throbber
j·
`'
`
`(12) UK Patent Application
`
`(19) GB (11) 2 205 837(1s1A
`
`(43) Appficalion published 21 Dec 19BB
`
`. ~ ...
`
`· 121) Application No 8811929
`
`(22) Date of llDng 20Nay1988
`
`(30) Priority data
`(31) 053281
`109680
`
`(32) 22 May 19B7
`190cl 1987
`
`(33) us
`
`(71) Applicant
`E. R. Squibb & Son• lno
`
`(Incorporated In USA-Delaware)
`
`Lawrenceville-Princeton Road, Princeton,
`New JerHy, United Statea of America
`
`(72) Inventors
`Donald Steven Karanewaky
`Scott Adema Biiier
`·
`Eric Michael Gordon
`
`(74) Agent and/or Address tor Service
`D. Youn9&Co
`10 Staple Inn, London, WC1V 7RD
`
`(51) INTCL'
`C07F 112811 7118
`
`(52) Domeslio classification (Edition J):
`.
`C2P 1L1 1L2 2E128 2E18C 2E19A 2E198
`2E19C 2E19D 2E23 2E25A 2E268 38128 3814A
`38148 3816 3818C 3819A 38198 38190 38190
`5879A
`.
`C2R S121 S122 S131 S143 S173 S211 S361 SOA
`U1S 1317 C2P C2R
`
`(56) Documents cited
`None
`
`(58) Field of search
`C2P
`
`(54) Phosphorus-containing HMG-CoA reductase Inhibitors
`
`(57) CCmpounds which are useful as inhibitors ol cholesterol blosynthesls and thus as hypocholesterolemic agents have
`o
`B
`the strudure
`11
`I
`X
`R-~-~-C-CBi-C02R
`da
`Jf
`<'fBi>n
`z
`including salts thereof, wherein R Is OH, lower alk.oxy or lower alkyl;
`R1 is 'H or alkyl;
`X~r-NH-;
`nis1or2
`Z Is a hydrophobic anchor, such as
`
`B.6
`
`.... M-t_
`
`or ~~-
`
`(R6a)
`R
`wherein the dotted lines represent optional double bonds.
`q
`New intermediates used in preparing the above compounds, e.g. compounds in which the OH group is silane
`blocked, pharmaceutical compositions containing such compounds and a method for using such compounds to inhibit
`cholesterol blosynthesls are also provided.
`
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`•I
`
`' \ ._,
`
`-l-
`
`220:5837
`
`PHOSPHORUS-CONTAINING HMG-CoA REDUCTASE
`INHIBITORS, NEW INTERMEDIATES AND ME'l'BOD
`
`5
`
`10
`
`15
`
`20
`
`25
`
`The present invention relates to new
`phosphorus-containing compounds which inhibit the
`aotivity of 3-hydroxy-3-methylglutaryl-coenzyme A
`reductase and thus is useful in inhibiting
`cholesterol biosynthesis, to hypocholesterolemic
`compositions containing such compounds, to new
`intermediates fonned in the preparation of such
`compounds and to a method of using such compounds
`for such purposes.
`
`F. M. Singer et al., Proc. Soc. Exper.
`Biol. Med., 102, 370 (1959) and F. B. Hulcher,
`Arch. Biochem. Biophys., 146, 422 (1971) disclose
`that certain mevalonate derivatives inhibit the
`biosyntbesis of cholesterol.
`Endo et al in u. s. Patents Nos. 4,049,495,
`4,137,322.and 3,983,140 disclose a fermentation
`
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`-2-
`
`·.
`
`product whi~ is active in the inhibition of
`cholesterol biosynthesis. This product is called
`compactin and was reported by Brown et al.,
`(J'. Chem. Soc. Perkin I. 1165 (1976)) to have a
`complex mevalonolactone structure.
`GB 1,586;~52 discloses a
`group of synthetic compounds of the formula
`
`CB Rio No
`R5-Q-R3
`
`R2
`
`E
`
`R4
`in which E represents a direct bond, a c1_3
`alkylene bridge or a vinylene bridge and the
`various R'~ represent a varietY.of substituents.
`The.activity reported in the U.K. patent
`is less th.an 1% that of compactin.
`U. S. Patent No. ~,375,475 to Willard et al
`discloses hypocholesterolemic and hypolipemic
`compounds having the structure
`
`a~Z.. ·o
`~·IF ..
`H 0
`
`:
`i
`
`.. ..
`
`5
`
`10
`
`~5
`
`20
`
`25
`
`30
`
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`
`:..._,·
`
`,
`"
`
`-3-
`
`5
`
`10
`
`wherein A is B or methll1 E is a direct bond,
`. -CB2-, -CBi-CBi-, -CBi-CBi-CBi- or -CB=CB- i ~, 1ti
`and ~ are each selected from B, halogen, c1~4
`alkyl, c1~4 haloalkyl, phenyl, phenyl substituted
`by halogen, c1 -4 alkoxy, c2_8 alkanoyloxy,
`· c1
`_4 alkyl, or c1
`_4 haloalkyl, and oa4 in which R4
`is B, c2_8 alkanoyl, benzoyl, phenyl, halophenyl,
`3 alkyl, c1 _9 alkyl, cinnamyl, c1_4 •
`phenyl c1
`_
`haloalkyl, allyl, cycloa~Jtyl-c1_3 -alkyl,
`adamantyl-Ci-3-alkyl, or .. substituted phenyl
`c1_3-alkyl in each of which the sUbstituents are
`selected from halogen, c 1 _4 alkoxy, c1 _4 alkyl, or
`c1
`_4 haloalkyl1 and the corresponding dihydroxy
`acids resulting from the hydrQlytic opening of the
`lactone ring, and the pharmaceutically acceptable
`salts of· said acids, and the c 1 _3 alkyl and
`phenyl, dimethylamino or acetylamino substituted
`c1 _3-alkyl esters of the dihydroxy acids; all of
`the compounds being the enantiomers having a 4 R
`configuration in the tetrahydropyran moiety of the
`trans racemate shown in the above formula.
