4,681,893
`
`
`
`Jul. 21, 1987
`
`
`
`
`[11] Patent Number:
`
`
`[45] Date of Patent:
`
`
`
`
`
`United States Patent
`
`
`Roth
`
`
`
`[19]
`
`
`
`'
`
`
`
`
`
`146, pp.
`
`
`
`
`
`
`(1976), pp.
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`
`
`
`OTHER PUBLICATIONS
`Singer, eta1.; Proc. Soc. Exper. Biol. Med.; vol. 102, pp.
`
`
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`
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`
`
`
`
`370-373, (1959).
`
`
`Hulcher; Arch. Biochem. Biophys., vol.
`
`
`
`
`
`
`422-427’ (1971)'
`Brown, et al.; New England Jour. of Med., vol. 305, No.
`
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`
`
`
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`
`
`
`
`
`
`9. pp. 515-517, (1931).
`>
`Brown, et al.; J. Chem. Soc. Perkin I,
`
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`
`
`1 165-1 170.
`
`Journal of the Americas Medical Assoc.; (1984), vol.
`
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`
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`
`
`
`
`
`
`251. pp- 351-364, 365-374.
`
`
`
`
`Primary Examiner—.loseph Paul Brust
`Attorney, Agent, or Ftrm—Jerry F. Janssen
`
`
`
`
`
`
`[57]
`ABSTRACT
`
`
`
`
`Certain t“‘"S'5'[2'(3' 0‘ 4'°*“"°X=““i“°'5“bS“*“‘€d PW‘
`
`
`
`
`ro1—1—yl)alky1]-4-hydroxypyran-2-ones and the corre-
`sponding ring-opened acids derived therefrom which
`
`
`
`
`
`
`are potent
`inhibitors of the enzyme 3-hydroxy-3-
`
`
`
`
`
`
`
`
`
`
`
`methylglutaryl-coenzyme A reductase (IIMG CoA
`reductase and are thus useful hypohpidemic or hypo-
`
`
`
`
`
`
`
`cholesterolemic agents. Pharmaceutical compositions
`
`
`
`
`
`
`
`
`
`
`containing such compounds, and a method of inhibiting
`the biosynthesis of cholesterol employing such pharma-
`
`
`
`
`
`
`.
`.
`.
`.
`
`
`
`
`
`ceutical composltions are also disclosed.
`
`
`
`9 Claims, No Drawings
`
`
`
`
`
`[54] TRANS-6-[2-(3- OR
`
`
`4-CARBOXAMIDO-SUBSTITUTED
`
`PYRROL-1-YL)ALKYL]-4-HYDROXYPY-
`
`RAN-2-ONE INHIBITORS OF
`
`
`CHOLESTEROL SYNTHESIS
`
`
`Bruce D Roth Ann Arbor Mich
`Inventor-
`
`
`
`
`
`
`'
`'
`’
`'
`’
`
`
`
`
`Assignee: Warner-Lambert Company, Morris
`Plains, NJ,
`
`
`
`
`
`
`AWL N°" 868367
`May 30, 1986
`Filed:
`
`
`
`Int. Cl.‘
`A61K 31/40; A61K 31/35;
`
`
`
`
`
`
`C0713 207/327
`
`
`
`
`
`US. Cl.
`551448//452127; 551448//45233.;
`
`
`
`
`Field of Search .........’....... 548/517, 537;'514/422,
`
`
`
`
`
`514/423
`
`
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`
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`
`
`References Cited
`
`
`U_S_ PATENT DOCUMENTS
`
`
`
`
`3533340 9/1975
`
`
`
`
`
`
`’
`’
`4,19s,42s 4/1930
`
`
`
`4,255,444
`3/1981
`4,262,013
`4/1981
`
`
`
`
`
`
`4,375,475
`3/1983
`
`
`
`*
`
`
`
`'
`
`_
`'
`
`
`
`
`’
`
`'
`
`'
`'
`
`
`
`.
`
`
`
`
`
`
`
`.
`
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`
`514/460
`549/292 X
`.549/292X
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`Sawai Ex 1031
`Page 1 of 20
`
`

`
`1
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`
`4,681,893
`
`
`2
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`zyme 3-hydroxy-3-methylglutaryl coenzyme A reduc-
`
`
`
`
`tase (HMG-CoA reductase).
`
`
`
`In particular, in its broadest aspect the present inven-
`
`
`
`
`
`
`
`
`tion provides compounds of structural formula I
`
`
`
`
`
`
`TRANS-6-[2-(3- OR
`
`4—CARBOXAMIDO-SUBSTITUTED
`
`PYRROL-1-YL)ALKYL]-4-I-IYDROXYPYRAN-
`
`2-ONE INHIBITORS OF CHOLESTEROL
`
`
`
`SYNTHESIS
`
`BACKGROUND OF THE INVENTION
`
`
`
`The present invention is related to compounds and
`
`
`
`
`
`
`
`pharmaceutical compositions useful as hypocholestero-
`
`
`
`
`lemic and hypolipidemic agents. More particularly, this
`
`
`
`
`
`
`
`invention concerns certain trans-6-[2-(3- or 4-carbox-
`
`
`
`
`
`
`
`amidosubstitutedpyrrol-1-y1)alkyl]-4-hydroxypyran-
`2-ones and the corresponding ring-opened acids derived
`
`
`
`
`
`
`
`therefrom which are potent inhibitors of the enzyme
`
`
`
`
`
`
`
`
`3-hydroxy-3-rnethylglutaryl-coenzyme A reductase
`
`
`(HMG CoA reductase), pharmaceutical compositions
`
`
`
`
`
`containing such compounds, and a method of inhibiting
`
`
`
`
`
`
`the biosynthesis of cholesterol employing such pharma-
`
`
`
`
`
`
`ceutical compositions.
