United States Patent
`Hoefle et al.
`[45] Date of Patent:
`Mar. 3, 1987
`
`
`[19]
`
`_ [11] Patent Number:
`
`4,647,576
`
`3/1931 Okaetal. ................. 549/292x
`4,255,444
`.. . . . .. .. 549/292
`4,308,378 12/1981 Stokker . . . .. .
`
`8/1982 Humaus eta. .. . .
`4,343,811
`. . . .. 514/415
`9/1922 Patchettetal. . .. .
`4,351,344
`. . . ..5l4/460
`4,375,425
`3/1983 Willard eta]. ..
`.549/292x
`4,376,863
`3/1933 Lam . . .. . . . . ....
`. . . .. 549/292
`4,440,927 4/1934 Prugh ................................ .. 549/292
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`895445
`
`4/1983 Belgiiim .
`OTHER PUBLICATIONS
`
`Hulcher, Archives of Biochemistry and Biophysics,
`146, (1971), pp. 422-427.
`
`Primary Examiner—Donald G. Daus
`Assistant Examiner——~Wil1iam A. Teoli, Jr.
`Attorney, Agent, or Firm—Jerry F. Janssen
`
`[57]
`
`ABSTRACT
`
`6-[2-(Substituted—pyrrol-1-yl)ak1yl]pyran-2-ones and the
`corresponding ring-opened
`hydroxy-acids derived
`therefrom are potent
`inhibitors of the enzyme 3-
`hydroxy-3—methylglutarylcoenzyme
`A
`reductasc
`(HMG-CoA reductase), and are thus useful hypolipi-
`demic and hypocholesterolemic agents. Pharmaceutical
`compositions containing such compounds,
`and a
`method of treatment employing such pharmaceutical
`compositions are also disclosed.
`
`19 Claims, No Drawings
`
`[54]
`
`[75]
`
`TRANS-6-[2-(SUBSTITUTEDPYRROL-1-
`YL)ALKYL]-PYRAN-2-ONE INHIBITORS OF
`CHOLESTEROL SYNTHESIS
`
`Inventors: Milton L. Hoefle; Bruce D. Roth;
`Charlotte D. Stratton, all of Ann
`Arbor, Mich.
`
`[73]
`
`Assignee:
`
`Warner-Lambert Company, Morris
`Plains, N..l .
`
`[21]
`
`[22]
`
`Appl. No.:
`Filed:
`
`679,676
`
`Dec. 10, 1984
`
`Related U.S. Application Data
`
`Continuation—in-part of Ser. No. 653,798, Sep. 24, 1984,
`abandoned.
`‘
`
`Int. Cl.‘ .................. .. C07D 405/06; A61K 31/40
`U.S. Cl. .................................. .. 514/422; 514/343;
`548/517; 548/562; 548/515; 548/465; 548/453;
`546/281; 546/270; 546/271; 546/272; 544/236
`Field of Search .............. .. 548/517, 562; 514/422,
`514/343; 546/281
`
`References Cited
`
`[63]
`
`[51]
`[52]
`
`[5 8]
`
`[56]
`
`U.S. PATENT DOCUMENTS
`3,983,140
`4,198,425
`4,219,560
`4,248,889
`
`........................ .. 549/292
`9/1976 Endo et al.
`..
`.... .. 514/460
`4/1980 Mistui et al.
`
`8/1980 Houlihan ......
`.. 544/372 X
`2/1981 Oka et al.
`.......................... .. 514/532
`
`Mylan Exhibit 1016, Page 1
`
`Mylan Exhibit 1016, Page 1
`
`
`
`

`
`1
`
`4,647,576
`
`2
`
`TRANS-6-[2-(SUBSTITUTEDPYRROL-1-YL)AL-
`KYL]-PYRAN-2-ONE INHIBITORS OF
`CHOLESTEROL SYNTHESIS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of copend-
`ing application Ser. No. 653,798 filed Sept. 24, 1984
`abandoned.
`
`10
`
`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-(substitutedpyr-
`rol—l-yl)alkyl]-2~ones
`and the
`corresponding ring-
`opened acids derived therefrom which are potent inhib-
`itors of the enzyme 3—hydroxy-3-methylglutaryl-coen-
`zyme A reductase (HMG-CoA reductase), pharmaceu-
`tical composition containing such compounds, and a
`method of lowering blood serum cholesterol
`levels
`employing such pharmaceutical compositions.
`High levels of blood cholesterol and blood lipids are
`conditions which are involved in the onset of arterio-
`sclerosis. It is well known that inhibitors of HMG-CoA
`reductase are effective in lowering the level of blood
`plasma cholesterol, especially low density lipoprotein
`cholesterol (LDL-C), in man (cf. M. S. Brown and J. L.
`Goldstein, New England Journal of Medicine (1981),
`305, No. 9, 515-517). It has now been established that
`lowering LDL-C levels affords protection from coro-
`nary heart disease (cf. Journal of the American Medical
`Association (1984) 251, No. 3, 351-374).
`Moreover,
`it
`is known that certain derivatives of
`mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid)
`and the corresponding ring-closed lactone form,
`mevalonolactone, inhibit the biosynthesis of cholesterol
`(of. F. M. Singer et al., Proc. Soc. Exper. Biol. Med.
