3
`
`6
`
`R
`
`R5
`
`R4
`
`2
`
`R
`
`R7
`
`R7
`
`fi‘°“2"“' e—§§‘;>
`N
`l
`N
`
`\
`
`(lZ‘=O (LIV)
`CH3
`
`Mylan Exhibit 1018, Page 8
`
`
`
`Mylan Exhibit 1018, Page 8
`
`

`
`115
`
`4,613,610
`
`-continued
`
`16
`
`
`
`BG
`
`NBS, NCS or NIS
`
`BD Pb(OAc)4
`
`\J
`
`CHZY = PyB“CHgY
`(LX)
`
`(LIX)
`
`R7
`
`
`
`l
`CH20—C—CH3
`
`R5
`
`R7
`
`R6
`
`
`
`BF
`
`SOY2’ (XLI) or
`PY3’ (XLII)
`
`CI-I3OH = PyB—CI-I201-I
`(LVIII)
`
` 0l
`
`(LVI)
`
`R5
`
`R6
`
`/7
`
`R5
`
`R7
`
`(LVII)
`
`R6
`
`_
`Reactlon Scheme VII
`.
`.
`.
`.
`The compounds of Formulae II and CCI wherein Py
`1s PyC may be synthes1zed by the followmg serles of
`reactions:
`
`60
`
`65
`
`Re
`
`R7
`
`R4
`
`E
`c—c1 + HZNNH
`
`R3 CA
`Base >
`
`5
`
`R
`
`(LXI)
`
`R2
`
`(LXII)
`
`Mylan Exhibit 1018, Page 9
`
`
`
`Mylan Exhibit 1018, Page 9
`
`

`
`17
`-continued
`
`- —
`if N” N”
`0
`
`R4
`
`R2
`
`R6
`_
`
`R7
`
`R5
`
`4,613,610
`
`R3
`
`CB
`%
`1=c15
`
`fl)
`-
`- -
`5 R'3° CO CH3 C
`
`_
`
`18
`
`R7
`
`R5
`
`R5 .
`DA
`————-—-9
`(1) Strong base
`(2) R.—co—c1
`(LXXII)
`
`R
`
`‘‘
`
`R7
`
`R5
`
`(LXIII)
`
`(f=N"NH
`C,
`
`(LXIV)
`
`R4
`
`R
`
`3
`
`R :__J£:?...9
`2Rr-CO-CH;-COOR13
`(LXV) + Base
`
`
`
`COOR13
`
`CD
`R1‘?
`
`R2
`
`R4
`
`(LXV1)
`
`R3
`
`R6
`
`10
`
`15
`
`20
`
`25
`
`30
`
`“xx”
`
`R7
`
`cook”
`R1-C—CH-C
`II
`II
`0
`0
`
`R5
`
`:-—————-——>DB
`R4
`
`115
`
`(Lxx111)
`
`R3
`
`NHNH2
`
`R2
`(LXII)
`
`R" DC
`LAI-I >
`
`R1
`
`COOR13 R7
`
`/
`N\ N
`
`R3
`
`R2
`
`R5
`
`R4
`
`(LXXIV)
`
`R7
`
`R5
`
`CH2OH
`
`"
`
`/
`N\
`
`N
`
`R1 = PyC—CHgOH
`(LXVIII)
`'
`
`(LXVII)
`
`R4
`
`R3
`
`R3
`
`CE
`
`SOY2' or
`(XLI)
`PY3’ (XLII)
`
`
`
`7
`
`CH2Y'
`
`,
`
`R1 = PyC—CH2Y
`(LXX)
`(LXIX)
`
`R2
`
`R4
`
`R3
`
`Reaction Scheme VIII
`The compounds of Formulae II and CCI wherein Py
`is PyD may be synthesized by the following series of
`reactions:
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`CH2OI-I R7
`
`R5
`
`R4
`
`R,
`
`/
`
`N\
`
`N
`
`R:
`
`R3
`
`R6 __§__%
`SOY’; (XLI)
`
`PY'3 o(rx1.11)
`= PyD—CH2OH
`V
`(LXX 1)
`
`(LXXV)
`
`R]
`
`CHZYI
`
`R7
`
`/
`N\
`
`N
`
`R2
`
`R3
`
`Rs
`
`R4
`
`(LXXVII)
`
`R6
`
`= PyD—Cl-lgY’
`(LXXVIII)
`
`DE
`—
`- —
`Z-——-——%
`R] CO CH; COOR13 (1) Strong base
`(LXV)
`R7
`
`R6
`
`(2)
`
`fl)
`C-C1
`
`R5
`(LXI)
`
`Mylan Exhibit 1018, Page 10
`
`
`
`Mylan Exhibit 1018, Page 10
`
`