`
`
`High levels of blood cholesterol and blood lipids are
`
`
`
`
`
`
`
`
`conditions involved in the onset of arteriosclerosis. It is
`
`
`
`
`
`well known that inhibitors of HMG-CoA reductase are
`
`
`
`
`
`
`
`effective in lowering the level of blood plasma choles-
`
`
`
`
`
`
`
`terol, especially low density lipoprotein cholesterol
`
`
`
`
`
`
`(LDL-C), in man (of. M. S. Brown and J. L. Goldstein,
`
`
`
`
`
`
`
`New England Journal of Medicine, 305, No. 9, 515-517
`
`
`
`
`
`
`
`(1981).
`It has now been established that
`lowering
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`LDL-C levels affords protection from coronary heart 30
`disease (cf. Journal of the American Medical Association.
`
`
`
`
`
`
`251, No. 3, 351-374 (1984).
`
`
`
`
`Moreover,
`is known that certain derivatives of
`it
`
`
`
`
`
`
`
`mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid)
`
`
`
`
`
`
`
`
`
`
`and the corresponding ring-closed lactone
`form, 35
`mevalonolactone, inhibit the biosynthesis of cholesterol
`
`
`
`
`
`(of. F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102:
`
`
`
`
`
`
`
`
`
`370 (1959) and F. H. Hulcher, Arch. Biac/rem. Biophys,
`
`
`
`
`
`
`
`
`146: 422 (1971)).
`
`
`
`U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322
`
`
`
`
`
`
`
`disclose the fermentative production of a natural prod-
`
`
`
`
`
`
`uct, now called compactin, having an inhibitory effect
`
`
`
`
`
`
`
`on cholesterol biosynthesis. Compactin has been shown
`
`
`
`
`
`
`
`to have a
`complex structure which includes
`a
`
`
`
`
`
`
`
`mevalonolactone moiety (Brown et al., J. Chem. Soc.
`
`
`
`
`
`
`
`Perkin I (1976) 1135.
`
`
`
`U.S. Pat. No. 4,255,444 to Oka et al. discloses several
`
`
`
`
`
`
`
`
`synthetic derivatives of mevalonolactone having an-
`
`
`
`
`
`
`
`
`tilipidemic activity.
`U.S. Pat. Nos. 4,198,425 and 4,262,013 to Mitsue et al.
`
`
`
`
`
`
`
`
`disclose aralkyl derivatives of mevalonolactone which
`
`
`
`
`
`are useful in the treatment of hyperlipidemia.
`
`
`
`
`
`U.S. Pat. no. 4,375,475 to Willard et al. discloses
`
`
`
`
`
`
`
`
`certain substituted 4-hydroxytetrahydropyran-2-ones
`
`
`
`which, in the 4(R)-trans-stereoisomeric form, are inhibi-
`
`
`
`
`
`
`tors of cholesterol biosynthesis.
`
`
`
`Published PCT application No. WO 84/01231 ‘dis-
`
`
`
`
`
`
`
`closes certain indole
`analogs and derivatives of
`
`
`
`
`
`
`
`mevalonolactone having utility as hypolipoproteinemic
`
`
`
`
`and antiatherosclerotic agents.
`
`
`
`SUMMARY OF THE INVENTION
`
`
`
`In accordance with the present invention, there are
`
`
`
`
`
`
`
`
`provided certain trans-6-[2-(3- or 4-carboxarnido-sub-
`
`
`
`
`
`stituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and
`
`
`
`
`
`
`
`
`the corresponding ring-opened hydroxy~acids derived_
`therefrom which are potent inhibitors of cholesterol
`
`
`
`
`
`
`
`biosynthesis by virtue of their ability to inhibit the en-
`
`
`
`
`
`
`
`
`
`
`OH
`
`
`
`
`
`
`
`wherein X is —CI-12-, —CH2CH2—, —CH2CH2C-
`H2— or —CH2CH(CH3)—.
`R1 is l-naphthyl; 2-naphthyl; cyclohexyl; norborne-
`
`
`
`
`
`nyl; 2-, 3-, or 4-pyridinyl; phenyl, phenyl substituted
`
`
`
`
`
`
`
`
`with fluorine, chlorine, bromine, hydroxyl;
`trifluoro-
`
`
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`
`
`methyl; alkyl of from one to four carbon atoms, alkoxy
`
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`
`
`
`
`of from one to four carbon atoms, or alkanoyloxy of
`
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`from two to eight carbon atoms.
