United States Patent
`
`[191
`
`Roth
`
`[11]
`
`[45]
`
`Patent Number:
`
`4,681,893
`
`Date of Patent:
`
`Jul. 21, 1987
`
`OTHER PUBLICATIONS
`
`Singer, et al.; Proc. Soc. Exper. Biol. Med.; vol. 102, pp.
`370-373, (1959).
`Hulcher; Arch. Biochem. Biophys., vol.
`422-427, (1971).
`Brown, et al.; New England Jour. of Med., vol. 305, No.
`9, pp. 515-517, (1981).
`Brown, et al.; J. Chem. Soc. Perkin I,
`1165-1170.
`
`(1976), pp.
`
`146, pp.
`
`Journal of the Americas Medical Assoc.; (1984), vol.
`251, pp. 351-364, 365-374.
`
`Primary Examiner—Joseph Paul Brust
`Attorney, Agent, or Firm—Jerry F. Janssen
`
`[57]
`
`ABSTRACI‘
`
`Certain trans-6-[2-(3- or 4-carboxamido-substituted pyr-
`rol-1—yl)alkyl]~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 (HMG CoA
`reductase and are thus useful hypolipidemic or hypo-
`cholesterolemic agents. Pharmaceutical compositions
`containing such compounds, and a method of inhibiting
`the biosynthesis of cholesterol employing such pharma-
`ceutical compositions are also disclosed.
`
`9 Claims, No Drawings
`
`Mylan Exhibit 1019, Page 1
`
`TRANS-6-[2-(3- OR
`4-CARBOXAMIDO-SUBSTITUTED
`PYRROL-1-YL)ALKYL]-4-HYDROXYPY-
`RAN-2-ONE INHIBITORS OF
`CHOLESTEROL SYNTHESIS
`
`Inventor:
`
`Bruce D. Roth, Ann Arbor, Mich.
`
`Assignee: Warner-Lambert Company, Morris
`Plains, N.J.
`
`Appl. No.: 868,867
`
`Filed:
`
`May 30, 1986
`
`Int. Cl.4 ................... .. A61K 31/40; A61K 31/35;
`C07D 207/327
`U.S. Cl. .................................. .. 514/422; 514/423;
`546/256; 546/275; 548/517; 548/537
`Field of Search .............. .. 548/517, 537; 514/422,
`514/423
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1976 Endo et al. ........................ .. 549/292
`3,933,140
`9/1977 Endo et al.
`..... .. 435/125
`4,049,495
`1/1979 Endo et al.
`.. 548/344 X
`4,137,322
`..
`4,198,425 4/1980 Mitsui et al.
`..... .. 514/460
`4,255,444
`3/1981 Oka et al.
`.... ..
`549/292 X
`4,262,013
`4/1981 Mitsui et al.
`..
`549/292 X
`4,375,475
`3/1983 Willard et al.
`.................... .. 514/460
`
`
`
`[54]
`
`[75]
`
`[73]
`
`[21]
`
`[22]
`
`[51]
`
`[52]
`
`[53]
`
`[56]
`
`Mylan Exhibit 1019, Page 1
`
`
`
`
`
`
`
`

`
`1
`
`4,681,893
`
`TRANS-6-[2-(3- OR
`4-CARBOXAMIDO-SUBSTITUTED
`PYRROL-1-YL)ALKYL]-4-HYDROXYPYRAN-
`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-yl)a1kyl]-4-hydroxypyran-
`2-ones and the corresponding ring-opened acids derived
`therefrom which are potent inhibitors of the enzyme
`3-hydroxy-3-methylglutaryl-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
`
`5
`
`10
`
`15
`
`20
`
`effective in lowering the level of blood plasma choles- 25
`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,
`it
`is known that certain derivatives of
`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. Biochem. 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
`
`50
`
`55
`
`60
`
`40
`
`45
`
`In accordance with the present invention, there are
`provided certain trans-6-[2-(3- or 4-carboxamido-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-
`
`65
`
`2
`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
`
`OH
`
`I
`
`wherein X is —Cl-12-, —CI-l2CH;;_—, —CH2CH2C-
`H2— or ——CH2CH(CH3)—.