`
`J19
`
`_con/finned
`
`COOR|3
`I
`R1‘.-C--CH=-C
`II
`II
`O
`O
`
`4,613,610
`
`R5
`
`5
`
`7
`
`R
`
`R5
`
`20
`
`-continued
`(136115
`o-—si—;-c4H9
`V
`I
`C6H<
`'
`
`_ _ \\\“
`(CeH5)3C 0 CH2
`
`V7
`
`OCH3
`
`0
`
`EG
`———.———-—-—>
`Tmyl ether
`cleaving agent
`
`(LXXIII)
`
`10
`
`(LXXXV11)
`
`Reaction Scheme IX
`The compound of Formula IV may be synthesized by 15
`the following series of reactions:
`
`AcO
`
`N
`Ac0—CH2‘‘\
`LXXXI
`
`‘
`
`AC9
`:
`
`0
`
`)
`
`____._§’_.°‘_.__....>
`(1) Na/Cl-I30}-I
`(2) Hg(OAc)2/
`CH3OI-I
`
`HQ
`5
`
`HO K
`
`\\\\\\Hg—OAc
`
`, \\\\
`H0-CH2‘
`
`0
`(LXXXII)
`
`V
`
`0CH3
`
`EB >
`(D Nam
`(2) NaBH4
`
`20
`
`'
`
`25
`
`30
`
`$6H5
`O—-?i—t_-C4H9
`CGH5
`
`EH
`Mild oxidizing agent >
`
`HO—CH2
`
`o
`
`OCH3
`
`(LXXXVIII)
`
`-———-
`
`$61-15
`'-— _
`5|‘
`194*“
`C6Hs
`
`OCH;
`
`E;
`
`0
`
`(LXXXIX)
`
`fl’
`H—C
`
`EI
`je-
`(CeH5)3P=CH2 >
`(LXXXIXA)
`
`C6H5
`o——Flai-t-C41-I9
`
`1 ‘C H
`5
`5
`
`E_
`
`_>H69
`
`CI-I2=CH“\\\
`
`OCH3
`
`(xc)
`
`C51-l5
`O-Sli-—t—C4I-I9
`I
`'
`V
`CEHS
`
`\\
`cH2=cH\“
`
`0
`(XCI)
`
`on
`
`EK
`Mild oxidizing agent >
`
`fafls
`o—s,i—s-we
`R C6115
`=0
`
`EL
`03
`
`(xcn)
`
`\
`CH2=CH-‘\\\ s
`
`C H
`.6 5
`Hz, °—'S|i‘5'C4H9
`’ R
`C51-I5
`
`O H
`\\
`ll
`\\\\\
`Hc‘“
`5
`
`=0
`
`(IV)
`
`.
`Reaction Scheme X
`The compounds of Formula X may be synthesized by
`the following series of reactions:
`
`Mylan Exhibit 1018, Page 11
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`EC
`.
`.
`‘°(C5H5)3CCl/ >
`Py"d‘“‘*
`
`OCH:
`
`H9
`’
`
`HO
`
`\
`\
`o
`HO-CH2“‘
`(LXXXIII)
`
`HO
`E
`=
`
`HO
`
`\
`\
`
`<c6Hs>3c—o—cHz“
`«xxxxv»
`
`V
`
`OCH:
`
`0
`
`>
`
`ED
`
`(1) Nal-I
`(2) 1-<2',4'.6'—:m-so.
`:;:;3::::::;::"
`(LXXXIVA)
`
`0
`
`\
`\
`
`<c5Hs>3c-o—cH2“
`(LXXXV)
`
`OH
`V
`
`EE
`LAH >
`
`0
`
`0CHs
`
`‘ \
`(C6H5)3C"°“CHZ\\
`(I-XXXVI)
`
`0
`
`>
`
`EF
`CeHs
`OCH3 I-C4H9“S|i—Cl
`V
`I
`c6H5
`(LXXXVIA)
`
`
`
`Mylan Exhibit 1018, Page 11
`
`