`
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`
`
`Either R2 or R3 is —CONR5R6 where R5 and R5 are
`
`
`
`
`independently hydrogen; alkyl of from one to six car-
`
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`
`
`
`
`
`
`bon atoms; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substi-
`
`
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`
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`
`
`
`
`tuted with fluorine, chlorine, bromine, cyano, trif1uoro-
`
`
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`
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`
`methyl, or carboalkoxy of from three to eight carbon
`
`
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`
`
`
`
`atoms; and the other of R2 or R3 is hydrogen; alkyl of
`
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`
`
`
`
`
`from one to six carbon atoms; cyclopropyl; cyclobutyl;
`
`
`
`
`
`
`
`cyclopentyl; cyclohexyl; phenyl; or phenyl substituted
`
`
`
`
`
`with fluorine, chlorine, bromine, hydroxyl; trifluoro-
`
`
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`
`
`
`methyl; alkyl of from one to four carbon atoms, alkoxy
`
`
`
`
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`
`
`
`of from one to four carbon atoms, or alkanoyloxy of
`
`
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`
`
`
`
`
`from two to eight carbon atoms.
`
`
`
`
`
`R4 is alkyl of from one to six carbon atoms; cyclopro-
`
`
`
`
`
`
`
`
`pyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoro-
`
`
`
`
`
`
`methyl.
`Also contemplated as falling within the scope of the
`
`
`
`
`
`
`present invention are the hydroxy acids, and pharma-
`
`
`
`
`
`
`
`
`ceutically acceptable salts thereof, derived from the
`
`
`
`
`
`
`
`opening of the lactone ring of the compounds of struc-
`
`
`
`
`
`
`
`tural formula I above.
`
`
`
`In another aspect of the present invention, there is
`
`
`
`
`
`
`
`provided a method of preparing the compounds of
`
`
`
`
`
`structural formula I above which comprises the steps of
`
`
`
`
`
`
`
`(a) first reacting a substituted [(pyrrol-1-yl)alkyl]alde-
`
`
`
`
`
`hyde compound of the formula
`
`
`
`
`
`
`
`R1
`
`
`
`R4
`
`
`
`
`
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`
`
`with the dilithio or sodio-lithio salt of methyl aceto-
`
`
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`
`
`
`
`
`
`acetate to form a compound of the structure
`
`
`
`
`
`
`R1
`
`1
`fl)
`OH
`N-X-CH--CI-I2-C-CH2—COOCH3
`
`R4
`
`
`
`
`
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`
`Sawai Ex 1031
`Page 2 of 20
`
`

`
`4,681,893
`
`3
`
`(b) reducing the product of step (a) with a trialkylbo—
`
`
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`
`
`
`
`
`rane compound such as tributylborane in the pres-
`
`
`
`
`
`
`ence of sodium borohydride in an inert solvent;
`
`
`
`
`
`(c) oxidizing the product of step (b) with alkaline aque-
`
`
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`
`
`
`
`
`
`ous hydrogen peroxide solution to produce a com-
`
`
`
`
`
`
`
`pound of the formula
`
`
`
`
`
`
`4
`
`
`are alkyl or trilluoromethyl with isopropyl being partic-
`
`
`
`
`
`
`
`ularly preferred.
`
`
`The preferred reaction sequence which is used to
`
`
`
`
`
`
`
`prepare compounds of the present invention involves
`
`
`
`
`
`
`the cycloaddition of a disubstituted acetylene, in which
`
`
`
`
`
`one substituent is carboxamido or N-substituted carbox-
`
`
`
`
`
`amido, to an appropriately substituted N-acylaminocar-
`
`
`
`
`boxylic acid to form a substituted pyrrole. This addition
`
`
`
`
`
`
`
`may occur in either of two ways, leading to a substi-
`
`
`
`
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`
`
`tuted pyrrole addition product in which the carbox-
`
`
`
`
`
`
`
`amido substituent resides on either carbon 3 or 4 of the
`
`
`
`
`
`
`
`pyrrole nucleus.
`
`
`the
`Thus,
`in compounds of the present invention,
`
`
`
`
`
`
`substituent at either position 3 or 4 of the pyrrole nu-
`
`
`
`
`
`
`cleus is -—CONR5R5 where R5 and R5 are indepen-
`
`
`
`
`
`
`
`
`dently hydrogen; alkyl of from one to six carbon atoms;
`
`
`
`
`
`
`
`
`2-, 3-, or 4-pyridinyl; phenyl; phenyl substituted with
`
`
`
`
`
`
`
`
`fluorine, chlorine, bromine, cyano, trifluoromethyl, or
`
`
`
`
`
`
`carboalkoxy of from three to eight carbon atoms and
`
`
`
`
`
`
`
`the other of the two positions is unsubstituted or is
`
`
`
`
`
`
`
`
`substituted with alkyl of from one to six carbon atoms;
`
`
`
`
`
`
`
`
`
`
`
`
`cyclopropyl;
`cyclobutyl;
`cyclopentyl;
`cyclohexyl;
`phenyl; or phenyl substituted with fluorine, chlorine,
`
`
`
`
`
`
`
`bromine, hydroxyl; trifluoromethyl; alkyl of from one
`
`
`
`
`
`
`
`to four carbon atoms, alkoxy of from one to four carbon
`
`
`
`
`
`
`
`
`
`atoms, or alkanoyloxy of from two to eight carbon
`
`
`
`
`
`
`
`
`atoms.