`WO 84/02131 (PCT/EP83/00308) (based on
`u. s. appl~cation Serial No. 443,668, filed·
`November 22, ·1992; and u. s. application Serial
`25 No. 548,850, filed November 4, 1983), filed in the
`name of Sandoz AG discloses heterocyclic analogs of
`mevalono lactone and derivatives thereof having the
`structure
`
`15
`
`20
`
`. 30.
`
`35
`
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`... . ~.
`
`r
`'- ./
`
`-4-
`
`wherein one of R and R0 is
`
`·.
`
`4
`
`and the
`
`5
`
`10
`
`lS
`
`20
`
`25
`
`30
`
`s
`Rsa
`other is primary or secondary c1_6 alkyl, c3 ~6
`·9Ycloalkyl or phenyl-(CH2 >m-'
`wherein R4 is hydrogen, c1_4 alkyl, c1_4
`alkoxy, (except t-butoxy), trifluoromethyl,
`fluoro, chloro, phenoxy or benzyloxy,
`Rs is hydro~en, c1_3 alkyl, c1 _3 alkoxy,
`trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy,
`Rsa is hydrogen,.c1_2 alkyl, c1 _2 alkoxy,
`fluoro or chloro, and
`m is 1, 2 or 3,
`with the provisos that both Rs and Rsa must
`·
`be hydrogen when R4 is hydrogen, Rsa must. be
`hydrogen when Rs is hydrogen, not more than one of
`R4 and Rs is trifluoromethyl, not more than one of
`R4 and R5 is phenoxy and not more than one of R4
`and Rs is benzyloxy,
`~ is hydrogen, cl-4 alkyl, c3-6
`cycloalkyl, c1_4 alkoxy (except t-butoxy),
`trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy,
`~ is hydrogen, c1_3 alkyl, c1_3 alkoxy,
`trifluoromethyl, fluoro, chloro, phenoxy ·or ·
`berizyloxy, with the provisos that R3 must·be
`hydrogen when R2 is hydrogen, not more· than .one of
`R2 and ~ is trifluoromethyl, not more than one of
`R2 and ~ is phenoxy, and not more than one of ~
`and ~ is benzyloxy.
`
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`
`-s-
`
`-
`
`. X is -<CBi>n- or -CB=CB- (n=O, 1, 2 or 3),
`R6
`31
`· 1
`2·
`5 4
`Z is -F-CB2-c-ca2-COOB
`6u
`OB
`wherein R6 is hydrogen or c1_3 alkyl in
`free acid form or in the form of a physiologically(cid:173)
`hydrolys able and -acceptable ester or a 6 lactone
`thereof or·in salt form.
`GB 2162-179-A discloses naphthyl analogues
`of mevalolactone·useful ~s cholesterol
`structure
`biosynthesis inhibitors
`
`II
`
`z
`
`wherein a1 = l-3C alkyl;
`z is a gp. of formula z1 or z2:
`
`5
`
`10
`
`15
`
`20
`
`B
`
`OB
`
`\fB
`
`-IHca2i8~coo~
`OB
`OB
`
`25
`
`:•
`
`~
`
`30
`
`(Zl)
`
`0
`
`(Z2)
`
`~ = B, a hydrolysable ester gp. or a
`cation.
`
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`
`(
`(
`
`.. -
`
`-6-
`
`·.
`
`European Patent No. 164-698-A discloses
`preparation of ·lactones useful as anti-hyper(cid:173)
`cholesterolemic agents by treating an amide with
`an organic sulpbonyl halide R5so2x, then removing
`the protecting group Pr •
`
`. al
`
`Protp' 0
`
`3.a4
`B
`l OB
`
`a2
`
`~ BOtir O
`
`I
`I
`•2
`R
`
`wherein X = halo;
`Pr = a carbinol-protecting .group;
`a1 = B or ~;
`a3 , a4 = B, l-3C alkyl.or phenyl-(l-3C
`alkyl), the phenyl being optionally substituted by
`l-3C alkyl, l-3C alkoxy or halo;
`R2 = a group of formula (A) or (B):
`
`0
`
`CB~9
`
`R'
`
`1
`CB
`3 I
`
`(A)
`
`. (B)
`
`5
`
`10
`
`15
`
`20
`
`25
`
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`
`;;
`
`5
`
`,.
`
`10
`
`is
`
`20
`
`25
`
`30
`
`·-7-
`
`I
`Q = R6-c•
`
`I .