`(1959), 102, 270) and F. H. Hulcher, Arch. Biachem.
`Biophys. (1971), 146, 422.
`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), 1165.
`-
`- U.S. Pat. No. 4,255,444 to Oka et al. discloses severa
`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.
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, there are
`provided certain trans-6-[2-(substitutedpyrrol-1-yl)al-
`kyl]pyran-2-ones and the corresponding ring-opened
`hydroxy-acids derived therefrom which are potent in-
`hibitors of cholesterol biosynthesis by virtue of their
`ability to inhibit
`the enzyme 3-hydroxy-3-methyl-
`glutarylcoenzyme A reductase (HMG-CoA reductase).
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`in its broadest chemical compound
`In particular,
`aspect, the present invention provides compounds of
`structural formula I
`
`
`
`wherein X is —-CH2——, —CH2CH2—, or —-CH(CH3)C-
`H2-—. R1 is 1-naphthyl; 2-naphthyl; cyclohexyl; nor-
`bornenyl; phenyl; phenyl substituted by fluorine, chlo-
`rine, hydroxy, 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; 2-,
`3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl-N-oxide; or
`
`R5 hal"
`
`+/N/
`
`\
`
`where R5 is alkyl of from one to four carbon atoms and
`hal— is chloride, bromide, or iodide. R2 and R3 are inde-
`pendently hydrogen; chlorine; bromine; cyano; trifluo-
`romethyl; phenyl; alkyl of from one to four carbon
`atoms; carboalkoxy of from two to eight carbon atoms;
`——CH2OR(, where R6 is hydrogen, alkanoyl of from one
`to six carbon atoms, or where R2 and R3 are —CH-
`2OCONHR7 where R7 is alkyl of from one to six carbon
`atoms, phenyl, or phenyl substituted with chlorine,
`bromine, or alkyl of from one to four carbon atoms. R2
`and R3 may also, when taken together with the carbon
`atoms to which they are attached, form a ring denoted
`by
`
`/‘ /
`(CH2)n
`
`\
`
`where n is three or four; a ring denoted by
`
`a ring denoted by
`
`0
`
`/
`
`\
`
`0
`\\
`
`R3""N
`
`//0
`
`/
`
`\
`
`Mylan Exhibit 1016, Page 2 i
`
`
`
`Mylan Exhibit 1016, Page 2
`
`

`
`3
`
`4,647,576
`
`4
`
`where R3 is hydrogen, alkyl of from one to six carbon
`atoms, phenyl, or benzyl; or a ring denoted by
`
`where R9 and R10 are hydrogen, alkyl of from one to
`four carbon atoms, or benzyl.
`R4 is alkyl of from one to four carbon atoms, cyclo-
`propyl, cyclobutyl, or trifluoromethyl.
`Also contemplated as falling within this aspect of the
`invention are the corresponding dihydroxy-acid com-
`pounds of formula II corresponding to the opened form
`of the lactone ring of compounds of formula I
`
`9
`\\\\
`
`COOH
`
`X
`R]
`R2 X N/H\\®
`
`OH
`
`R3
`
`R4
`
`where X, R1, R2, R3, and R4 are as defined above, and
`the pharmaceutically acceptable salts thereof, all of the
`compounds being in the trans racemate of the tetrahy-
`s dropyran moiety.
`In another aspect of the present invention, there is
`_, provided a method of preparing compounds of formula
`I above by (a) first reacting a substituted [(pyrrol-1-
`yl)alkyl]aldehyde compound of formula III
`
`R,
`R2 / N
`
`H0
`{-1 OH\\H
`V\\\\‘ Y§\\
`/X--CCH2C H2COOH
`
`V
`
`R3
`
`R4
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`and finally (d) cyclizing, if desired, the acid compound
`of formula V to a lactone compound of formula I by
`heating in an inert solvent or, alternatively converting,
`if desired, the acid compound of formula V to a pharma-
`ceutically acceptable salt.
`invention provides
`In another aspect,
`the present
`pharmaceutical compositions, useful as hypolipidemic
`or hypocholesterolemic agents, comprising a hypolipi-
`demic or hypocholesterolemic affective 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 a phar-
`maceutical composition in accordance with the present
`invention as defined above.
`
`DETAILED DESCRIPTION
`
`In a first preferred subgeneric’ chemical compound
`aspect, the present invention provides compounds of
`formula I above wherein X is —CH2CH2—, R1 is as
`defined above, R2 and R3 are independently hydrogen,
`chlorine, or bromine, and R4 is as defined above.‘
`In a second preferred subgeneric chemical compound
`aspect, the present invention provides compounds of
`formula I above where X is —CH2CH2—, R1 is phenyl
`or phenyl substituted by fluorine, chlorine, hydroxy,
`trifluoromethyl, alkyl of from one to four carbon atoms,
`alkoxy of from one to four carbon atoms, or al-
`kanoyloxy of from two to eight carbon atoms, or where
`R1 is 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl-N-oxide,
`or
`
`R1
`
`X—CljlO
`
`III
`
`45
`
`R2 / N/
`
`R3
`
`R4
`
`50
`
`where X, R1, R2, R3, and R4 are as defined above, with
`the alkali metal salt of the dianion of methyl acetoace-
`tate to form a compound of structural formula IV
`
`OH
`0
`n
`I
`X— CHCH2CCH2COOCH3
`
`R1
`
`55
`
`IV
`
`where R5 is alkyl of from one to four carbon atoms and
`hal- is chloride, bromide, or iodide. In this aspect of the
`invention, R2 and R3 are preferably independently hy-
`drogen, chlorine, or bromine, and R4 is alkyl of from
`one to four carbon atoms or trifluoromethyl.