`
`Preferred groups for R5 and R6 are hydrogen, phenyl,
`
`
`
`
`
`
`or substituted phenyl. In a particularly preferred group
`
`
`
`
`
`
`of compounds within the present invention, R5 is hydro-
`
`
`
`
`
`
`
`gen and R5 is phenyl or substituted phenyl.
`
`
`
`
`
`The compounds of this invention are prepared by the
`
`
`
`
`
`
`
`general reaction scheme outlined in Reaction Sequence
`
`
`
`
`
`
`1 which takes advantage of the chemistry of mesionic
`
`
`
`
`
`
`
`compounds of the type described originally by R. Huis-
`
`
`
`
`
`
`gen et al., Ang. Chem. Int. Ed., 3: 136 (1964).
`
`
`
`
`
`
`
`
`The known, or readily prepared, a-haloesters of
`
`
`
`
`
`
`structural formula II are reacted with the known 2-[l-
`
`
`
`
`
`
`
`
`(2—aminoalky1)]-1,3-dioxalane, III, in the presence of an
`
`
`
`
`
`acid scavenger such as triethylamine to produce the
`
`
`
`
`
`
`
`N-alkyl-ct-aminoesters, IV. The aminoesters, IV are
`
`
`
`
`
`
`
`
`
`
`—CH2COOCH3
`
`
`
`(d) cyclizing the product step (c) to a lactone of formula
`
`
`
`
`
`
`
`
`I above by heating in an inert solvent such as toluene
`
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`
`
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`
`
`or, alternatively converting the product of step (c) to
`
`
`
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`
`
`a pharmaceutically acceptable salt by conventional
`
`
`
`
`
`
`methods.
`
`In yet another aspect, the present invention provides
`
`
`
`
`
`
`
`
`pharmaceutical compositions useful as hypolipidemic or
`
`
`
`
`hypocholesterolemic agents comprising a hypolipi-
`
`
`
`
`demic or hypocholesterolemic effective amount of a
`
`
`
`
`compound in accordance with this invention as set forth
`
`
`
`
`
`
`
`above, in combination with a pharmaceutically accept-
`
`
`
`
`
`able carrier.
`
`
`In another aspect, the present invention provides a
`
`
`
`
`
`
`
`method of inhibiting cholesterol biosynthesis in a pa-
`
`
`
`
`
`tient in need of such treatment by administering an
`
`
`
`
`
`
`
`
`
`effective amount of a pharmaceutical composition as
`
`
`
`
`defined above.
`
`
`DETAILED DESCRIPTION
`
`
`The compounds of the present invention comprise a
`
`
`
`
`
`
`class of trans-6-[2—(3- or 4-carboxamidosubstituted pyr-
`
`
`
`
`rol-1-yl)a1kyl]-4-hydroxypyran-2-ones in which the py-
`
`
`
`ran-2-one moiety is attached, through an alkyl chain, to
`
`
`
`
`
`
`the substituted pyrrole nucleus at the nitrogen, or 1~
`
`
`
`
`
`
`
`position, of the pyrrole. The alkyl group may be methy-
`
`
`
`
`
`
`
`
`lene, ethylene, propylene, or methylethylene. The pre-
`
`
`
`
`
`
`ferred alkyl chain linking the substituted pyrrole nu-
`
`
`
`
`
`
`
`
`cleus and the 4-hydroxypyran-2-one ring is ethylene.
`
`
`
`
`
`
`The compounds of structural formula I above possess
`
`
`
`
`
`
`two asymmetric carbon centers, one at the 4-hydroxy
`
`
`
`
`
`
`
`position of the pyran-2-one ring, and the other at the
`
`
`
`
`
`
`
`
`
`6-position of the pyran-2-one ring where the alkylpyr-
`
`
`
`
`
`
`
`role group is attached. This asymmetry gives rise to
`
`
`
`
`
`
`
`
`four possible isomers, two of which are the R-cis- and
`
`
`
`
`
`
`
`
`
`S-cis-isomers and the other two of which are the R-
`
`
`
`
`
`
`
`
`trans- and S-trans-isomers. This invention contemplates
`
`
`
`
`
`
`only the trans- form of the compounds of formula I
`
`
`
`
`
`
`
`above.
`
`In the compounds of the present invention, position 2
`
`
`
`
`
`
`
`of the substituted pyrrole nucleus is substituted with
`
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`
`
`1-naphthylg 2-naphthyl; cyclohexyl; norbornenyl; 2-, 3-,
`
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`
`
`or 4—pyridinyl; phenyl, phenyl substituted with fluorine,
`
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`chlorine, bromine, hydroxyl; trifluoromethyl; alkyl of
`
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`from one to four carbon atoms, alkoxy of from one to 60
`
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`four carbon atoms, or alkanoyloxy of from two to eight
`
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`carbon atoms. Preferred substituent groups at the 2-
`
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`position of the pyrrole nucleus are phenyl and substi-
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`
`
`tuted phenyl.