`or R6-ca ;
`I
`
`I
`I
`I
`I
`CB3
`a6 = B or OH;
`R = B or ~;
`a, b, c and d = optional double bonds;
`R7 = phenyl or benzyloxy, the ring in each
`case being optionally.substituted by 1-3C alkyl or
`halo;
`
`R~, R9 = l-3C alJtYl or halo;
`R5 = l-3C alkyl, phenyl or mono- or
`di-(l-3C alkyl)phenyl.
`Anderson, Paul Leroy, Ger. Offen.
`DE 3,525,256 discloses naphthyl analogs of
`mevalonolactones of the structure
`
`:y-yoe
`o'(
`
`.
`7
`-CHCR2CBCB2co2R
`'
`&
`.
`OB
`OB
`Q
`
`Q'
`I
`wherein R1 is alkyl, z = Q, Q1 ; R7 = B, or a
`hydrolyzable ester group useful as inhibitors of
`choleste+ol biosynthesis and in treatment of
`atherosclerosis.
`WO 8402-903 (based cn_u.s. application
`Serial No. 460,600, filed January 24, 1983) filed
`in the name of Sandoz AG Discloses mevalono-lactone
`analogues useful as hypolipoprateinaemic agents
`having th~ structure
`
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`
`j
`l
`
`c
`
`.
`
`-8-
`
`x-z
`
`RS
`
`I
`
`wherein the two groups Ro together form a radical
`of formula
`
`t7 7
`
`c - c
`
`6 =~}
`
`or
`
`-<c:Bi>4-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`R2
`
`I
`~
`wherein Ri is hydrogen, c1_4 alkyl,
`c1_4 alkoxy, (except t-butoxy), trifluoromethyl,
`fluoro, chloro, phenoxy or benzyloxy,
`~ is hydrogen, c1_3 alkyl, c1_3 alkoxy,
`trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy, with the provisos that not more than
`one of ~ and ~ is trifluoromethyl, not more than
`one of ~·and ~ is phenc:>xy, and not more than one
`of ~ and ~ is benzyloxy,
`·
`Ri. is hydrogen, c1_6 alkyl, fluoro, chloro
`or benzyloxy,
`a4 is hydrog~n, c1_4 alkyl, c1_4 alkoxy,
`(except t-butoxy), trifluoromethyl, fluoro,
`chloro, phenoxy or benzyloxy,
`.
`. a5 is hydrogen, c1_3 alkyl, c1_3 alkoxy,
`trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy,
`a5a is hydrogen, c1_2 alkyl, c1_2 alkoxy,
`fluoro or chloro, and with the provisos that not
`
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`;;·
`
`-9-
`
`more than one of R4 and a5 is trifluoromethyl, not
`·more than one of R4 and a5 is pbenoxy and not more
`than one of a4 and Rs is benzyloxy,
`/(CB2 )g
`B,·
`x is -<CBi >n-'
`/c = c,
`-(~)g
`B
`
`wherein n is O, l, 2 or 3 and both g•s are o.or
`?ne is O and the other is l,
`Z is
`
`II
`
`6
`1
`2
`3r
`5 4
`-ru-~--bc-cs2-COOB
`OH
`.
`H
`wherein a6 is hydrogen or c1_3 alkyl, with
`the general proviso that -x-Z.and the a4 bearing
`phenyl group are ortho to eacb other;
`in free acid form or in~the form of a
`physiologically-hydrolysable and acceptable
`ester or a 6 lactone thereof or in·salt form.
`
`European patent· application 127 ,848-A (Merck.
`& Co, Inc.) discloses derivatives of 3-bydroxy-s-
`thia-w~aryl-alkanoic acids having the structural
`formula:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`
`f
`l
`
`r I ..___...,
`
`·.
`
`-10-
`
`wherein Z is:
`
`Rl
`
`~ R6
`
`R2
`
`R3
`
`4 R
`
`~
`
`s
`
`n is o, 1 or 2;
`E is -~-, -~-~-, -CB2-cs2-cs2-,
`-CB=CH-~-; or -~-CB=CB-;
`Ri, R2 and a, are, e. q. , hydrogen, chloro,
`bromo, fluoro, c1-alkyl, phenyl, substituted phenyl
`or o~ in which~ is, e.g., hydrogen,
`.
`c2_8alkanoyl, benzoyl, phenyl, substituted
`phenyl, c1_9alkyl, cinnamyl, c1_4haloalkyl, allyl,
`cycloalJtYl-c1_3alkyl, adamantyl-c1_3-alkyl, or
`·
`phenyl c 3 al·kyl;
`Rl~ a5 and a6 are hydrogen, chloro, bromo,
`fluor.o or c1_3 alkyl; and
`Xis, e.g., hydrogen, c1_3 alkyl, a cation
`derived from an alkali metal or is ammonium.
`Those compounds have antihypercholesterolemic
`activity by virtue of their ability to inhibit ·
`3-hydroxy-3-methylglutaryl-coenzyme A (BMG~CoA)
`reductase and antifungal activity.
`French patent application 2,596,393 A filed
`on April 1, 1986 (Sanofi SA) discloses
`3-carboxy-2-hydroxy-propane-phosphonic acid ·
`derivatives including salts thereof which are
`useful as hypolipaemic agents and have the formula:
`
`5
`
`10
`
`· 15
`
`20
`
`25
`
`30
`
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`
`G
`
`·:;
`
`. -11-
`
`5
`
`10
`
`"15
`
`20
`
`25
`
`wherein Ri and ~ = B, lower alkyl or optionally
`substituted aralkyl;
`~ and R4 = B, lower alkyl or optionally
`substituted aryl or aralkyl.