`In a third preferred subgeneric chemical compound
`aspect, the present invention provides compounds of
`‘ formula I above where X is —CH2CH2—, R1 is phenyl
`or phenyl substituted by fluorine, chlorine, hydroxy,
`trifluoromethyl, alkoxy of from one to four carbon
`atoms, or alkanoyloxy of from two to eight carbon
`atoms, R2 and R3 are independently hydrogen, chlorine,
`or bromine, and R4 is isopropyl or trifluoromethyl.
`In a fourth preferred subgeneric chemical compound
`aspect, the present invention provides compounds of
`formula I above where X is —CH2CH2—, and R1 is
`phenyl or phenyl substituted by fluorine, chlorine, tri-
`fluoromethyl, alkyl of from one to four carbon atoms,
`alkoxy of from one to four carbon atoms, or al-
`
`R2 Z N/
`
`R3
`
`R4
`
`where X, R1, R2, R3, and R4 are as defined above, then
`successivly (b) reducing compound IV with a triall<y1-
`borane and sodium borohydride and (c) oxidizing with
`alkaline hydrogen peroxide to produce an acid com-
`pound of formula V
`
`60
`
`65
`
`Mylan Exhibit 1016, Page 3
`
`
`
`Mylan Exhibit 1016, Page 3
`
`

`
`5
`kanoyloxy of from two to eight carbon atoms, or where
`R1 is l-naphthyl, or 2-naphthyl. In this preferred aspect
`of the invention, R2 and R3 are independently hydrogen,
`chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl
`of from one to four carbon atoms, carboalkoxy of from
`two to eight carbon atoms, —CH2OR(, where R5 is
`hydrogen or alkanoyl of from one to six carbon atoms,
`—CH2OCONHR7 where R7 is alkyl of from one to six
`carbon atoms, phenyl, or phenyl substituted with chlo-
`rine, bromine, or alkyl of from one to four carbon
`atoms. In this aspect of the invention, R2 and R3 may
`also, when taken together with the carbon atoms to
`which they are attached, form a ring denoted by
`
`(CH2)n
`
`/
`
`\
`
`where n is three or four; a ring denoted by
`
`a ring denoted by
`
`O
`
`/
`
`\
`
`O
`\\
`
`Rg—N
`
`//0
`
`/
`
`\
`
`where R3 is hydrogen, alkyl of from one to four carbon
`atoms, phenyl, or benzyl; or a ring denoted by
`
`where R9 and R10 are hydrogen, alkyl of from one to
`four carbon atoms, or benzyl. In this aspect of the in-
`vention, R4 is preferably alkyl of from one to four car-
`bon atoms, cyclopropyl, cyclobutyl, or trifluoromethyl.
`In a fifth preferred subgeneric chemical compound
`aspect, the present invention provides compounds of
`formula I above where X is ——CH2CH2-—, and R1 is
`phenyl or phenyl substituted by fluorine, chlorine, tri-
`fluoromethyl, alkyl of from one to four carbon atoms,
`alkoxy of from one to four carbon atoms, or al-
`kanoyloxy of from two to eight carbon atoms. R2 and
`R3 are preferably independently hydrogen, chlorine,
`bromine, phenyl, or carboalkoxy of from two to-eight
`carbon atoms. In this aspect of the invention R2 and R3
`may also, when taken together with the carbon atoms to
`which they are attached, form a ring denoted by
`
`4,647,576
`
`5
`
`l0
`
`15
`
`20
`
`30
`
`40
`
`45
`
`S0
`
`55
`
`60
`
`65
`
`//\
`(CH2)nA
`
`where n is three or four; a ring denoted by
`
`O
`\\
`
`Rg—'N
`
`//0
`
`/
`
`\
`
`where R3 is hydrogen, or alkyl of from one to four
`carbon atoms; or a ring denoted by
`
`where R9 and R10 are hydrogen or alkyl of from one to
`four carbon atoms. In this aspect of the invention, R4 is
`preferably alkyl of from one to four carbon atoms, or
`trifluoromethyl.
`-
`In a sixth preferred subgeneric chemical compound
`aspect, the present invention provides compounds of
`formula I above where X is -—CH2CH2—, R1 is is
`phenyl or phenyl substituted by fluorine, chlorine, tri-
`fluormethyl, alkyl of from one to four carbon atoms,
`alkoxy of from one to four carbon atoms, or al-
`kanoyloxy of from two to eight carbon atoms. R2 and
`R3 are preferably independently carboalkoxy of from
`two to eight carbon atoms or, when taken together with
`the carbon atoms to which they are attached form a ring
`denoted by
`I
`
`\\
`
`R3-N
`
`//0
`
`/
`
`\
`
`where R3 is hydrogen or alkyl of from one to four car-
`bon atoms. In this aspect of the invention, R4 is prefera-
`bly isopropyl or trifluoromethyl.