`
`
`
`In the compounds of this invention, position 5 of the 65
`
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`
`
`
`pyrrole nucleus is substituted with alkyl of from one to
`
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`
`
`six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl;
`
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`
`
`cyclohexyl; or trifluoromethyl. Preferred substituents
`
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`
`REACTION SEQUENCE I
`
`
`.
`.
`|
`
`COOCH3
`1'31"
`
`
`R1-(III-I
`R1CI-ICOOCH3
`II
`
`
`l'\IHx
`III
`
`A0
`
`\_/
`IV
`
`(1) R4COCl
`
`
`(2) NaOH, H20
`
`
`
`
`
`o
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`Sawai Ex 1031
`Page 3 of 20
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`

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`5
`
`-continued
`
`REACTION SEQUENCE I
`
`
`
`
`R;
`
`COOH
`
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`6
`
`known in the art, and subsequently further purified, if
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`
`
`desired, by recrystallization. On the other hand, in the
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`
`
`case where R4 is 1-methylethyl, the cyclo-addition reac-
`
`
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`
`
`
`tion yields predominantly one product which can be
`
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`
`purified by recrystallization alone.
`
`
`
`Hydrolysis of the acetal function of compounds VIIa
`
`
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`
`
`\/CH
`and VIIb in aqueous acid solution affords the aldehydes
`
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`
`
`
`
`I
`Ac2O
`VIIIa and VIIIb. The aldehydes, VIII, are further con-
`
`
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`
`
`
`
`
`verted to compounds of the present invention by the
`"4icT“‘\ /N\
`
`
`
`
`
`
`
`
`C
`10
`processes depicted in Reaction Sequence 2.
`
`
`
`
`
`
`
`V]
`:=."Y°]
`The aldehyde compounds, VIII, are reacted with the
`
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`
`
`dilithium or lithio-sodio salt of methyl acetoacetate to
`
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`
`
`produce the corresponding 7—(substituted—pyrrolyl)-5-
`
`
`
`
`hydroxy-3-oxoheptanoates, IX. The heptanoates,
`IX,
`
`
`
`
`
`are dissolved in a polar solvent such as tetrahydrofuran,
`
`
`
`
`
`
`through which a small amount of air has been bubbled.
`
`
`
`
`
`
`
`A slight excess of a trialkylborane, such as tributylbo-
`
`
`
`
`
`
`rane, is added to the mixture which is then cooled to a
`
`
`
`
`
`
`
`temperature of preferably between about 0° C. and
`
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`
`
`-78“ C. after which sodium borohydride is added.
`
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`The mixture is stirred for about one to two hours and
`
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`
`
`then oxidized by the addition of basic aqueous hydro-
`
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`
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`
`
`gen peroxide solution. The reaction produces the, 7-
`
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`
`
`
`(substituted-pyrrolyl)-3,5—dihydroxyheptanoic acids,
`
`
`
`4,681,893
`
`
`
`
`
`15
`
`
`
`REACTION SEQUENCE I]
`
`
`
`
`
`0I
`
`OH
`
`IC
`
`I
`
`
`l-lCH3CCH2COOCI-I3
`Ix
`
`
`
`
`
`
`NVR
`
`2
`
`R3
`
`
`
`
`
`IX
`
`
`
`
`
`
`;
`
`
`
`R3
`
`I R
`
`
`
`
`
`0
`
`, e ll e
`
`NaLl(CH2CCHCOOCH3
`
`R4 ——————————9R.
`
`
`
`
`
`
`
`
`
`
`
`lXa
`IXb
`
`
`(1) Tributylborane
`
`
`(2) Sodium borohydride
`
`
`(3) H202, 0H9
`
`
`
`\e\
`$\
`H
`\\H HO
`I-IO
`
`
`
`« \
`«\\\\\\‘
`C-CH2—-C-CHQCOOH
`
`
`
`
`
`
`
`
`
`
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`
`
`
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`
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`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`acylated with an acid halide and subsequently hydro-
`
`
`
`
`
`
`
`lyzed in aqueous base solution to produce the N-acyl-N-
`
`
`
`
`
`
`
`alkyl arninoacids, V.
`
`
`The N-acyl-N-alkyl aminoacids, V, are reacted with
`
`
`
`
`
`
`the appropriately substituted carboxamido acetylenic
`
`
`
`
`
`compounds, VI, in the presence of an acid anhydride to
`
`
`
`
`
`
`produce a mixture of the isomeric substituted pyrrole
`
`
`
`
`
`
`
`compounds VIIa and VIIb. Depending upon the sub-
`
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`
`
`
`
`
`
`stituents present,
`this cyclo-addition reaction affords
`
`
`
`
`
`
`differing ratios of the two products. For example, in the
`
`
`
`
`
`
`
`
`situation where R4 is
`trifluoromethyl,
`the reaction
`
`
`
`
`
`
`yields roughly equimolar amounts of the two isomeric
`
`
`
`
`
`
`
`products. In such situations, the two isomeric products
`
`
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`
`
`
`are separated by chromatographic techniques well
`
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`
`
`X, in which the product contains a predominance of the
`
`
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`
`
`
`desired R*,R* configuration at carbon atoms three and
`
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`
`
`five which bear the hydroxy groups.