`R1 is 1-naphthyl; 2-naphthyl; cyclohexyl; norborne-
`nyl; 2-, 3-, or 4-pyridinyl; phenyl, phenyl substituted
`with fluorine, chlorine, bromine, hydroxyl;
`trifluoro-
`methyl; 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.
`Either R2 or R3 is —-CONR5R6 where R5 and R5 are
`independently hydrogen; alkyl of from one to six car-
`bon atoms; 2-, 3-, or 4-pyridinyl; phenyl; phenyl substi-
`tuted with fluorine, chlorine, bromine, cyano, trifluoro-
`methyl, or carboalkoxy of from three to eight carbon
`atoms; and the other of R2 or R3 is hydrogen; alkyl of
`from one to six carbon atoms; cyclopropyl; cyclobutyl;
`cyclopentyl; cyclohexyl; phenyl; or phenyl substituted
`with fluorine, chlorine, bromine, hydroxyl; trifluoro-
`methyl; 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.
`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.
`
`Inanother 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-l-yl)alkyl]alde-
`hyde compound of the formula
`
`R1
`
`N—X-CHO
`
`R4
`
`.
`
`with the dilithio or sodio-lithio salt of methyl aceto-
`acetate to form a compound of the structure
`
`OH
`I
`l
`N-X-CH-CH2-C-Cl-l2—CO0CH3
`
`0l
`
`R1
`
`R4
`
`Mylan Exhibit 1019, Page 2
`
`
`
`Mylan Exhibit 1019, Page 2
`
`

`
`3
`(b) reducing the product of step (a) with a trialkylbo-
`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-
`ous hydrogen peroxide solution to produce a com-
`pound of the formula
`
`//
`
`/,,//0
`O-CHZCOOCH3
`
`and
`
`(d) cyclizing the product step (c) to a lactone of formula
`I above by heating in an inert solvent such as toluene
`or, alternatively converting the product of step (c) to
`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-
`ro1-1-yl)alkyl]-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
`1-naphthyl; 2-naphthyl; cyclohexyl; norbornenyl; 2-, 3-,
`or 4-pyridinyl; phenyl, 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 substituent groups at the 2-
`position of the pyrrole nucleus are phenyl and substi-
`tuted phenyl.
`'
`In the compounds of this invention, position 5 of the
`pyrrole nucleus is substituted with alkyl of from one to
`six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl;
`cyclohexyl; or trifluoromethyl. Preferred substituents
`
`4,681,893
`
`4
`
`are alkyl or trifluoromethyl 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-
`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 R6 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, on-haloesters of
`structural formula II are reacted with the known 2-[1-
`(2-aminoalkyl)]-1,3-dioxalane, III, in the presence of an
`acid scavenger such as triethylamine to produce the
`N-alkyl-a-aminoesters, IV. The aminoesters, IV are
`
`REACTION SEQUENCE I
`
`1'3:
`R1CI-ICOOCI-I3
`11
`
`III
`
`c|:oocH3
`R1-(I21-I
`If“
`x
`
`0
`
`0
`
`IV
`
`(1) R4COCl
`(2) NaOH, H20
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Mylan Exhibit 1019, Page 3
`
`Mylan Exhibit 1019, Page 3
`
`

`
`5
`-continued
`REACTION. SEQUENCE 1
`
`4,681,893
`
`6
`known in the art, and subsequently further purified, if
`. desired, by recrystallization. On the other hand, in the
`case where R4 is 1-methylethyl, the cyclo-addition reac-
`tion yields predominantly one product which can be
`purified by recrystallization alone.
`Hydrolysis of the acetal function of compounds VIIa
`and VIIb in aqueous acid solution affords the aldehydes
`VIIIa and VIIIb. The aldehydes, VIII, are further con-
`verted to compounds of the present invention by the
`processes depicted in Reaction Sequence 2.
`The aldehyde compounds, VIII, are reacted with the
`dilithium or lithio-sodio salt of methyl acetoacetate to
`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
`-78“ C. after which sodium borohydride is added.
`The mixture is stirred for about one to two hours and
`then oxidized by the addition of basic aqueous hydro-
`gen peroxide solution. The reaction produces the, 7-
`(substituted-pyrrolyl)-3,5-dihydroxyheptanoic acids,
`
`Y
`)|(
`N
`
`VIIb
`
`R .