`As used throughout this specification and the ap-
`pended claims, the term “alkyl? denotes a branched or
`unbranched saturated hydrocarbon group derived by
`the removal of one hydrogen atom from an alkane.
`The term “alkoxy” denotes an alkyl group, as just
`defined, attached to the parent molecular
`residue
`through an oxygen atom.
`The term “alkanoyloxy” is meant to denote an alkyl
`group, as defined above, attached to a carbonyl group
`
`Mylan Exhibit 1016, Page 4
`
`
`
`Mylan Exhibit 1016, Page 4
`
`

`
`4,647,576
`
`to the parent
`
`7
`and thence, through an oxygen atom,
`molecular residue.
`The term “carboalkoxy” is meant to denote an alkyl
`group, as defined above, attached to an oxygen atom
`and thence, through a carbonyl group, to the parent
`molecular residue.
`The term “norbornenyl” denotes a group derived by
`the removal of a hydrogen atom (other than at a bridge-
`head carbon atom) from bicyclo[2.2.1]hept-2-ene.
`Specific examples of compounds contemplated as
`falling within the scope of the present invention include
`the following:
`trans-6-[2-[2-Cyclobutyl-5-(4-fluoropheny1)-1H—pyrro1-
`1-yl]ethy1]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-Cyclohexyl-5-(4-fluorophenyl)-1H-pyrrol-
`1-yl]ethyl]tetrahydro-4-hydroxy-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-(2-methyl-5-phenyb
`1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one.
`trans-6-[2-[2-(4-Chlorophenyl)-5-methyl-1H-pyrrol-]-
`yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(4-methoxy-
`phenyl)-5-methyl-1H-pyrrol-1-y1]ethy1]-2H-pyran-
`2-one.
`
`—
`
`trans-6-[2-[2-([1,1’-Biphenyl]-4-yl)-5-methyl-1H-pyrrol-
`1-yl)ethy1]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-[3-(tri-
`fluoromethy1)pheny1]-1H-pyrro1-1-yl]ethy1]-2H-
`~ pyran-2-one.
`trans-6-[2-[2-(2,5-Dimethy1phenyl)-5-(1-methylethyl)-
`1H-pyrro1-1-yl]ethy1]tetrahydro-4-hydroxy-2H-
`pyran-2-one. _
`trans-6-[2-[2-(2,6-Dimethoxyphenyl)-5-(1-methylethyl)-
`1H-pyrrol-1-y1]ethy1]tetrahydro-4-hydroxy-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-methy1-5-(2-naph-
`tha1enyl)-1H-pyrrol-1-y1]ethyl]-2H-pyran-2-one.
`trans-6-[2-(2-(Cyclohexy1-5-trifluoromethy1-1H-pyrrol-
`1-yI)ethy1]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-3,4-dimethyl-5-(1-
`methylethy1)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-2-(4-Fluorophenyl)-5-(1-methylethyl)-1-[2-(tet-
`rah ydro-4-hydroxy—6-oxo-2H-pyran-2-yl)ethyl]- 1 H-
`pyrroIe—3,5-dicarboxylic acid.
`trans-2-(4-Fluorophenyl)-N3,N3,N4,N4-tetramethyl-5-
`(1-methylethy1)-1-[2-(tetrahydro-4—hydroxy-6-o2io-
`2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxamide.
`trans-6-[2-—[3,4-Dich1oro—2-(3-fluorophenyl)-5-( 1 -
`methylethyl)- 1H-pyrro1- 1 -yl]ethy1]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans—2-(4-Fluorophenyl)-5-(1-methylethyl)- 1 -[2-(tet-
`rahydro)-4-hydroxy-6-oxo-2H-pyran-2-y1)ethy1]- 1H-
`pyrrole-3,4-dicarbohitrile.
`trans-6-[2-[3,4-Diacetyl-2-(4-fluorophenyl)-5-(1 -
`methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-Diethyl
`2-(4-F1uorophenyl)- l-[2-(tetrahydro)-4-
`hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-(trifluorome-
`thy1)-1H—pyrro1e-3,4-dicarboxylate.
`trans-Bis(1-methylethyl)
`2-(4-Fluorophenyl)-5-( 1 -
`methylethyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-
`pyran-2-yl)ethyl]- l H-pyrrole-3,4-dicarboxylate.
`trans-6-[2-[3,4-Diethyl-2-(4-fluorophenyl)-5-( 1 -
`methylethy1)-1H-pyrro1-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-F1uoropheny1)-3,4-bis(hydroxymethy1)-
`5-(1-methylethy1)-1H-pyrrol-1-y1]-ethy1]tetrahydro-
`4-hydroxy-2H-pyran-2-one.
`
`8
`.
`trans-l-Methylethyl 4-Ch]oro-2-(4-fluorophenyl)-5-(1-
`methylethyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-
`pyran-2-yl)ethyl]-1H-pyrrole-3-carboxylate.
