Unlted States Patent mi
`I-Ioefle et al.
`
`[:11 Patent Number:
`[45] Date of Patent:
`
`4,647,576
`Mar. 3, 1987
`
`......'.........
`
`.
`.
`
`549/292 x
`3/1931 Oka et al.
`4,255,444
`549/292
`4,303,333 I2/198] Stoklcer
`514/415
`4,343,811 B/1932 Humans et al.
`514,-M60
`4,351,844 9/I982 Patchctt et al.
`S-‘-W292 X
`4.375.425 M1983 Winard et al.
`549/292
`4.3?6,863 3/ I983 Lam .............
`4.440.927 4/1984 Prugh ................................_. 549/292
`
`
`
`FOREIGN PATENT DOCUMENTS
`895445
`4x19s3 Belgiiirn .
`OTHER PUBLICATIONS
`Hulcher, Archives of Biochemistry and Biophysics,
`146, (l9'?l), pp. 422-421
`Primary Examf:rer—-«Donald G. Dans
`Am-Mam Examfnerwwilliam A Teen’ JR
`Attorney. Agent, or F:'rm—Jerry F. Janssen
`
`ABSTRACT
`[Sn
`6-[2-(Substitut::d—pyr1'ol~1-yl)aklyl]pyran—2-ones and the
`corresponding ring~opened
`hydroxy-acids
`derived
`therefrom are potent
`inhibitors of the enzyme 3-
`hydroxy—3-methylglutarylcoenzyme
`A
`reductase
`(HMG-COA reductase), and are thus useful h3.rpolipi-
`demic and hypocholesterolemic agents. Pharmaceutical
`compositions containing such compounds,
`and 21
`‘“‘°*'"‘°d.‘?f "“a‘“‘°“‘ "?“P'°3'i“3 “Ch P“3““3°5““°a1
`°°mD05"'0nS are also d1SC10S€d-
`
`I9 Claims, N0 Drawings
`
`[54] TRANS-6-[2-(SUBSTITUTEDPYRROL-L
`YL)ALKYL]-pyRAN.2.oNE 1NH[};1ToR3 017
`CHOLESTEROL SYNTHESIS
`I
`Inventors: Milton L. I-Ioefle; Bruce D. Roth;
`Charlotte D. Stratton, all of Ann
`Arbor, Mich_
`
`[75]
`
`[73] Assignee: Warner-Lambert Company, Morris
`P'a’“5' N-1
`[2]] A1’P“”°" “7°"""5
`[22] Filed:
`Dec‘ 10’ 1934
`_
`Related U.S. Application Data
`I
`1
`‘
`Continuation-in-part of Ser. No. 653,798, Sep. 24, 1984.
`abandoned‘
`CUTD 405/06; A6lK 31/40
`Int. Cl.‘
`[5]]
`[52] U.S. (:1. .................................... 514/422; 514/343;
`543/517; 543/562; 543/515; 543/455; 543,/453;
`546/28]; 546/270; 546/271; 546/272; 544/236
`Field of Search
`548/51‘.-', 562; 514/422,
`514/343; 546/231
`
`[63]
`
`[53]
`
`_
`References Clted
`U.S. PATENT DOCUMENTS
`3,933,140
`9/1976 Endo et al.
`.......................... 549x292
`4,193,425
`4/1930 Mistui et ai.
`514/460
`4,219,560
`3/‘I930 Houlihan
`. 54-4/3'i'2X
`
`
`
`4,248,889 2/1981 Oka et al. .................. .. 514/532
`
`[56]
`
`1 of18
`
`PENN EX. 2194
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`I
`
`4,647,576
`
`2
`
`in its broadest chemical compound
`In particular,
`aspect, the present invention provides compounds of
`structural formula I
`
`on
`\s\\‘‘
`
`I
`
`X
`R|
`R; / N/ He‘
`
`0
`
`"*0
`
`R3
`
`R4
`
`wherein X is —CH2——, —CI‘I2CH2—, or —CH(CH3)C-
`H2—-. R1 is
`l-uaphthyl; 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
`
`hal‘
`
`+/’
`IN"
`
`IQ
`
`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; trlfluc-
`romethyl; phenyl; alkyl of from one to four carbon
`atoms; carboalkoxy of from two to eight carbon atoms;
`—CH3OR.5 where Rgis hydrogen, all-zanoyl of from one
`to six carbon atoms, or where R; and R3 are —-CH-
`QOCONHR1 where R1 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
`
`where n is three or four; a ring denoted by
`
`/ \
`
`a ring denoted by
`
`TRANS-6-[2—(SUBSTlTUTEDPYRROL-I-YL)Ab
`KYL]-PYRAN-2-ONE INHIBITORS OF
`CHOLESTEROL SYNTHESIS
`
`CROSS—REFEREN CE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of copend-
`ing application Ser. No. 653,798 filed Sept. 24, 1984
`abandoned.