`These comounds are disclosed as·giving
`greater·reductions· in cholesterol, triglyceride
`and phospholipid.levels than meglutol.
`European patent application 142,146-A (Merck
`& Co., Inc) discloses mevinolin-like compounds of
`the structural formula:
`
`BOYO OR1
`
`~o.
`
`E
`I
`z
`
`wherein:
`~l is, e.g., hydrogen or c1 _4 alkyl;
`E is -ca2cs2 , -CB=CB-, or -(CB2 )r-; and
`Z is
`l)
`
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`
`t
`l,
`
`5
`
`10 wherein X is -o- or -NR9 wherein R9 is hydrogen or
`c1_3alkyl;
`R~ is c2
`8alJtYl; and
`R8 is hydrogen or ca3;
`
`_
`
`2)
`
`15
`
`.
`
`20
`
`25
`
`30
`
`Rl1
`
`Rl2
`
`wherein R10 , a11 and R12 are independently, e.g.,
`hydrogen, halogen·or cl-4alkyl;
`3)
`
`In accordance with the present invention,
`there is provided phosphorus-containing compounds
`
`I
`
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`
`0
`
`-13-
`
`which inhibit the enzyme 3-hydroxy-3-methylglutaryl(cid:173)
`coenzyme A reductase (BMG-CoA Reductase) and thus
`are useful as hypocholesterolemic agents and
`include the following moiety
`
`5
`
`10
`
`15
`
`20
`
`wherein X is -o- or -NB-, n is 1 or 2 and Z is a
`"hydrophobic anchor".
`The term hydrophobic anchor as employed
`herein refers to a lipophilic group which when
`linked to the BMG-like upper side chain of the
`molecule by the appropriate linker ( 0 X11 ) , binds to
`a hydrophobic pocket of the enz}rme not utilized in
`binding the.substrate BMG CoA, resulting in
`enhanced potency relative to compounds where Z=B.
`In preferred embodiments, the compounds of
`the invention have the formula I
`
`25
`
`I
`
`30
`
`including salts thereof, wherein R is OH, lower
`alkoxy or lower alkyl;
`Rx is B or lower alkyl;
`
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`
`r"\.
`~._)
`
`-14- .
`
`x is ~o- or -NH-;
`n is 1 or 2;
`z is a hydrophobic anchor;
`and including pharmaceutically •cceptable
`salts thereof.
`The terms "salt" and "salts" refer to basic
`salts formed with inorganic and organic bases.
`such salts include ammonium salts, alkali.metal
`salts like, lithium, sodium and potassium salts
`(which are prefe~red), alkaline earth metal salts
`like the calcium and magnesium salts, salts with
`organic bases, such as amine like salts, e.g.,
`dicyclohexylamine salt, benzathine, N-methyl-D(cid:173)
`glucami'ne, hydrabamine salts, salts with amino
`a~ids like arginine, lysine and the like. The
`nontoxic, pharmaceutically acceptable salts are
`preferred, although other salts are also useful,
`e.g., i~ isolating or purifying the product.
`Examples of hydrophobic anchors which may be
`included in accordance with the present invention
`include, but are not limited to
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`
`..__,
`
`-15-
`
`5
`
`or
`
`lkyl
`
`10 wherein the dotted lines represent·optional double
`bonds, for example.
`
`15
`
`20
`
`25
`
`R6
`I
`0
`
`R6
`I
`0
`
`RS
`
`5' R
`
`R6
`I
`0
`
`R.6
`·I
`
`R
`
`a.~kyl
`
`alkyl
`
`alkyl
`,
`
`16 of 91
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`
`-16-
`
`alkyl
`
`,
`
`alkyl
`
`or
`
`wherein R1 , R2 , R2a and R2b may be the same or
`different and are each independently selected from
`B, halogen, lower alkyl, haloalkyl, phenyi,
`substituted phenyl or oaY wherein aY is B,
`alkanoyl, benzoyl, phenyl, halophenyl,
`phenyl-lower alkyl, lower alkyl, cinnamyl,
`haloalkyl, allyl, cycloalkyl-lower alkyl,
`adamantyl-lower aikyl or substituted phenyl-lower
`alkyl.
`Where z is
`
`5
`
`10
`
`20
`
`25
`
`17 of 91
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`
`-17-
`
`alkyl
`
`. R6
`
`I
`
`0
`
`a5 and a5 ' are the same or different and
`are B, lower alkyl or OB;
`?.
`0
`a6 is lower ~lkyl-C such as CB -CJL.-c-8-,
`.
`3 -~4-'' 7
`~R
`
`or aryl~-;
`a6a is lower alkyl, hydroxy, oxo or halogen;
`q is o, 1, 2 or 3, and
`a7 is B or lower alkyl;
`Thus, the compounds of formula I encompass
`0
`X
`.