`trans-6-[2-[4-(4—Fluorophenyl)-6-( l -methyleth yl)- 1 H-
`furo[3,4-c]pyrrol-5(3H)-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-(l-methylethyl)-3,4-
`bis[[[(phenylamino)carbonyl]oxy]methyl]-1H-pyrrol-
`1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-1-Methylethyl 4-Ch1oro-5-(4-fluorophenyl)-2-( 1-
`methylethyl)-1—[2-(tetrahydro)-4-hydroxy-6-oxo-2H-
`pyran—2-y1)ethyl]-1H-pyrrole-3-carboxylate.
`trans-Ethyl
`5-(4-Fluorophenyl)- 1-[2-(tetrahydro)-4-
`hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-(trifluorome-
`thy1)-1H-pyrrole—3-carboxylate.
`trans-Ethyl
`5-(4-Fluorophenyl)-2-(1-methylethyl)-4-
`phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-
`2-yl)ethy1]-1H-pyrrole-3-carboxylate.
`trans-6-[2-[1-(4-Fluorophenyl)-4,5,6,7-tetrahydro—3-
`methyl-2H-isoindol-2-yl]ethy1]tetrahydro-4-hydroxy-
`2H-pyran-2-one.
`trans-4-(4—Fluoropheny1)-2-methyl-6-(1-methylethyl)-5-
`[2-(tetrahydro-4—hydroxy-6-oxo-2H-pyran-2-yl)e-
`thyl]-pyrrolo[3,4-c]pyrrole-1,3(2H,5H)-dione.
`trans-6-[2-[1-(4-Fluorophenyl)-5,6-dihydro-3-(1-
`methylethyl)pyrrolo[3,4-c]pyrrol-2(4H)-yl]ethyl]-tet-
`rahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[1-(4-Fluorophenyl)-5,6-dihydro-5-methyl-3-
`(1-methylethy1)pyrrolo[3,4-c]pyrrol-2(4H)-y1]-ethyl]-
`tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[3-Ch1oro-5-(4-fluorophenyl)-2-(1-methyle-
`thyl)-4-phenyl- 1H-pyrro1- 1 -y1]ethy1]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-(1-methylethy1)-3,4-
`diphenyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`Particularly preferred compounds in accordance
`with the present invention are:
`trans-6-[2-[3,4-Dich1oro—2-(4-fluorophenyl)-5-(1-
`methylethyl)- 1H-pyrro1- 1 -y1]ethy1]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans—6-[2-[3,4-Dibromo-2-(4-fluoropheny1)-5-(1-
`methylethyl)-lH—pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-(trifluoromethyl)—1H-
`pyrrol-1-y1)ethyl]tetrahydro-4-hydroxy-2H-pyram
`2-one.
`
`trans-Dimethyl 2-(4-Fluorophenyl)-5-(1-methylethyl)-
`1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)e-
`thyl]-1H-pyrrole-3,4-dicarboxylate.
`trans-6-[2-[2-(4-F1uorophenyl—5-methyl-1H-pyrrol-1-
`y1]ethy1]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[2—(4-Fluorophenyl-5-(1-methylethyl)-1H-
`pyrro1-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-
`2-one.
`
`trans-6-[2-[2-Cyclopropyl-5-(4-fluorophenyl)-1H-pyr-
`rol-1-yl]ethyl]tetrahydro-4-hydroxy—2H-pyran-2-one.
`trans-6-[2-[2-(1, 1-Dimethy1ethyl)-5-(4-fluorophenyl)-
`1H-pyrrol-1-y1]ethyl]tetrahydro-4-hydroxy-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-
`phenyl)-5-trifluoromethy1-1H-pyrrol-1-yl]ethy1]-2H-
`2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-
`phenyl)-5-(1-methylethyl)-lH-pyrrol-1-yl]ethyl]-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naph-
`thaleny1)-lH-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
`
`Mylan Exhibit 1016, Page 5
`
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`
`50
`
`55
`
`60
`
`65
`
`
`
`Mylan Exhibit 1016, Page 5
`
`

`
`9
`trans-6-[2-(2-Bicyclo[2.2,1]hep-5—en-2-yl-5-methyl-1H-~
`pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-
`2-one.
`
`4,647,576
`
`10
`
`5
`
`through
`in a polar solvent such as tetrahydrofuran,
`which a small quantity of air has been bubbled. A slight
`excess of a trialkylborane, such as tributylborane,
`is
`trans-6-[2-[2-(4-Fluorophenyl)-5-(l-methylphenyl)- 1 H-
`added to the mixture which is then cooled to a tempera-
`ture of preferably between about 0'’ C. and -78” C.
`pyrrol-1-yl]propyl]tetrahydro-4-hydroxy-2H-pyran-
`after which sodium borohydrideiis added.
`2-one.
`After stirring this mixture for about one to two hours,
`Compounds of the present invention where R; and
`the mixture is oxidized with basic hydrogen peroxide.
`R3 are hydrogen are prepared by the methods outlined
`The reaction produces the 7-(substituted-pyrrolyl)-3,5-
`in Reaction Sequence l or Reaction Sequence 2. As
`shown in Reaction Sequence 1, the aldehydes, VI, are 10 dihydroxyheptanoic acids, XIV, in which the product
`reacted with the appropriately substituted vinylketones,
`contains a predominance of the desired R*, R* configu-
`VII, in the presence of the thiazolium salt, VIII, and a
`ration at carbon atoms three and five which bear the
`base such as triethylamine, to produce the diketones,
`hydroxy groups.