`
`coon
`
`/
`
`CH
`\
`I
`AcoO
`Rrcéc-R3 R'\ /N\
`VI
`§"x"]
`
`10
`
`15
`
`20
`
`REACTION SEQUENCE Il
`
`OH
`
`IC
`
`I
`
`0
`
`, e ll e
`NaLI(CH3CCHCOOCH3
`R4————————%R;
`
`0 I
`
`I
`HCH2CCI-IZCOOCI-I3
`
`R2
`
`R3
`
`IX a
`IX b
`
`(l) Tributylborane
`(2) Sodium borohydride
`(3) H202. 0H9
`\‘\~
`\
`3‘
`C--CH2——C-CH2COOH
`
`H
`
`VIII a
`VIII b
`
`
`
`acylated with an acid halide and subsequently hydro-
`lyzed in aqueous base solution to produce the N-acyl-N-
`alkyl aminoacids, 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-
`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
`are separated by chromatographic techniques well
`
`60
`
`65
`
`X, in which the product contains a predominance of the
`desired R*,R* configuration at carbon atoms three and
`five which bear the hydroxy groups.
`The acids may be converted to a corresponding phar-
`maceutically acceptable salt by conventional means, if
`desired, or cyclized to the trans-6-[2-(substituted-pyr-
`rol-1-yl)alkyl]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
`to produce material containing from 85-90% of the
`desired trans-configuration of the 4-hydroxy group
`relative to the 6-(substituted-pyrrol-1-yl)alkyl group on
`the pyran-2-one lactone ring.
`
`Mylan Exhibit 1019, Page 4
`
`Mylan Exhibit 1019, Page 4
`
`

`
`4,681,893
`
`7
`8
`The ring-opened hydroxy acids of structural formula
`lipid by the rat liver homogenate is measured. The mi-
`II above are intermediates in the synthesis of the lactone
`cromolar concentration of compound required for 50%
`compounds of formula I and may be used in their free
`inhibition of sterol synthesis over a one-hour period is
`measured, and expressed as an IC5o value.
`acid form or in the form of a pharmaceutically accept-
`A second method (designated COR screen) em-
`able metal or amine salt in the pharmaceutical method 5
`ployed the procedure detailed by T. Kita, et al., J. Clin.
`of the present invention. These acids react to form phar-
`Invest,
`(1980), 66: 1094-1100.
`In this method,
`the
`maceutically acceptable metal and amine salts. The
`amount of 14C-HMG-CoA converted to ‘4C-mevalon-
`term “pharmaceutically acceptable metal salt” contem-
`ate in the presence of a purified enzyme preparation of
`plates salts formed with the sodium, potassium, calcium,
`magnesium, aluminum, iron, and zinc ions. The term 10 HMG-CoA reductase was measured. The micromolar
`“pharmaceutically acceptable amine salt” contemplates
`concentration of compound required for 50% inhibition
`salts with ammonia and organic nitrogenous bases
`of cholesterol synthesis was measured and recorded as
`strong enough to form salts with carboxyl.ic acids. Bases
`an IC5o value.
`useful for the formation of pharmaceutically acceptable
`The activity of several representative examples of
`nontoxic base addition salts of compounds of the pres- 15 compounds in accordance with the present invention
`ent invention form a class whose limits are readily un-
`appears in Table l, and is compared with that of the
`derstood by those skilled in the art.
`prior art compound, compactin.
`The free acid form of compounds of the present in-
`For preparing pharmaceutical compositions from the
`vention may be regenerated from the salt form, if de-
`compounds of this invention, inert, pharmaceutically
`sired, by contacting the salt with a dilute aqueous solu- 20 acceptable carriers can be either solid or liquid. Solid
`tion of an acid such as hydrochloric acid.
`form preparations include powders, tablets, dispersable
`The base addition salts may differ from the free acid
`granules, capsules, cachets, and suppositories.