`II
`R-r-ca2-~-CH2-C02R
`0
`OB
`I
`<f52>n
`z
`
`and
`
`IA
`
`IB
`
`0 n
`x
`R-f-~-~-~-co2R
`OB
`NB
`I
`(~)n
`z
`The term "lower alkyl" or "alkyl" as employed
`herein alone or as part of another group includes
`
`I
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`18 of 91
`
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`IPR2015-01836
`
`

`
`15
`
`both straight and branched chain hydrocarbons, ·
`containing l to 12 carbons in the normal chain)
`preferably 1 to 7 carbons, such as methyl, ethyl,
`propyl., isopropyl, butyl, t-butyl, isobutyl,
`· ·
`pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl-
`- pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,
`undecyl, dodecyl, the.various branched chain
`isomers thereof, and the like as well as such
`groups including a halo-substituent, such as F, Br,
`10 Cl or I or CF3 , an alkoxy substituent, an aryl
`substituent, an alkyl-aryl substituent, a haloaryl
`substituent, a cycloalkyl substituent, an alkyl(cid:173)
`cycloalkyl substituent, hydroxy, and alkylamino
`substituent, an alkanoylamino substituent, an aryl-
`.
`.
`carbonylamino substituent, a nitre substituent, a
`cyano substituent, a thiol substituent or an
`alkylthio substituent.
`The term "cycloalkyl" as employed herein
`alone or as part of another group includes
`saturated cyclic hydrocarbon groups containing 3 to
`12 carbons, preferably 3 to 8 carbons 1 • which
`include cyclopropyl, cyclobutyl, cyclopentyl,
`cyclohexyl, cy.Cloheptyl, cyclooctyl, cyclo$fecyl and
`cyclododecyl, any of which groups may be substi-
`tuted with 1 or 2 halogens, 1 or 2 lower alkyl
`·.groups, 1 or 2 lower alkoxy groups, l or 2 hydroxy
`groups, 1 or 2 alkylamino groups, 1 or 2 alkanoyl(cid:173)
`amino groups, 1 or 2 arylcarbonylamino groups, 1 or
`2 amino groups I 1 or 2 ni trO groups I 1 or 2 cyano
`groups, 1 or 2 thiol.groups, and/or·l or 2'alkyl(cid:173)
`thio groups.
`The term "aryl" or "Ar" as employed herein
`refers to monocyclic or bicyclic aromatic groups
`
`-18-
`
`.
`
`I
`
`5
`
`20
`
`25
`
`~o
`
`19 of 91
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`

`
`i
`1.
`
`-19-
`
`containing from 6 to 10 carbons in the ring
`portion, such as phenyl, naphthyl, substituted
`phenyl or substituted naphthyl wherein the
`substituent on either the phenyl or naphthyl may
`be 1, 2 or 3 lower alkyl groups, halogens (Cl, Br
`or F), l; 2 or 3 lower alkoxy groups, 1, 2 or~·
`hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3
`alkan~yloxy group, 1, 2 or 3benzoyloxy.groups,.1,
`2 or 3 haloalkyl groups, l, 2·or 3 halophenyl
`groups, 1, 2 or 3 allyl groups, 1, 2 or 3 cyclo(cid:173)
`alkylalkyl groups, 1, 2 or 3 adamantylalkyl groups,
`1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoyl(cid:173)
`amino groups, 1, 2 or 3 arylcarbonylamino groups,
`1, 2 or 3 amino groups, 1, 2 or 3 nitro groups, 1,
`2 or 3 ~yano groups, 1, 2 or 3 thiol groups, and/or
`l, 2 or 3 alkylthio groups with the aryl group
`pr~ferably containing 3 substituents.
`·The term 11aralkyl 11 , "aryl-alkyl" or
`11 aryl-lower alkyl• as used herein alone or as part
`of another group refers to lower alkyl groups as
`discussed above having an aryl substituent, such as
`benzyl.
`The term 11 lower alkoxy", 11 alkoxy 11 , or
`"aryloxy" or 11aralkoxy" as employed herein ~lone or
`as part of another group includes any of the above
`lower alkyl, alkyl,~~aralkyl or aryl groups linked
`to an oxygen atom.
`The term_ 11lower alkylthio 0 , "alkylthio",
`"arylthio" or "aralkylthio" as employed herein alone
`or as part of another group i~cludes any of the
`above lower alkyl, alkyl, aralkyl or aryl groups
`linked to a sulfur atom.
`
`.5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`20 of 91
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`
`I
`\
`
`-20-
`
`The terin "lower alkylamino", "alkylamino",
`"arylam.ino 11 , "arylalkylamino 11 as employed herein
`alone or as part of another group includes any of
`the above lower alkyl, alkyl, aeyl or arylalkyl
`groups linked to a nitrogen atom.
`The term "alkanoyl" as used herein as part
`of another group refers to lower alkyl linked to a
`carbonyl group.
`'I'he term "halogen° or "halo" as used herein
`refers to chlorine, bromine, ·nuorine, i:odine and
`CF3 , with chlorine or fluorine being preferred.
`Preferred are those compounds of formula I
`which have the following structure
`
`5
`
`10
`
`15
`
`II
`
`20
`
`25
`
`30
`
`wherein R. is OB, OLi; .Rx is Li or B;
`X is·o or NH; and-
`z is
`
`RY;J.R2
`y-~
`
`~herein R1 is phenyl
`which includes an alkyl
`and/or halo substitutent
`
`R2a
`
`..
`
`or R1 is beniyloxy which includes a halo
`substituent;
`R2 and R2a are the same and are halogen or ·
`lowe~ alkyl;
`
`21 of 91
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`
`Z may also preferably be
`
`1
`R
`
`.