`IX. (See Ang. Chem. Int. Ed., 15: 639-712 (1976)).
`The acids may be converted to a corresponding phar-
`The diketones,
`IX, are reacted with an omega- 15 maceutically acceptable salt by conventional methods
`aminoalkylnitrile
`(compound Roman numeral
`ten
`or, alternatively, cyclized to the 6-[2-(substituted-pyr-
`where the value of X is methylene, ethylene, or 1-
`rol-1-yl)alkyl]pyran-2-ones,
`I, by dehydration in an
`methylethylene) in acetic acid to produce the disubsti-
`inert solvent such as refluxing toluene with azeotropic
`tuted pyrrole nitriles, XI.
`removal of water. This cyclization reaction is found to
`Treatment of
`the
`pyrrole‘ nitriles, XI, with 20 produce material containing from 85-90% of the de-
`diisobutylaluminum hydride in an inert solvent such as
`sired active trans-configuration of the 4-hydroxy group
`dichloromethane produces the corresponding pyrrole
`relative to the 6-(substitutedpyrrolyl)alky1 group on the
`aldehydes, XII.
`pyran-2-one lactone ring.
`
`REACTION SEQUENCE l
`
`O
`O
`II
`II
`R;CC1 + R2CCH=Cl-I2
`VI
`VII
`
`0
`O
`II
`II
`(H5Cz)3N
`:——:OIi—-—-9 R1CCHgCH2CR2
`IX
`
`H3C /
`
`+N ___/
`/
`¢H2C
`
`S
`
`_
`
`C1
`vm
`
`Diisobutylaluminum
`hydride
`
`E
`
`HOAc
`HgN—X—CN
`x
`
`R1
`
`X—CN
`
`[ N/
`
`R3
`
`XI
`
`R1
`
`X--CHO
`
`[ N
`
`R2
`
`XII
`
`0
`e ll 9
`NaLi(CI-I2C—CH—.COOCH3)
`
`0
`OH
`ll
`I
`CHZCHZCHCHZCCHZCOOCH3
`
`R1
`
`Z N
`
`R2
`
`XIII
`
`R1
`
`,
`H//0
`/ N—cH2cH2
`
`R2
`
`I
`
`1 Tribut lborane
`
`(2) Sodium borohydride
`(3) H202. OH‘
`
`
`
`H \\OH
`ts
`
`R1
`
`\
`\0
`
`0
`
`(«-
`
`/ N
`
`/CH2CH\§2CH2\\\CI‘I2COOH
`a“\om$‘\ ‘on
`
`R2 _
`
`XIV
`
`Reaction of the pyrrole aldehydes, XII, with the
`dilithium or lithium sodium salt methyl acetoacetate
`produces the 7-(substitutedpyrrolyl)-5-hydroxy-3-oxo-
`heptanoates, XIII. The heptanoates, XIII, are dissolved
`
`Alternative procedures for preparing compounds of
`formula I of this invention where R; and R3 are hydro-
`
`Mylan Exhibit 1016, Page 6
`
`
`
`Mylan Exhibit 1016, Page 6
`
`

`
`4,647,576
`
`11
`gen, and for preparing intermediates, are illustrated in
`Reaction Sequence 2. As shown in Reaction Sequence
`2, the diketones, IX, can be prepared by reacting the
`known alpha-haloketones, XV, with the sodium salt of
`known beta-ketoesters, XVI, followed by hydrolysis 5
`and decarboxylation in the conventional manner. The
`diketones, IX, are reacted with ammonium acetate in
`acetic acid to produce the cyclized 2,5-disubstituted
`pyrroles, XVII.
`
`REACTION SEQUENCE 2
`
`12
`by starting with compounds of formula XIX. In this
`latter instance, the hydroxy functionality of compounds
`of formula XIX is converted to the p-toluenesulfonate
`by conventional means, and the tosylate group is subse-
`quently displaced by cyanide ion to produce the nitriles
`of formula XXII. The compounds of formula XXII are
`subsequently used in the preparation of compounds of
`formula I of this invention by methods detailed in Reac-
`tion Sequence 1 above.
`Starting materials and intermediates employed in
`Reaction Sequences 1 and 2 above may be prepared by
`the general methods outlined in Reaction Sequence 3.
`For example, as shown there, the vinyl ketones, XII, are
`prepared by either of the two methods illustrated. In
`one method, the known acid chlorides, XXIII, are re-
`acted with the trimethylsilylethene, XXIV, in the pres-
`ence of anhydrous aluminum chloride in dichlorometh-
`ane.
`
`In the alternative method of preparing the vinyl ke-
`tones, VII, which is preferred when R1 is an aromatic
`substituent such as phenyl or substituted phenyl, the
`
`REACTION SEQUENCE 3
`
`REACTION SEQUENCE 3
`
`0
`O
`ll
`AICI3
`II
`RCCI + CH2=CHSi(CH3)3 R‘C—CH=CH2
`XXIII
`XXIV
`VII
`
`0
`H H
`ArCC 3
`XXV
`
`(CH20)"
`
`O
`NCH
`H H
`ArCC 2Cl-I2 (
`‘ XXVI
`
`3);
`
`(I) CH3I
`(2) NaHCO3
`
`0l
`
`l
`ArCCH=CH2
`
`VII
`
`known methyl aryl ketones, XXV, are converted to
`(dimethylaminoethy1)aryI ketones, XXVI, and then by
`deamination to the vinyl ketones, VII.