`forms of the compounds of this invention in such physi—
`A solid carrier can be one or more substances which
`cal characteristics as solubility and melting point, but
`may also act as diluents, flavoring agents, solubilizers,
`are otherwise considered equivalent to the free acid 25 lubricants, suspending agents, binders, or tablet disinte-
`form for the purposes of this invention.
`grating agents; it can also be an encapsulating material.
`The compounds of the present invention may exist in
`In powders, the carrier is a finely divided solid which
`solvated or unsolvated form. In general, the solvated
`is in a mixture with the finely divided active compo-
`forms with pharmaceutically acceptable solvents such
`nent. In tablets, the active compound is mixed with the
`as water, ethanol and the like, are equivalent to the 30 carrier having the necessary binding properties in suit-
`unsolvated forms for the purposes of this invention.
`able proportions and compacted in the shape and size
`The compounds of this invention are useful as hypo-
`desired.
`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
`through inhibition of the enzyme 3-hydroxy-3-methyl- 35 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
`The ability of compounds of the present invention to
`molds and allowed to cool and solidify.
`inhibit the biosynthesis of cholesterol was measured by
`Powders and tablets preferably contain between
`two methods. A first method (designated CSI screen) 40 about 5 to about 70% by weight of the active ingredi-
`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,
`method,
`the level of HMG-CoA enzyme activity in
`tragacanth, methyl cellulose, sodium carboxymethyl
`standard laboratory rats is increased by feeding the rats
`cellulose, a low-melting wax, cocoa butter, and the like.
`a chow diet containing 5% cholestyramine for four 45
`The term “preparation” is intended to include the
`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
`tion of cholesterol-14C-acetate into nonsaponifiable
`active component (with or without other carriers) is
`TABLE 1
`OH
`
`i R2
`
`R3
`
`R1
`
`N—x°°H 0 To
`
`R4
`
`1Cso
`(Micromoles/liter)
`
`Compound
`X
`R1
`R2
`R3
`R4
`CS1
`COR
`
`1
`
`—CH2CH2—
`
`O.
`
`__CONH
`
`—CH(CH3)2
`
`0.035
`
`0.050
`
`Mylan Exhibit 1019, Page 5
`
`Mylan Exhibit 1019, Page 5
`
`

`
`4,681,893
`
`TABLE l-continued
`OH
`
`R1
`
`R2
`
`R3
`
`_CONH
`
`N—X
`
`0 T0
`
`R4
`
`R2
`
`:
`
`R3
`
`:
`
`__CONH
`
`10
`
`R4
`
`-CF3
`
`-CF3
`
`IC50
`(Micromoles/liter]
`CSl
`COR
`
`0.40
`
`0.018
`
`0.026
`
`0.40
`
`0.020
`
`0.028
`
`Compound
`
`X
`
`R1
`
`2
`
`3
`
`-CH2CH2-
`
`—CHzCH2-‘
`
`Compactin (Prior art)
`
`: F
`
`: F
`
`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,
`ethanol, or propylene glycol may be mentioned as ex-
`amples of liquid preparations suitable for parenteral
`administration.
`
`35
`
`40
`
`45
`
`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
`prepared by dissolving the active compound in water
`and adding suitable flavorants, coloring agents, stabiliz-
`ers, and thickening agents as desired. Aqueous suspen-
`sions for oral use can be made by dispersing the finely
`divided active component in water together with a
`viscous material such as natural or synthetic gums, res-
`ins, methyl cellulose, sodium carboxymethyl cellulose,
`and other suspending agents known to the pharmaceuti-
`cal formulation art.
`Preferably, the pharmaceutical preparation is in unit
`dosage form. In such form, the preparation is divided
`into unit doses containing appropriate quantities of the
`active component. The unit dosage form can be a pack-
`aged preparation, the package containing discrete quan-
`tities of the preparation, for example, packeted tablets,
`capsules, and powders in vials or ampoules. The unit
`dosage form can also be a capsule, cachet, or tablet
`itself, or it can be the appropriate number of any of
`these packaged forms.
`In therapeutic use as hypolipidemic or hypocholes-
`terolemic agents, the compounds utilized in the pharma- 65
`ceutical method of this invention are administered to
`the patient at dosage levels of from 40 mg to 600 mg per
`day. For a normal human adult of approximately 70 kg
`
`50
`
`S5
`
`60
`
`or body weight, this translates to a dosage of from about
`0.5 mg/kg to about 8.0 mg/kg of body weight per day.