`
`
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`
`
`The acids may be converted to a corresponding phar-
`
`
`
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`
`
`maceutically acceptable salt by conventional means, if
`
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`
`
`desired, or cyclized to the trans-6-[2-(substituted-pyr-
`
`
`
`
`
`
`rol—1-yl)a1kyl]pyran-2-ones,
`I, by dehydration in an
`
`
`
`
`
`
`inert solvent such as refluxing toluene with azeotropic
`
`
`
`
`
`
`
`removal of water. This cyclization step has been found
`
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`
`to produce material containing from 85-90% of the
`
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`
`
`
`
`desired trans-configuration of the 4-hydroxy group
`
`
`
`
`
`
`relative to the 6-(substituted-pyrroL1-yl)alkyl group on
`
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`
`
`the pyran-2-one lactone ring.
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`Sawai Ex 1031
`Page 4 of 20
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`

`
`4,681,893
`
`
`7
`8
`
`
`The ring-opened hydroxy acids of structural formula
`lipid by the rat liver homogenate is measured. The mi-
`
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`
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`
`
`
`
`II above are intermediates in the synthesis of the lactone
`cromolar concentration of compound required for 50%
`
`
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`
`
`compounds of formula I and may be used in their free
`inhibition of sterol synthesis over a one-hour period is
`
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`
`
`
`
`
`
`measured, and expressed as an IC5o value.
`acid form or in the form of a pharmaceutically accept-
`
`
`
`
`
`
`
`
`
`
`
`able metal or amine salt in the pharmaceutical method
`A second method (designated COR screen) em-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ployed the procedure detailed by T. Kita, et al., J. Clin.
`of the present invention. These acids react to form phar-
`
`
`
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`
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`
`
`
`
`
`
`
`
`
`
`
`(1980), 66:
`l094—l100.
`In this method,
`the
`Invest,
`maceutically acceptable metal and amine salts. The
`
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`
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`
`
`
`
`
`
`
`
`amount of 14C-HMG-CoA converted to l4C-mevalon-
`term “pharmaceutically acceptable metal salt” contem-
`
`
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`
`
`
`
`
`
`
`plates salts formed with the sodium, potassium, calcium,
`ate in the presence of a purified enzyme preparation of
`
`
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`
`
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`
`
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`
`
`
`
`HMG-CoA reductase was measured. The micromolar
`magnesium, aluminum, iron, and zinc ions. The term
`
`
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`
`
`
`
`
`
`
`
`
`
`
`concentration of compound required for 50% inhibition
`“pharmaceutically acceptable amine salt” contemplates
`
`
`
`
`
`
`
`
`
`
`
`of cholesterol synthesis was measured and recorded as
`salts with ammonia and organic nitrogenous bases
`
`
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`
`
`an IC5o value.
`strong enough to form salts with carboxylic acids. Bases
`
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`
`
`
`useful for the formation of pharmaceutically acceptable
`The activity of several representative examples of
`
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`
`
`nontoxic base addition salts of compounds of the pres-
`compounds in accordance with the present invention
`
`
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`
`
`
`
`
`
`ent invention form a class whose limits are readily un-
`appears in Table l, and is compared with that of the
`
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`
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`
`
`
`derstood by those skilled in the art.
`prior art compound, compactin.
`
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`
`
`The free acid form of compounds of the present in-
`For preparing pharmaceutical compositions from the
`
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`
`
`
`
`
`
`
`vention may be regenerated from the salt form, if de-
`compounds of this invention,
`inert, pharmaceutically
`
`
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`
`
`
`
`
`
`
`sired, by contacting the salt with a dilute aqueous solu-
`acceptable carriers can be either solid or liquid. Solid
`
`
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`
`
`
`
`
`
`tion of an acid such as hydrochloric acid.
`form preparations include powders, tablets, dispersable
`
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`
`
`The base addition salts may differ from the free acid
`granules, capsules, cachets, and suppositories.
`
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`
`
`A solid carrier can be one or more substances which
`forms of the compounds of this invention in such physi-
`
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`
`
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`
`
`
`
`cal characteristics as solubility and melting point, but
`may also act as diluents, flavoring agents, solubilizers,
`
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`
`
`are otherwise considered equivalent to the free acid
`lubricants, suspending agents, binders, or tablet disinte-
`
`
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`
`
`
`
`form for the purposes of this invention.
`grating agents; it can also be an encapsulating material.
`
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`
`
`In powders, the carrier is a finely divided solid which
`The compounds of the present invention may exist in
`
`
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`
`
`
`
`
`
`
`solvated or unsolvated form. In general, the solvated
`is in a mixture with the finely divided active compo-
`
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`
`
`forms with pharmaceutically acceptable solvents such
`nent. In tablets, the active compound is mixed with the
`
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`
`
`
`
`
`
`as water, ethanol and the like, are equivalent to the
`carrier having the necessary binding properties in suit-
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`unsolvated forms for the purposes of this invention.
`able proportions and compacted in the shape and size
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`desired.