`
`wherein a1 and a2 are as defined immediately above
`with respect to the compound of formula II, or
`
`2 is
`
`R~
`wherein R5 is B, CB3 or OB and a6 is
`(j
`II
`/c......_,r
`/CH2
`~ ~'l?
`
`ClL ? r or (substituted)phenylmethyl
`
`·
`
`wherein R i: B or~·
`
`The compounds of formula I of the invention
`may be prepared according to the following
`reaction sequence and description thereof.
`
`5
`
`10
`
`15
`
`20
`
`22 of 91
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`
`(
`
`.,
`
`. ~../
`
`.N
`N
`I
`
`f 6"s
`os1-vccu3)3
`I c6us
`I-CH2-c-cu2-co2alkyl
`A
`
`H
`
`Ra-P(Oalkyl) 2
`,
`III
`'
`~-Arbuzov Reaction
`m lower alkyl or
`(~8
`lower alkoxyJ
`
`0
`.
`. a •'
`R -P-CH -CH-CH -CO alkyl
`2 ~
`2
`2
`I
`Oalky~~C(CH3 ) 3
`
`C6HS C6HS
`
`IV
`
`IV
`
`1. (a13.> 3-siBr, cu 2c1 2
`2. "20
`' /
`
`Phosphorus ester
`cleavage
`
`)
`
`3
`
`0
`a, II
`R -P-CH -CH-CH -CO alkyl
`2 :
`2
`2
`p
`I
`011
`Si-C(CH
`~~6°5 .
`
`.
`
`3
`
`VA. - Ra'=lower alkyl where Ra was lower alkyl
`a'
`a
`VB. - R =OH where R was lower alkoxy
`
`·
`
`fl'
`
`P•·
`
`'~
`
`~
`
`23 of 91
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`

`
`,,
`
`,.
`
`.,
`
`•'·
`
`()
`
`VB
`(Ra' a OH)
`
`. RbOH-DCC
`
`. (Rb = lower i!lkyl)'-,
`Pyridine
`(Esterification):
`
`0
`b
`,
`II
`R o-~-CH2-~H-cu2C02alkyl
`OH
`::
`·
`0
`I
`Si-C(CHJ)l
`/'\
`C6HS C6HS
`
`VI
`
`tJ
`w
`I
`
`24 of 91
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`

`
`VI
`or
`VA.
`
`1),
`2)
`
`(COCl) 2 r CH 2cl 2 (Acid Cl Formation)
`)n-XH (coupling reaction)
`·2-(CH
`2
`(C2H5 ) 3N, DMAP
`
`" "
`
`('" j
`
`0
`c fl
`R -f-CH2-2u-cn 2co2alkyl
`~ •. p
`(Cll2 )n Si-C(CH3) J
`~ /\
`
`C6H5 C6H5
`
`VII
`
`.
`c
`(R = lower alkyl or lower al~oxy)
`
`N .. I
`
`VII
`
`l) (n-C 4H
`9
`
`)
`4
`
`NF, cu
`
`cOOll, THF (silyl
`3
`ether cleavage)
`2) OH-,· dioxane (Hydrolysis)
`
`\.. ,
`
`0
`x
`,.
`R-P-CH -CH-CH -CO R
`I
`2 :
`2
`2
`OH
`x
`I
`.
`(CH2J n
`
`' z
`
`I.
`
`t
`
`II/!
`
`!.h
`
`\(\
`
`25 of 91
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`
`:.
`
`"'
`
`-25-
`
`As seen in the above reaction sequence,.
`compounds of Formula I may be prepared by
`·subjecting iodide A to an Arbuzov reaction by
`heating iodide A
`
`5
`
`~
`
`10
`
`T68 5
`I I
`o-si-c(ca >
`3 3
`C6Bs
`I-ca2-c-CH2-co2alkyl
`B
`
`and phosphonite/phosphite III
`
`III
`
`15
`
`Ra-P(<?alkyl) 2
`
`wherein Ra is lower alkyl or lower alkoxy,
`employing standard Arbuzov con~itions and
`procedures to form phosphinate/phosphonate IV
`
`20
`
`IV
`
`25
`
`Phosphinate/phosphonate IV is a novel
`· compound arid as su~ is a part of the present
`invention.
`-
`.Phosphinate/phosphonate IV is then subjecte~
`to a phosphorus ester cleavage by treating ~
`· 30. solution of compound IV in an inert organic solvent,
`such as methylene chloride, sequentially with
`bis(trimethylsilyl)trifluoroacetamide (BSTFA) and
`trimethylsilyl bromide, under an inert .atmosphere
`
`26 of 91
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`
`-26-
`
`such as argon to form the pbospbinic acid VA where
`Ra in IV is lower alkyl, that is,
`
`s
`
`VA
`
`10
`
`or phosphonic acid VB (wherein Ra in IV is lower
`alkoxy}; that is
`
`VB
`
`15
`
`0
`II
`Bo-;-~-!8-~-co2 ~lkyl
`?