`The dosages, however, may be varied depending
`upon the requirements of the patient, the severity of the
`condition being treated, and the compound being em-
`ployed. Determination of optimum dosages for a partic-
`ular situation is within the skill of the art.
`
`The following examples illustrate particular methods
`for preparing compounds in accordance with this in-
`vention. These examples are illustrative and are not to
`be read as limiting the scope of the invention as it is
`defined by the appended claims.
`EXAMPLE 1
`
`Preparation of
`trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphe-
`nyl-1-[2-(tetrahydro-4-hydroxy-6-oxo2H-pyran-2-yl)e-
`thyl]-pyrrole-3-carboxamide
`
`Step A: Preparation of 0L-[[2-(1,3-dioxalan-2-yl)ethyl-
`]amino]-4-tluorobenzeneacetic acid, ethyl ester
`A solution of 26 g (220 mmol) of 2-[l-(2-aminoethyl)]-
`1,3-dioxalane in 50 ml of acetonitrile was added at room
`temperature with stirring to a solution of 200 mmol of
`a-bromo-4-fluorobenzeneacetic acid, ethyl ester (J. W.
`Epstein et al., J. Med. Chem., 24: 481-490 (1981)) and 42
`ml (300 mmol) of triethylamine in 350 ml of acetonitrile.
`The resulting mixture was stirred at room temperature
`overnight and then poured into 500 ml of diethyl ether.
`The resulting suspension was extracted with 300 ml of
`water and then twice with 300-ml portions of 2M hy-
`drochloric acid. The combined extracts were made
`basic with 25% aqueous sodium hydroxide solution and
`extracted twice with 500-ml portions of ethyl acetate.
`The ethyl acetate extracts were combined, washed suc-
`cessively with water and brine, and then dried over
`anhydrous magnesium sulfate. The drying agent was
`removed by filtration, and the residue concentrated to
`yield 49.5 g of on-[[2-(1,3-dioxalan-2-yl)ethyl]amino]-4-
`fluorobenzeneacetic acid, ethyl ester.
`-
`The 90 MHz proton magnetic resonance spectrum of
`the product in deuterochloroform exhibited signals at
`1.18 (triplet, 3H, J =7 Hz); 1.85 (multiplet, 2H); 2.20
`
`Mylan Exhibit 1019, Page 6
`
`Mylan Exhibit 1019, Page 6
`
`

`
`11
`(broad singlet, 1H); 2.6 (multiplet, 2H); 3.85 (multiplet,
`4H); 4.1 (quartet, 2H, J =7 Hz); 4.22 (singlet, IH); 4.83
`(triplet, 1H, J =4.5 Hz); and 6.8-7.3 (multiplet, 4H)
`parts per million downfield from tetramethylsilane.
`Step B. Preparation of a-[[2-(1,3-dioxolan-2-y1)ethyl]— 5
`(2-methyl-l-oxopropyl)amino]-4-fluorobenzeneacetic
`acid, ethyl ester.
`Thirty grams (100 mmol) of a-[[2-(l,3-dioxalan-2-
`yl)ethyl]amino]-4-fluorobenzeneacetic acid, ethyl ester
`from Step A were dissolved in 200 ml of dichlorometh-
`ane together with 28.6 ml (205 mmol) of triethylamine
`and the resulting mixture was cooled to 0° C. under dry
`nitrogen. A solution of 11 ml (105 mmol) of isobutyryl
`chloride in 50 ml of dichloromethane was slowly added
`with stirring. After addition was complete, the mixture
`was stirred for an additional 60 minutes and then poured
`into 100 ml of diethyl ether. The ether solution was
`washed successively with portions of water, 2M hydro-
`chloric acid, sodium bicarbonate solution, and brine,
`and then dried over anhydrous magnesium sulfate.
`Evaporation of the solvents yielded 35 g of a-[[2-(1,3-
`dioxolan-2-yl)-ethyl]—(2-methyl-1-oxopropy1)amino]-4-
`_ fluorobenzene-acetic acid, ethyl ester.