`
`I0
`
`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)all<yl]-2-ones and the
`corresponding ring-
`opened acids derived therefrom which are potent inhib-
`itors of the enzyme 3-hydroxy-3-methyIglutaryl—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 (I981),
`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
`Assocr‘an‘cn (1984) 25], 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 Iactone
`form,
`Inevalonolactone, inhibit the biosynthesis of cholesterol
`(cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med.
`(1959), 102, 270) and F. H. Hulcher, Arch. Biachem.
`Biuphys. (1971), M6. 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
`mevalonolaetone moiety (Brown et al., J. Chem. Soc.
`Perkin I, (1976), 1165.
`U8. 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.
`
`15
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, there are
`provided certain trans-6-[2-(suhstitutedpyrrol-l-yI)aI-
`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-rnethyh
`glutarylcoenzyme A reductase (HMG-COA reductase).
`
`65
`
`2uf18
`
`PENN EX. 2194
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`3
`where R3 is hydrogen, alkyl of from one to six carbon
`atoms, phenyl, or benzyl; or a ring denoted by
`
`4,647,576
`
`R1
`
`I-I OH?!-l
`H0
`x—ccH;c?:H;._cooH
`
`V
`
`R;
`
`R3
`
`N/
`
`R4
`
`where R9 and Rm 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
`
`0
`e“
`
`COOH
`
`F‘.
`
`l
`
`R3
`
`R3
`
`N/Hp
`
`OH
`
`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-
`dropyran moiety.
`In another aspect of the present invention, there is
`__ provided a method of preparing compounds of formula
`1 above by (a) first reacting a substituted [(pyrrol-l-
`yl)alkyl]aldchyde compound of formula III
`
`I0
`
`25
`
`30
`
`35
`
`and finally (cl) 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,
`ifdesired, the acid compound of formula V to a pharma-
`ceulically acceptable salt.
`invention provides
`In another aspect,
`the present
`pharmaceutical compositions, useful as hy-polipidemic
`or hypocholesterolemic agents. comprising a hypolipi-
`clemic 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 1 above wherein X is —CH2CH;—, R1 is as
`defined above, R3 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 —CH1CH2—, 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
`
`4/
`
`/ N
`
`x—cno
`
`R4
`
`R3
`
`R3
`
`III
`
`45
`
`where X, R;, 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
`
`55
`
`.0
`OH
`ll
`I
`X—CHCHgCCl-l3C00CH3
`
`IV
`
`R1
`/ /N
`
`R3
`
`R4
`
`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, chlorinc. 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 —CHgCH2—, 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, R: 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 1 above where X is —CH1CH2—, 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-
`
`where X, R], R2, R3, and R4 are as defined above, then
`snccessivly {b} reducing compound IV with a trialkyl-
`borane and sodium borohydride and (c) oxidizing with
`alkaline hydrogen peroxide to produce an acid com-
`pound of formula V
`
`65
`
`3ofl8
`
`PENN EX. 2194
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`4,64?,576
`
`5
`kanoyioxy of from two to eight carbon atoms. or where
`R1 is 1-naphthyi, or 2~naphthyl. In this preferred aspect
`of the invention, R; and R3 are independently hydrogen,
`chlorine, bromine, cyano, trifluoroniethyl, phenyl. alkyl
`of from one to four carbon atoms, carboalkoxy of from
`two to eight carbon atoms, —CH20R¢, where Rt. is
`hydrogen or alkanoyl of from one to six carbon atoms,
`—CH2OC0NHR-; where R: 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, R; and R3 may
`also, when taken together with the carbon atoms to
`which they are attached, form a ring denoted by
`
`/“/
`(CH2)ar
`
`\\
`
`where n is three or four; a ring denoted by
`
`O
`\\
`
`Rg'''N
`
`-I’0
`
`/
`
`\\
`
`where R5; is hydrogen, or alkyi of from one to four
`carbon atoms; or a ring denoted by
`
`where R9 and Rmare 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 —~CH2CH3—, 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. R; 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
`
`O
`\\
`
`Rg—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 trifluorornethyl.
`As used throughout this specification and the ap-
`pended claims, the term “aikylf denotes a branched or
`unbranched saturated hydrocarbon group derived by
`the removal of one hydrogen atom from an alkane.