`The compounds of the present invention of formula I
`where the groups R2 and R3 are other than hydrogen or
`halogen can be synthesized by the methods detailed in
`Reaction Sequences 4-8.
`Employing the method detailed in Reaction Se-
`quence 4 the compounds of the present invention where
`R2 and R3 are both halogen can be prepared by the
`halogenation of the unsubstituted compounds with N-
`halosuccinimide in a three-step process involving the
`prior protection of the 4-hydroxy group of the lactone
`ring. Thus, for example, the 2,5-disubstitutedpyrrol-l-yl
`compounds, XXVII, are first converted to the corre-
`sponding tert-butyl-dimethylsilyl ethers, XXVIII. The
`protected compounds and then chlorinated with N-
`chlorosuccinimide in a polar solvent such as dimethyl-
`formamide to produce the silylated 3,4-dichloro com-
`pounds, XXIX. The protecting silyl ether group is then
`subsequently removed by reaction with a buffered fluo-
`ride reagent such as tetrabutylammonium fluoride in a
`mixed acetic acid/tetrahydrofuran solvent system to
`produce the dichloro compounds, XXX.
`Alternatively, as detailed in Reaction Sequence 5,.the
`(2,5-disubstitutedpyrrol-1-y1)a1kyl nitriles, XI (see Re-
`
`Mylan Exhibit 1016, Page 7
`
`10
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`
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`
`2
`
`60
`
`65
`
`it
`if
`if
`if
`R1CCH2X + R2CCH2COOC2H5 %R1CCH2(l3HCR;v_
`(X = halogen)
`c00C2H5
`XV
`XVI
`\L
`R1
`/ N
`
`NH40Ac
`<Tx6AT:—
`
`O
`O
`II
`II
`R1CCH2CH2CR2
`
`IX
`
`/H
`
`R2
`
`XVIII
`
`(1) NaH
`(2) Br—X—Cl-I(OCI-I3)2
`(3) H4’, H20
`
`(XXI)
`
`R1
`
`
`
`/X-Cl-IO
`
`/ N
`
`H2N-X—OH
`
`(XVIII)
`
`R1
`
`/X-CN
`
`/ N
`
`R2
`
`XX
`
`R2
`
`(XXII in Reaction Sequence 1)
`
`(XIII in Reaction Sequence 1)
`
`(I) Tosyl chloride
`(2) CN”
`
`R1
`
`/X-OH
`
`Z N
`
`R2
`
`XIX
`
`___.___m
`‘X H2N-X-OI-I
`XVIII
`
`An alternative for this step, preferred when R1 and-
`/or R4 are sterically bulky groups, involves reaction of
`the diketones, IX, with an omega-hydroxyalkyl amine
`(compound XVIII where X is methylene, ethylene,
`1-methylethylene), to produce the N-(omega-hydroxy-
`alkyl)-2,5-disubstitutedpyrroles, XIX.
`The 2,5-disubstitutedpyrroles, XVII, are converted
`to the omega-(substitutedpyrrolyl)aldehydes, XX, by
`sequential reaction with sodium hydride, a 1,1-dime-
`thoxy-omega-bromoalkane (compound XXI where X is
`methylene, ethylene, I-methylethylene, or vinyl), and
`then acid. The aldehydes, XX, are subsequently used in
`the preparation of compounds of formula I of this in-
`vention as illustrated above in Reaction Sequence 1.
`The 2,5-disubstituted pyrroles, XVII, are converted
`to the corresponding (2,5-disubstitutedpyrroly1)nitriles,
`XXII (when X is ethylene), by reaction with acryloni-
`trile or, alternatively (when X is other than ethylene),
`
`
`
`Mylan Exhibit 1016, Page 7
`
`

`
`13
`
`4,647,576
`
`action Sequence 1) are halogenated by employing an
`N-halosuccinimide in dimethylformamide to provide
`the 2,5-disubstituted-3,4-dihalopyrroles, XXXI.
`(See
`Aiello, et al., J. Het. Chem., 19: 977 (1982)). These com-
`pounds can then be subsequently converted to the com-
`pounds of the present invention by conventional meth-
`ods detailed in Reaction Sequence 1.
`A third method takes advantage of the chemistry of
`mesionic compounds of the type described originally by
`R. Huisgen, et al., Ang. Chem. Int. Ed., 3: 136 (1964). In
`this procedure, detailed in Reaction Sequence 6, an
`
`10
`
`,
`HO///0
`
`REACTION SEQUENCE 4
`.
`-
`_
`t-Butyl(Me)2SiCl
`¢O m t Bu(Me)2S1O,/,0
`
`14
`XXXIII is acylated with an acid chloride and subse-
`quently hydrolyzed in base to produce the N-acyl-N-
`alkyl aminoacid, _XXXIV. Reaction of this latter com-
`pound with the desired substituted acetylenic com-
`pound, XXXV, produces the substituted pyrrole com-
`pounds, XXXVI. Acidic hydrolysis of XXXVI yields
`the aldehyde compounds, XXXVII, analogous to com-
`pounds XII of Reaction Sequence 1. Compounds of
`formula XXXVII are used in subsequent steps in a man-
`ner detailed in Reaction Sequence 1 to produce com-
`pounds of the present invention.