`The 90 MHz proton magnetic resonance spectrum of 25
`a deuterochloroform solution of the product exhibited
`signals at 1.2 (multiplet, 9H); 1.7 (multiplet, 2H); 2.85
`(multiplet,
`lH); 3.35 (multiplet, 2H); 3.80 (multiplet,
`4H); 4.20 (quartet, 2H, J =7 Hz); 4.60 (triplet, 1H,
`J =4.5 Hz); 5.81 (singlet, 1H); and 6.8-7.3 (multiplet,
`4H) parts per million downfield from tetramethylsilane.
`Step C. Preparation of a-[[2-(1,3-dioxolan-2-yl)ethyl]-
`(2-methyl-1-oxopropy1)amino]-4-fluorobenzeneacetic
`acid
`
`10
`
`15
`
`20
`
`30
`
`A solution of 35 g (95.3 mmol) of the ester from Step 35
`B and 12 g (300 mmol) of sodium hydroxide in 480 ml of
`5:1 methanol water was heated under reflux and stirred
`
`40
`
`45
`
`for two hours. The solution was cooled to room temper-
`ature, concentrated, and diluted by the addition of 500
`ml of water. The resulting solution was extracted with
`ether and the aqueous layer was acidified with ice-cold
`6M hydrochloric acid and then extracted twice with
`300-ml portions of ethyl acetate.
`The combined extracts were washed with brine,
`dried over anhydrous magnesium sulfate, and evapo-
`rated to yield 30 g of crude "a-[[2-(1,3-dioxolan-2-yl)e-
`thyl]-(2-methyl-1-oxopropyl)amino]-4-fluorobenzenea-
`cetic acid which was used without further purification.
`The 90 MHz proton magnetic resonance spectrum of
`a deuterochloroform solution of the product exhibited
`signals at 1.11 (doublet, 6H, J =7 Hz); 1.4-1.9 (multi-
`plet, 2H); 2.85 (multiplet, 1H); 3.32 (multiplet, 2H); 3.75
`(multiplet, 4H); 4.52 (triplet, 1H, J =4.5 Hz); 5.73 (sin-
`glet, 1H); and 6.8-7.3 (multiplet, 4H) parts per million
`downfield from tetramethylsilane.
`Step D. Preparation of N,3-diphenylpropynamide
`A solution of 171 mmol of dicyclohexylcarbodiimide
`in 250 ml of dichloromethane was added dropwise over
`a two hour period at 0° C. to a suspension of 171 mmol 60
`of propiolic acid, 179.6 mmol of aniline, and 5 mmol of
`4-dimethylaminopyridine in 400 ml of dichloromethane.
`After addition was complete, the mixture was stirred
`for an additional 30 minutes and then diluted with di-
`ethyl ether. The resulting mixture was filtered through 65
`silica gel, concentrated, and the residue recrystallized to
`provide 30.5 g of N,3-diphenyl-2-propynamide, mp
`122°—123° C.
`
`50
`
`55
`
`4,681,893
`
`12
`Analyzed for C151-I13NO: Calc.: C, 80.69%; H,
`5.87%; N, 6.27%; Found: C, 80.54%; H, 5.58%; N,
`6.52%.
`The infrared spectrum of a KBr pellet of the com-
`pound showed principal peaks at 2215, 1630, 1595,1549,
`1490, 1445, 1330, 756, and 691 reciprocal centimeters.
`Step E. Preparation of l-[2-(1,3-dioxalan-2-yl)ethyl]-5-
`(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl~IE-
`pyrrole-3-carboxamide
`A solution of 95 g (280 mmol) of a-[[2-(1,3-dioxolan-
`2-yl)ethyl]-(2-methyl-1-oxopropyl)amino]-4-fluoroben-
`zeneacetic acid, prepared as described in Step C above,
`and 98 g (439 mmol) of N,2-diphenylpropenoic carbox-
`amide, prepared as described in Step D above, was
`heated at 90° C. with stirring for four hours, (Vigorous
`gas evolution occurred for two hours.) After this time,
`the mixture was cooled to room temperature and chro-
`matographed twice on silica gel, eluting with 4:1 hex-
`anezethyl acetate to separate the product (RF 0.35)
`from the starting material (R/=O.5).