`The term “all-tony" denotes an alkyl group, as just
`defined, attached to the parent molecular
`residue
`through an oxygen atom.
`The term “a]kanoyIoxy" is meant to denote an alkyl
`group, as defined above, attached to a carbonyl group
`
`10
`
`15
`
`20
`
`30
`
`40
`
`4-5
`
`50
`
`55
`
`60
`
`65
`
`\
`
`where n is three or four; a ring denoted by
`
`a ring denoted by
`
`0
`
`/
`
`\.
`
`0
`\\
`
`Rg—N
`
`/10
`
`/
`
`‘\.
`
`where R3 is hydrogen, alkyl of from one to four carbon
`atoms, phenyl, or benzyl; or a ring denoted by
`
`where R9 and R19 are hydrogen, alkyl of from one to
`four carbon atoms, or benzyl. In this aspect of the in-
`vention, R4is preferably aikyl of from one to four car-
`bon atoms, cycloprupyl, cyclobutyl, or trifluoromethyl.
`In a fifth preferred subgeneric chemical compound
`aspect, the present invention provides compounds of
`formula I above where X is —CH;:_CH2—, 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. R; and
`R3 are preferably independently hydrogen, chlorine,
`bromine, phenyl, or carboalkoxy of from two to-eight
`carbon atoms. In this aspect of the invention R1 and R3
`may also, when taken together with the carbon atoms to
`which they are attached, form a ring denoted by
`
`4ofl8
`
`PENN EX. 2194
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`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.l]hept-2-ene.
`Specific examples of compounds contemplated as
`falling within the scope of the present invention include
`the following:
`tran5-6-[2-[2-Cyclobutyl-5-(4-fluorophenyl)-1H-pyrrol-
`J-y]]ethyl}telrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-Cyclohexyl-S-(4-fluorophenyl)-IH-pyrrol-
`l-yl]ethyl]tetrahydro-4-hydroxy-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-(2-methyl-5-phenyk
`lH-pyrrol-1-yl)ethy1]-2H-pyran-2-one.
`tra.ns-6-[2-[2-(4-Chlorophenyl)-S-methyl-lH-pyrro]-l-
`yl]ethy]]tetrahydro-4-hydroxy-2H-pyran—2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(4-methoxy-
`phenyl)-5-methyl-1H-pyrrol-l-yl]ethyl]-2H-pyran-
`2-one.
`
`trans-6-[2-[2-([1,1'-Biphenyl]-4-y])~5-methybIH-pyrrol-
`l-yI)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2~n1ethyl-S-[3-(tri-
`fluorornethyl]phenyl]-1H-pyrrol-l-yl]ethyl}-2H-
`pyran-2-one.
`trans-6-[2-[2-(2,S-Dimethylpl1enyl)-5-(1-methyIethyl)-
`lH—py rrol- l -yl]eth ylhetrahyd ro-4-hydroJLy-2H-
`py ran-2-one. _
`trans-6-[2-[2-(2,6-Dimethoxyphenyl)-5-( 1 -methylethyl)-
`1H-pyrrol-l -yl]ethyl]tetrahyd ro -4-hyd roxy-2H-
`py ran-2-one.
`trans-Tetrahyd ro-4-h yd roxy-6-[2-[2—methyl-5-(2-na ph-
`thalenyl)-1I-I-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
`trans-6-[2-(2-(Cyclohexyl-5-triflnoromethyl-1H-pyrrol-
`l-yl)ethyl}tet1-ahydro-4-hydroxy-21-I-pyran-2-one.
`trans-6-[2-[2 -(4-Fluorophen yl)-3,4-dimethyl-5-( I-
`methyleth yl)- 1 H-pyrrol- ] -yl] eth yl]tet rahydro-IL
`hyd roxy-2H-p yran-2-one.
`trans—2—{4—Fluorophenyl)-5-(1 -meth yleth y1)- l—[2—(iet—
`rah ydro-4—hyd roxy-6—oxo-2H-py ran-2-y1)ethy1]-I H-
`py rrole-3. 5-dicarbox ylic acid.
`trans-2-(4-Fluo rop henyl)-N3, N3,N“',N4-tet rameth yl-5-
`(l —methylethyl)- l-[2-(tetrahydro-4-h yd roxy-6-oJEo-
`2H-py ran-2-yl)eth yl]- l H-pyrrole-3,4-dicarboxamide.
`trans-6-[2-[3,4-Dich1oro-2-(3-fluorophenyi)-S-( I -
`methy]ethyl)-1H-pyrrol-l-yl]ethyl]tetrahydro-4-
`hyd roxy-2H-py ran-2-one.