`The compounds of this invention are useful as hypo-
`
`
`
`
`
`
`
`
`cholesterolemic or hypolipidemic agents by virtue of
`For preparing suppositories, a low-melting wax such
`
`
`
`
`
`
`
`
`
`
`
`
`
`their ability to inhibit the biosynthesis of cholesterol
`as a mixture of fatty acid glycerides and cocoa butter is
`
`
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`
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`
`
`
`
`
`
`
`
`
`
`35
`through inhibition of the enzyme 3-hydroxy-3-methyl-
`first melted, and the active ingredient
`is dispersed
`
`
`
`
`
`
`
`
`
`
`
`
`
`glutaryl-coenzyme A reductase (HMG—CoA reduc-
`therein by, for example, stirring. The molten homoge-
`
`
`
`
`
`
`
`
`
`
`
`
`tase).
`neous mixture is then poured into convenient sized
`
`
`
`
`
`
`
`
`molds and allowed to cool and solidify.
`The ability of compounds of the present invention to
`
`
`
`
`
`
`
`
`
`
`
`
`inhibit the biosynthesis of cholesterol was measured by
`Powders and tablets preferably contain between
`
`
`
`
`
`
`
`
`
`
`
`
`about 5 to about 70% by weight of the active ingredi-
`two methods. A first method (designated CSI screen)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`utilized the procedure described by R. E. Dugan et al.,
`ent. Suitable carriers are magnesium carbonate, magne-
`
`
`
`
`
`
`
`
`
`
`
`
`
`Archiv. Biochem. Biophys.,
`(1972), 152, 21-27. In this
`sium stearate, talc, lactose, sugar, pectin, dextrin, starch,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`tragacanth, methyl cellulose, sodium carboxymethyl
`method,
`the level of HMG-CoA enzyme activity in
`
`
`
`
`
`
`
`
`
`
`
`
`
`cellulose, a low-melting wax, cocoa butter, and the like.
`standard laboratory rats is increased by feeding the rats
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The term “preparation” is intended to include the
`a chow diet containing 5% cholestyramine for four
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`days, after which the rats are sacrificed.
`formulation of the active compound with encapsulating
`
`
`
`
`
`
`
`
`
`
`
`
`
`The rat livers are homogenized, and the incorpora-
`material as a carrier providing a capsule in which the
`
`
`
`
`
`
`
`
`
`
`
`
`
`active component (with or without other carriers) is
`tion of cholesterol-14C-acetate into nonsaponifiable
`
`
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`
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`
`
`
`
`TABLE 1
`
`
`
`
`OH
`
`
`
`
`N—X‘°\H 0
`
`
`
`
`TO
`
`
`'1 R1
`
`
`R3
`
`
`
`R1
`
`
`R1
`
`
`
`R4
`
`
`
`R2
`
`
`(1.
`
`O
`
`Compound
`l
`
`
`
`
`X
`
`—CH2CH1'—
`
`
`"'CONH
`
`R3
`
`
`
`
`
`R4
`
`—CH(CH3)1
`
`IC50
`
`(Micromoles/liter)
`
`CS1
`COR
`
`
`0.035
`
`0.050
`
`
`
`
`
`
`
`Sawai Ex 1031
`Page 5 of 20
`
`

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`4,681,893
`
`
`TABLE l-continued
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'-CON}-l
`
`R2
`
`
`
`
`
`
`
`
`
`
`
`
`
`R3
`
`
`
`
`
`O
`
`
`
`-—CONH :
`
`Compound
`2
`
`
`
`
`X
`
`"Cl'l2CHz"'
`
`—Cl‘lzCH2-‘
`
`
`
`Compactin (Prior art)
`
`
`
`
`
`
`
`
`
`
`
`fad.
`
`<1.
`
`
`
`
`
`
`
`
`
`K350
`
`(Micromoles/liter!
`
`CS1
`COR
`
`
`0.40
`0.40
`
`
`
`
`
`0.018
`
`
`
`
`
`
`
`
`
`0.028
`
`
`
`
`
`surrounded by a carrier, which is thus in association
`
`
`
`
`
`
`with it. In a similar manner, cachets are also included.
`
`
`
`
`
`
`
`
`Tablets, powders, cachets, and capsules can be used as
`
`
`
`
`
`
`
`solid dosage forms suitable for oral administration.
`
`
`
`
`
`
`
`Liquid form preparations include solutions suitable 30
`
`
`
`
`
`
`for oral or parenteral administration, or suspensions and
`
`
`
`
`
`
`emulsions suitable for oral administration. Sterile water
`
`
`
`
`
`
`
`solutions of the active component or sterile solutions of
`
`
`
`
`
`
`the active component in solvents comprising water,
`
`
`
`
`
`
`35
`ethanol, or propylene glycol may be mentioned as ex-
`
`
`
`
`
`
`
`amples of liquid preparations suitable for parenteral
`
`
`
`
`
`
`
`administration.
`
`Sterile solutions may be prepared by dissolving the
`
`
`
`
`
`
`active component in the desired solvent system, and
`
`
`
`
`
`
`
`then passing the resulting solution through a membrane
`
`
`
`
`
`
`
`filter to sterilize it or, alternatively, by dissolving the
`
`
`
`
`
`
`
`
`sterile compound in a previously sterilized solvent
`
`
`
`
`
`under sterile conditions.