`Recrystallization of the product from isopropyl ether
`provided 59.5 g (119.3 mmol) of 1-[2-(1,3-dioxalan-2-
`yl)ethyl]-5-(4-fluorophenyl)-2-(l-methylethyl)-N,4-
`diphenyl-1H-pyrrole-3-carboxamide, mp l59°—162° C.
`Analyzed for C31H31FN2O3: Calc.: C, 74.68%; H,
`6.27%; N, 5.62%; Found: C, 75.04%; H, 6.12%; N,
`5.89%.
`‘
`
`Step F. Preparation of 5-(4-fluorophenyl)-2-(1-methyle-
`thyl)-1-(3-oxopropyl)-N,4-dipheny1-lg-pyrrole-3-can
`boxamide
`_
`A solution of 59 g (118.3 mmol) of l-[2-(l,3-dioxalan-
`2-yl)ethyl]-5-(4-fluorophenyl)-2-(1-methy1ethyl)-N,4-
`diphenyl-1H-pyrrole-3-carboxamide,
`from Step E
`above, and 0.4 ml of concentrated hydrochloric acid in
`1200 ml of anhydrous ethanol was heated under reflux
`with stirring for 24 hours. After this time the mixture
`was cooled to room temperature, concentrated, and the
`residue taken up in 1200 ml of 3:1 acetonezwater and 5
`g of p-toluenesulfonic acid was added. This mixture was
`heated under reflux with stirring for two days after
`which time the solution was cooled to room tempera-
`ture and partitioned between 1 liter of diethyl ether and
`200 ml of brine solution.
`The organic phase was separated, washed succes-
`sively with sodium bicarbonate solution and brine, dried
`over anhydrous magnesium sulfate and concentrated.
`The oil which resulted was dissolved in the minimum
`amount required of hot isopropyl ether. The crystals
`which formed upon cooling were collected by filtration
`to yiled 36.8 g of 5-(4-fluorophenyl)-2-(1-methylethyl)-
`1-(3-oxopropyl)-N,4-diphenyl-lH-pyrro1e-3-carboxa-
`mide. A further crop of 9.8 g of crystals were obtained
`from the mother liquor.
`Analyzed for C29H27FN2O3: Calc.: C, 76.63%; H,
`5.99%; N, 6.16%; Found: C, 76.48%; H, 6.20%; N,
`6.14%.
`Step G. Preparation of 2-(4-fluorophenyl)-8-hydroxy-5-
`(1-methylethyl)-/3-oxo-3-phenyl-4-[(phenylamino)car-
`bonyl]-lg-pyrrole-1-heptanoic acid, methyl ester
`A solution of methyl acetoacetate (26.4 ml, 243
`mmol) in 250 ml of anhydrous tetrahydrofuran was
`added dropwise to a stirred suspension of hexane-
`washed sodium hydride (6.4 g, 267 mmol) in 200 ml of
`tetrahydrofuran at 0° C. When gas evolution was com-
`plete, 97.2 ml of 2.5M n-butyl lithium was added drop-
`wise over a period of 60 minutes.
`The resulting solution was stirred for 30 minutes at 0°
`C. and then cooled to -78’ C. after which a solution of
`
`Mylan Exhibit 1019, Page 7
`
`Mylan Exhibit 1019, Page 7
`
`

`
`4,681,893,
`
`14
`
`EXAMPLE 2
`
`13
`36.8 g (80.9 mmol) of 5-(4-fluorophenyl)-2-(1-methyle-
`thyl)-1-(3-oxopropyl)-N,4-diphenyl-lg-pyrrole-3-can
`boxamide, from Step F above, in 100 ml of tetrahydro-
`furan was added over a period of thirty minutes. The
`resulting solution was stirred for 30 minutes at —78° C.
`and then warmed to 0° C. where it was held for an
`additional 60 minutes.
`The mixture was then acidified by the dropwise addi-
`tion of 300 ml of ice-cold 3M hydrochloric acid, diluted
`with ether, washed successively with water and brine,
`dried over anhydrous magnesium sulfate, and concen-
`trated. Flash chromatography of the residue yielded
`3