`
`21
`
`4,613,610
`
`22
`
`CH3—CO—CH2"COOR1z'
`(XIX)
`
`(1) Strong base
`FA (2) CH3=CH—CHO
`(XCIII)
`
`cHz=cH—c|:H—cH3——fi—cHg——cooR.g' cH2=cH-on—cH2—fi:H—cHz—cooR,2'
`OH
`0
`336'"
`OH
`OH
`(XCIV)
`(XCV)
`
`Rloa_Mg__Y
`(XCIX)
`
`C'?6H5
`FC [-C4H9—S|i—Cl
`ca]-15
`
`(LXXXVIA)
`
`lllioa
`FE
`Cl-I =CH-CH-CH —C—CH —COOR '————-—-9cH =CH—CH
`I
`compound
`2
`1
`2
`2
`12
`2
`I
`OH
`OH
`LXXXVIA
`(I)
`C(,H5-'S|i—C6H5
`L-C4H9
`
`(C)
`
`CH
`
`2
`
`Irio
`FF
`'
`C—CH — o
`I
`2 C ORF2 -53-}
`(I)
`C(,H5—Si—C(,H5
`1.-C4!-I9
`
`(XCVI)
`
`if
`H"'C—'$H
`0
`|.
`C5H5—?1—C5H5
`1-C4H9
`
`CH2
`
`E?
`rm
`FG
`,
`(l:—CHz—'COOR12 H—C-CH2—?H CH2
`Q
`+ Strong base
`0
`|_
`(2) Aldehyde of
`|_
`3 H
`C5H5—Slx—C5H5
`Foegmula XCVII
`C5H5—?1—C5H5
`L-C41-I9
`E-C4119
`( )
`
`‘rm
`(II-CH2—COOR12
`O
`|_
`C(,H5—S|1-'C5H5
`1-C4H9
`
`,
`
`(XCVII)
`
`(XCVIII)
`
`40
`
`.
`Reactlon Scheme XI
`The compounds of Formula XV wherein X5 is»
`—(CH2)m— or (E)——CH=CH and those of Formula IX
`
`wherein X1 is —CH2CH2— may be synthesized by the
`following series of reactions:
`
`Py-CH2OH
`
`(CCI)
`
`A Mild oxidizing
`agent
`
`/CI-IO
`H\
`Py—cHo /c=c\
`ccn
`\ _ /
`Py
`(
`) m
`C"C
`(ccrv)
`
`OCQH5
`
`Li
`(CCIII)
`(2) }_)-TSOH/H20
`$
`(1) (C5H5)3P—CH2OCH3Cle +
`(CCV)
`Strong base
`GC (2) Aldehyde of Formula CCII
`(3) H93
`
`H
`
`Mylan Exhibit 1018, Page 12
`
`
`
`Mylan Exhibit 1018, Page 12
`
`

`
`23
`
`4,613,610
`
`24
`
`-continued
`
`GI
`Py—CH2-CH0 Mild reducing >Py—cH2cH2oH
`(CCVI)
`“gem
`(ccxm)
`(1) Compound CCV +
`SOY2'
`Strong base
`(XLI)
`GD (2) Aldehyde of
`or
`Formula CCVI
`PY3’
`(3) H69
`\/(XLII)
`
`G]
`
`Py—CH3CI-I2-CH0
`
`Py—CHgCH2—Y'
`
`(ccvu)
`
`(CCXIV)
`
`(1) Compound CCV +
`Strong base
`GE (2) Aldehyde of Formula ccvu
`(3) H63
`V
`
`GK
`
`Py'-CH2CH2CH3—CHO
`
`(CCVIII)
`
`GF
`(a) (C6H5)3P=CI-I-COOR13
`(CCIX) or
`(b) (1) (R130)2P0—CH2—C00R13
`(CCX) + Strong base
`(2) Aldehyde of Formula
`CCII
`
`H
`> \C=
`/
`lay
`
`(CCX1)
`
`(C6H5)3P
`
`V
`
`EB
`Py'—CH2CHz—P(C5H5)3Ye
`
`(CCXV)
`
`COOR13
`
`GG
`Reducing agent
`
`\
`
`H
`
`H
`> \C.=C/
`/
`\
`py
`
`(CCXH)
`
`CHZOH
`
`GH
`Mild oxidizing
`agent
`
`>
`
`H
`
`H
`
`Py
`
`\
`
`/
`
`CH0
`
`C=C
`
`/
`
`\
`
`H
`
`(CCIV)
`
`In the foregoing reaction schemes,
`Rma is C1.3alky1, preferably methyl,
`each R13 is independently C1.3a1kyl, preferably n-C1.
`3a1ky1 and most preferably C1.2alkyl,
`R14 is C1_2a1kyl,
`Py is
`
`40
`
`45
`
`55
`
`50
`
`wherein R1—R7 are as defined above, with the pro-
`visos that (i) the free valence is in the 4- or 5-posi-
`tion of the pyrazole ring, and (ii) the R1 group is
`ortho to the free valence,
`PyA-PyD are as defined in Reaction Schemes V--
`VIII, respectively,
`X1 is —CH2— or —CHgCH2—,
`X2 is a direct bond or —CH2—,
`X3 is —CH=CH—, —-CH=CH—CH2—— or —CH-
`2—CH:CH—,
`preferably
`(E)-—CH=CH-,
`(E)—CH=CH—CH2—~
`or
`(E)——CHz—CH.:
`CH-- and especially (E)——CH=CH—,
`X4 is ——CH2CH2— or —CH2CH2CH2—, especially
`—CH2CH—,
`X5 is —(CH2)m— or (E)—CH:CH—, especially
`(E)—CH=CH—, wherein m is O, 1, 2 or 3,
`Y is chloro, bromo or iodo,
`Y9 is chloride, bromide or iodide,
`Y’ is chloro or bromo,
`M293 is sodium or potassium, and each of the other
`variables is as defined above.
`
`60
`
`65
`
`Mylan Exhibit 1018, Page 13
`
`
`
`Mylan Exhibit 1018, Page 13
`
`

`
`25
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`
`Mylan Exhi
`
`it 1018, Page 14
`
`
`
`Mylan Exhibit 1018, Page 14
`
`

`
`27
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`Mylan Exhi
`
`it 1018, Page 15
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`
`Mylan Exhibit 1018, Page 15
`
`

`
`29
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`4,613,610
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