`
`
`
`Aqueous solutions for oral administration can be
`
`
`
`
`
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`prepared by dissolving the active compound in water
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`and adding suitable flavorants, coloring agents, stabiliz-
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`ers, and thickening agents as desired. Aqueous suspen-
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`sions for oral use can be made by dispersing the finely
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`divided active component in water together with a
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`viscous material such as natural or synthetic gums, res-
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`ins, methyl cellulose, sodium carboxymethyl cellulose,
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`and other suspending agents known to the pharmaceuti-
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`cal formulation art.
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`Preferably, the pharmaceutical preparation is in unit
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`dosage form. In such form, the preparation is divided
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`into unit doses containing appropriate quantities of the
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`active component. The unit dosage form can be a pack-
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`aged preparation, the package containing discrete quan-
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`tities of the preparation, for example, packeted tablets,
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`capsules, and powders in vials or ampoules. The unit
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`dosage form can also be a capsule, cachet, or tablet
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`itself, or it can be the appropriate number of any of
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`these packaged forms.
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`In therapeutic use as hypolipidemic or hypocholes-
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`terolemic agents, the compounds utilized in the pharma- 65
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`ceutical method of this invention are administered to
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`the patient at dosage levels of from 40 mg to 600 mg per
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`day. For a normal human adult of approximately 70 kg
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`or body weight, this translates to a dosage of from about
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`0.5 mg/kg to about 8.0 mg/kg of body weight per day.
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`The dosages, however, may be varied depending
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`upon the requirements of the patient, the severity of the
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`condition being treated, and the compound being em-
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`ployed. Determination of optimum dosages for a partic-
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`ular situation is within the skill of the art.
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`The following examples illustrate particular methods
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`for preparing compounds in accordance with this in-
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`vention. These examples are illustrative and are not to
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`be read as limiting the scope of the invention as it is
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`defined by the appended claims.
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`EXAMPLE 1
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`Preparation of
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`trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphe-
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`nyl-1-[2-(tetrahydro-4-hydroxy-6-oxo2H-pyran~2-yl)e-
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`thyl]-pyrrole-3-carboxamide
`Step A: Preparation of a-[[2-(l,3-dioxalan-2-yl)ethyl-
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`]amino]-4-fluorobenzeneacetic acid, ethyl ester
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`A solution of 26 g (220 mmol) of 2-[l-(2-aminoethyl)]-
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`1,3-dioxalane in 50 ml of acetonitrile was added at room
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`temperature with stirring to a solution of 200 mmol of
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`a-bromo-4-fluorobenzeneacetic acid, ethyl ester (J. W.
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`Epstein et al., J. Med. Chem, 24: 481-490 (1981)) and 42
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`ml (300 mmol) of triethylamine in 350 ml of acetonitrile.
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`The resulting mixture was stirred at room temperature
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`overnight and then poured into 500 ml of diethyl ether.
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`The resulting suspension was extracted with 300 ml of
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`water and then twice with 300-ml portions of 2M hy-
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`drochloric acid. The combined extracts were made
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`basic with 25% aqueous sodium hydroxide solution and
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`extracted twice with 500-ml portions of ethyl acetate.
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`The ethyl acetate extracts were combined, washed suc-
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`eessively with water and brine, and then dried over
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`anhydrous magnesium sulfate. The drying agent was
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`removed by filtration, and the residue concentrated to
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`yield 49.5 g of on-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-
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`fluorobenzeneacetic acid, ethyl ester.
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`The 90 MHZ proton magnetic resonance spectrum of
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`the product in deuterochloroform exhibited signals at
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`1.18 (triplet, 3H, J :7 Hz); 1.85 (multiplet, 2H); 2.20
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`60
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`Sawai Ex 1031
`Page 6 of 20
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`12
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`Analyzed for C15H13NO: Calc.: C, 80.69%; H,
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`5.87%; N, 6.27%; Found: C, 80.54%; H, 5.58%; N,
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`6.52%.
`The infrared spectrum of a KBr pellet of the com-
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`pound showed principal peaks at 2215, 1630, 1595,1549,
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`1490, 1445, 1330, 756, and 691 reciprocal centimeters.
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`Step E. Preparation of l—[2—(1,3-dioxalan-2-yl)ethyl]-5-
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`(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-lH_-
`pyrrole-3-carboxamide
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`A solution of 95 g (280 mmol) of a-[[2—(l,3-dioxolan-
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`2-yl)ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluoroben-
`zeneacetic acid, prepared as described in Step C above,
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`and 98 g (439 mmol) of N,2-diphenylpropenoic carbox-
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`amide, prepared as described in Step D above, was
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`heated at 90” C. with stirring for four hours, (Vigorous
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`gas evolution occurred for two hours.) After this time,
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`the mixture was cooled to room temperature and chro-
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`matographed twice on silica gel, eluting with 4:1 hex-
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`ane:ethyl acetate to separate the product (R/=0.35)
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`from the starting material (R/= 0.5).
`Recry