`OB
`.,/ s,i-C(~ )3
`C5B5 C6BS
`
`compounds VA and VB are novel intermediates
`and as such as part of the present invention. ·
`Where phosphonic acid VB is obtained, it is
`esterified by treating VB in dry pyridine with
`alcohol
`
`Rb OB
`
`VC
`
`(where Rb is lower alkyl)
`··:!:
`and dicyclohexyl carbodiimide and the resulting
`reaction mixture is stirred under an inert
`atmosphere, such as argon, to form phosphonic morio
`alkyl ester VI
`
`2 O
`
`25
`
`30
`
`ii-
`
`27 of 91
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`
`' ·....._,·
`
`VI
`
`-27-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Ester VI or phosphinic acid VA is then
`dissolved in an inert organic solvent, such as,
`methylene chloride, benzene or te~ahydrofuran
`(TBF) and treated with trimethylsilyldiethflamine
`and stirred under-an inert atmosphere such as
`argon; the mixture is evaporated and then d~ssolved
`in methylene chloride (or other appropriate inert
`organic solvent). The resulting solution is cooled
`to a· temperature within the range of ~rom about 0°C
`to about 25°C, treated with oxalyl chloride and
`then evaporated to give crude phosphonochloridate.
`.
`The phosphonochloridate is dissolved in inert
`organic s~lvent such as methylene chloride,
`benzene, pyridine or TBF; the solution is cooled to
`a temperature within the range of from about -20°c
`to about 0°C and treated with
`
`employing a molar ratio of VI or VA:! of within
`the range of from about O. S: 1 to about 3: l and
`preferably from about 1:1 to about 2:1,
`followed by triethylamine and catalytic
`4-dimethylaminopyridine (DMAP) to form adduct VII
`
`28 of 91
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`
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`
`VII
`
`5
`
`wherein Rc is lower alkyl or lower al:koxy.
`
`10 Compound VII is subjected to silyl ether cleavage
`by treating a VI~ in an inert organic solvent. such
`as tetrahydrofuran, with glacial acetic acid and
`tetrabutylammonium fluoride to form ester VIII
`
`15
`
`20
`
`25
`
`30
`
`VIII
`
`(Rx = alkyl)
`
`The ester VIII may then be hydrolyzed to
`the corresponding alkali metal salt or acid, that
`is, where Rx is alkali metal or H by treatment with
`strong base such as lithium hydroxide in the
`presence of dioxane, tetrahydrofuran or other inert
`organic solvent, under an inert atmosphere such as
`argon, at 25°C, employing a molar ratio of
`base:ester VIII of within the range of from about
`1:1 to about 1.1:1 to form the correspondi~g alkali
`metal salt
`
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`
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`
`VII IA
`
`5
`
`10
`
`15
`
`20
`
`wherein R is lower alkyl or lower alkoxy.
`
`compound VIIIA may then·be.treated with strong
`·acid such as BCl to form the corresponding acid
`VIIIB
`
`VIIIB
`
`0
`II
`a-1-ca2-iH-CB2-C02H
`f
`OB
`<~2>n
`z
`
`The ester VIII wherein R is lower alkoxy
`may be converted to the corresponding di-alkali
`metal salt by tJ:eating ester VIII with strong base
`at ·s0-60°C employing a molar ratio of base:ester
`25 VIII of within the range of from about 2:1 to
`about 4:1 to form VIIIC
`
`30
`
`0
`II
`•
`VIIIC alkali metalO-~-ca2-~-CH2 -co2 alkali metal
`X
`OH
`I
`<rs2>n
`z
`
`30 of 91
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`
`-30-
`
`The di-alkali metal salt VIIIC may be
`converte~ to the corresponding acid wherein R is
`OB by treatment with strong acid such as BCl to
`form VIIID
`
`VII ID
`
`0
`"
`BO-P-CH--CB-CB--CO B
`.-~= -~ 2
`X
`OB
`•
`. <r82>n
`z
`
`The iodide starting material A may be
`prepared starting witli the bromide £
`
`(prepared employing procedures as described
`in Tetrahedron Lett.·26, 2951 (1985))
`which is dissolved in solution in dimethylformamide
`(DMF) ·with imidazole and 4-dimethylamino pyridine
`and the resulting solution is treated with
`t-butyldiphenyl silyl chloride under an inert
`atmosphere such as argon to form the silyl ether Q
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`31 of 91
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`
`-31-
`
`-
`.
`A solution of. silyl ether D in an inert organic·
`.
`solvent such as methyl ethyl ketone or DMF
`is ·treated with sodium iodide under an inert
`atmosphere such as argon, to form iodide A.
`The starting compound !
`
`may be prepared as described below depending upon
`the defirii~on of z and x.
`Thus, compounds of formula ~ wherein Z is
`
`.. - ...
`
`;
`
`5
`
`10
`
`15
`
`20
`
`and X is o, that is, compounds of the structure
`
`25
`
`may be prepared by treating aldehy~e E
`
`32 of 91
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`
`' ....
`
`-32-
`
`s
`
`10
`
`20
`
`25
`
`30
`
`with a reducing agent such as lithium aluminum
`hydride or sodium borohydride.
`Compounds of formula B where Z is
`
`and X is N~ that is compounds o! the structure
`
`may be prepared b~ oxidizing the aldehyde ! by
`treating ! in so.lution with acetone with, for
`example, Jones reagent to form the acid !
`
`33 of 91
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`
`1 · .....
`
`-33-
`
`·1
`R
`
`!
`
`.
`
`R2a
`
`s
`
`10
`
`15
`
`20
`
`25
`
`·.;
`
`. which in sus~ension w~th methylene chloride is
`treated with oxalyl chloride to form the
`corresponding acid chloride which is dissolved in
`an inert organic solvent such as tetrahydro~uran,
`and treated with a mixture of concentrated ammonium
`hydroxide in teµahydrofuran to form an amide of
`the.structure
`
`Amide G is then reduced to the corresponding amide
`B2 by ~eating ~ with a reducing agent such as
`lithium aluminum hydride.