`
`O
`
`R4
`
`'
`
`R]
`
`N
`
`XXVII
`
`¢O
`
`0
`
`R1.
`
`: N :
`
`.R4
`
`XXVIII
`
`DMF
`
`l_\1_'—Chloro-
`succinimide
`
`Ho//////
`
`¢O
`0
`
`T
`b
`1-
`éammotiitiliiamutzlltlioride
`HOAc/TI-IF
`
`-
`t‘Bu(Me)2S1O/////
`
`¢O
`0
`
`R1;
`
`C1
`
`:N:
`
`XXIX
`
`:R4
`
`C1
`
`45
`
`R1;
`
`C1
`
`:N:
`
`XXX
`
`:R4
`
`C1
`
`REACTION SEQUENCE 5
`
`§_-Chloro- or [\1_-Bromo-
`
`succinimide ‘
`.
`D‘"‘°‘hY”°""‘"“‘d°
`
`9
`
`CN
`
`l/
`
`R1
`
`N
`
`I
`
`l
`
`XI
`
`CN
`
`Preferred substituents for the substituted acetylenic
`compounds in this method of making compounds of the
`50 present invention include carboalkoxy groups, phenyl
`groups, alkanoyl groups, alkyl groups and cyano
`groups. The reaction between the disubstituted acety-
`lene compound and the N-acyl-N-alkyl aminoacids,
`XXXIV, generally proceeds smoothly; for example, the
`
`H 55 dicarbomethoxy acetylene reacts smoothly at 25° C.
`
`R‘
`
`N
`
`R4
`
`I
`
`I
`
`(B00
`
`C103,) 60
`
`XXXI
`
`N-alkyl-N-acylamino acid is treated with an acid anhy-
`dride and a substituted acetylenic compound to produce
`a pyrrole. For example, Reaction Sequence. 6 shows
`how reaction of an alpha-halo ester, XXXII, with 2-(l-
`(2-aminoethyl))-1,3-dioxalane in triethylamine provides
`the N-alkyl-alpha-aminoester, XXXIII. The aminoester,
`
`65_
`
`However, when only one activating group is attached
`to the acetylene, the reaction mixture must generally be
`warmed to 70"—l10° C. to obtain high yields of the
`pyrrole compounds.
`A variety of other pyrroles can be derived from com-
`pounds of the general formula XXXVI when the groups
`R2 and R3 are carbomethoxy. Some of these transforma-
`tions are detailed in Reaction Sequences 7 and 8. For
`example, as shown in Reaction Sequence 7, reduction of
`XXXVI with a reducing agent such as lithium alumi-
`num hydride results in the bis(hydroxymethyl)pyrro1e
`which can be subsequently further reduced to the di-
`methyl compound,
`
`r
`
`Mylan Exhibit 1016, Page 8
`
`
`
`Mylan Exhibit 1016, Page 8
`
`

`
`a
`
`15
`
`REACTION SEQUENCE 6
`
`4,647,576
`
`Br
`COOCH3
`R1(l3HCOOCH3 R,cHNH
`XXXII
`>___[
`
`O
`
`5
`
`xxxm
`
`0
`
`0
`
`10
`
`16
`XXXVIII, by means of triethylsilane and trifluoroacetic
`acid employing the procedure of West, et al., J. Org.
`Chem., 38: 2675 (1973)).
`Alternatively, as shown in Reaction Sequence 8, re-
`action of the compounds of formula XXXVI with a
`Grignard reagent or an alkyl-lithium reagent
`in the
`conventional manner followed by reduction and stan-
`dard work-up affords
`the higher dialkylpyrroles,
`XXXIX.
`Reaction of the diesters, XXXVI, or the correspond-
`ing diacids (obtained by conventional hydrolysis) with
`secondary amines provides the bis(dialkylamides), XL.
`Alternatively,
`reaction of XXXVI with primary
`amines, followed by thermal cyclizationa in the conven-
`tional manner, provides the pyrrolosuccinimides, XLI,
`which can be reduced to XLII, if desired by reducing
`agents such as lithium aluminum hydride.
`The bis(hydroxymethyl)pyrrole compounds derived
`from the lithium aluminum hydride reduction of
`XXXVI can be converted to their corresponding esters
`or carbamates by reaction with the desired acid anhy-
`dride or isocyanate, respectively. (See Anderson, et al.,
`J. Med. Chem, 22: 977 (1979)).
`The acids, XLIII, derived by convention hydrolysis
`of compounds of formula XXXVI can also be con-
`verted to the bis(amido)pyrroles, XLIV, which in turn
`can be dehydrated to produce the bis(nitrilo)pyrroles,
`XLV. Lastly,
`if desired,
`the bis(alkanoyl)pyrro1es,
`XLVI, can be derived from the bis(nitrilo)pyrro1es by
`reaction in the convention manner with the appropriate
`Grignard reagents.
`The ring-opened dihydroxy-acids of structural for-
`mula 11 above are intermediat