`Starting compounds of formula !!wherein Z
`
`is
`
`34 of 91
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`

`
`.....
`
`-34-
`
`s• R
`
`!!
`
`5
`
`(R6a)q
`
`and x i,s o or -NH-,
`structure
`
`10
`
`that is,
`
`compounds of the
`
`R S'
`
`RS
`
`15
`
`H'
`
`(CB2)n-XB.
`
`(R6a)q
`where X is o are disclosed by c. B. Heathcock et al,
`J. Org. Chem. ~. 1190 (1985). Compounds of
`formula B' ~ere X is NB may be prepared by the
`reductive amination of
`
`CHO
`
`alkyl
`
`·20
`
`25
`
`30
`
`(prepared as disclosed by c. B. Heathcock et
`al, supra)
`
`35 of 91
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`
`·. -
`
`-35-
`
`by treatinq ~ with ammonium acetate and sodium
`cyanobo~ohydride in the presence of an alcohol
`solvent such as methanol.
`Starting compound of formula ! wherein Z is
`
`5
`
`10
`
`15
`
`and X is O, that is,. compounds of the structure
`
`25
`
`are disclosed in WO 8402-903-A and GB 2, 162, 1.79A
`both filed in the name of Sandoz.
`Starting compounds of formula B wherein z
`
`is
`
`36 of 91
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`
`-36-
`
`5
`
`10
`
`and Xis NB, that.is, compounds of the structure
`
`20 may be prepared by the reductive amination of the
`aldehyde Q
`
`25
`
`Q
`
`30
`
`by treatinq.Q with ammonium acetate and sodium
`cyanoborohydride in the presence of an alcohol
`solvent such as methanol.
`
`I
`
`37 of 91
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`
`-37-
`
`5
`
`The compounds of the invention may be
`prepared· as racemic mixtures and may later be
`resolved to obtain the S-isomer which is
`preferrced. However, the compounds of the
`invention may be prepared directly in the form of
`their s-i-somers as described herein and in the
`working examples set out hereinafter.
`The compounds of the invention are
`inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme
`10 A (BMG-CoA) reductase and thus are useful in
`inhibiting cholesterol biosynthesis as
`demonstrated by the following tests.
`
`15
`
`20
`
`25
`
`30
`
`l} Rat Hepatic BMG-CoA Reductase
`Rat hepatic BMG-CoA reductase activity is
`measured using a modification of the method
`described by Edwards (Edwards, P.A., et al.,
`J. Lipid Res. ~:40, 1979). Rat hepatic
`microsomes are used as a source.of enzyme, and the
`enzyme activity is determined by measuring the
`conversion of the 14c-BMG-CoA substrate to
`14c-mevalonic acid.
`
`a. Preparation of Microsomes
`Livers are removed from 2-4
`cholestyramine-fed.-<!' decapitated, Sprague Dawley
`rats, and homogenized in phosphate buffer A
`(potassium phosphate, 0.04 M, pB 7.2; KCl, 0.05 M;
`sucrose, O.l M; EDTA, 0.03 M; aprotinin, 500 KI
`units/ml). The homogenate is spun at 16,000 x g
`·for 15 minutes at 4°C. ?;he supernatant is removed
`and recentrifuged under the same conditions a
`second time. The second 16,000 x· g supernatant is
`
`38 of 91
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`
`-38-
`
`spun at 100,000 x g for 70 minutes at 4°C.
`Pelleted microsomes are resuspended in a minimum
`volume of buffer A (3-5 ml per liver), and
`homogenized in a glass/glass homogenizer.
`5 Dithiothreitol is added (10 DIM), and the
`preparation is aliquoted, quick frozen in
`acetone/dry ice, and stored at -so 0 c. The
`specific activity of the first microsomal
`preparation was 0.68 nmole mevalonic acid/mg
`protein/minute.
`
`10
`
`15
`
`20
`
`25
`
`bl Enzyme Assay
`The reductase is assayed in 0.25 ml which
`contains the following components at the indicated
`final concentrations:
`
`Potassium phosphate, pB 7.0
`0.04 M
`KCl
`0.05 M
`sucrose
`0.10 M
`0.03 M
`EDTA
`Dithiothreitol
`O.Ol M
`NaCl
`3.5 mM
`.Dimethylsulfoxide
`1%
`50-200 ~g Microsomal protein
`14c-[DL]BMG-CoA (0.05 pCi,
`100 pM
`30~0 mCi/mmole)
`~PB (nicotinamide adenine
`dinucleotide phosphate)
`
`2.7 mM
`
`30 Reaction mixtures are incubated at 37°C. Under
`conditions described, enzyme activity increases
`linearly up to 300 pg microsomal protein per
`reaction mixture, and is linear with respect to
`
`39 of 91
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`
`' ·,
`
`-39~
`
`incubation time up to 30 minutes. The standard
`incubation time chosen for drug studies is 20
`minutes, which results in 12-15% conversion of
`BMG-CoA substrate to the mevalonic acid product.
`[DL-]BMG-CoA substrate is used at 100 µM, twice
`the concentration needed to saturate the enzyme
`under t

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