`trans-2-(4-Fluorophenyl)-S-(1-methylethyl)-1-[2-(teb
`rahydro)-4-hydro xy-6-oxo-2H-pyran-2-yl)ethyl]-1H-
`pyrrole-3,4-dic arbonitrile.
`tran s-6-[2-[3,4—Diacetyl-2-(4-fluorophenyl)-5-( I -
`'methylethyl)—1H-pyrrol-l-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-Diethyl
`2-(4-Fl l1orophenyl)- 1 -[2-(tetrahydro)-4-
`hydrox y-6-oxo-2H-pyran-2-yl) ethyl]-5-(t rifl noron1e-
`thyl)-1H-pyrrole-3,4-dicarboxylate.
`trans-Bis( 1 -met hylethyl)
`2-(4-Fluoro phenyl)-5-(L
`methylethyl}1-[2-(tetrahydro)-4-hyclroxy-6-oxo-2H-
`pyran-2-yl)ethyl]-1 H-pyrrole-3.4-dicarb oxylate.
`trans-6-[2-[3,4-Diethyl-2-{4-fluorophenyl)-5-(I -
`methylethyl}1H-pyrrol-l-yl]ethyI]tetrahydro—4-
`hyd roxy-2H-pyran-2-on e.
`trans-6-[2-[2-(4-Fluoropheny])-3,4-bis(h yd roxymethyl)-
`5-(1-rnethyleth yl]- l H- pyrrol-l -yl]-ethyl]tetrah yd ro-
`4-h ydroxy-2H-pyran-2-one.
`
`8
`.
`trans-l-Melhylethyl 4-Chloro-2-(4-fluorophenyl]-5-{1-
`methylethyl}l-[2-{tetrahydro}-4-hydroxy-6-oxo-2H-
`pyran-2-yI)ethyl]-1H-pyrrole-3-carboxylate.
`tran s-6-[2-[4—(4-Fluorophenyl}-6-{ 1 -met hyleth y1}- 1 H-
`furo[3,4-c]pyrrol-5(3I-1)-yl]ethy|]tetrahydro-4-
`hydroxy-21-I-pyran-2-one.
`trans-6-[2-[2-(4-Fluoropheny1)-5-(l-methylethyl)-3,4-
`biSI[[(phenylamino)carbony]}oxy]mcthyl]-lH-pyrrol-
`I-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-l-Methylethyl 4-Chloro-5-(4-—fluorophenyl)-2-(l-
`methylethyI)-l-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-
`pyran-2-yl)ethyl]-1H-pyrrole-3-carboxylate.
`Iran s-Eth yl
`5-(4-Fluoroph en yl}- l -[2-(tetrah yd1'o)-4-
`hydroxy-6-oxo-2]-I-pyran-2-yl)ethyl]—2—{trifluorome-
`thy!)-IH-pyrrole-3-carboxylate.
`trans-Ethyl
`5-(4—F1uorophenyl)-2-(l-methylethy])-4-
`phenyl-1-[2-(tetrahydro~4—hydroxy-6-oxo-21-l-pyran-
`2-yI)ethyl]-1H-pyrnole-3-carboxylate.
`lrans-6-[2-[l-(4-Fluorophenyl)-4,5.6,7-tetrahydro—3-
`methyl—2H—isoindol-2-yl]ethyl]tetrahydro-4-hydroxy-
`2H-pyran-2-one.
`trans-4-(4—Fl11orophenyl)-2-methyl-6-(l-methylethy])-5-
`[2-(tetrahydro-4—hydroxy-6-oxo-2H-pyran-2-yl)e-
`thyl]-p yrrolo[3.4-c]pyrrole-l ;3 (2H,5H)-dione.
`trans-6-[2-[1-(4-Fluorophenyl)-5,6-dihydro-3-(1-
`methylethy])pyrrolo[3,4-c]pyrrol-2(4H)-yl]etl1yl]-tet-
`rahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[1—(4-Flnorophenyl)-S,6-clihyclro-5-methyl-$
`(l-rnethylethyl)pyrrolo[3,4-c]pyrrol-2(4H)-yl]-ethy]]-
`tetrahydto-4—hydroxy-2H-pyran—2-one.
`trans-6-[2-[3-Chlortr5-(4-fluorophenyl)-2-(l-methyle-
`thyl)-4-phenyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Flnorophenyl)-5-(1-methylethyl)-3,4-
`diphen yl- I ]-I-pyrrol- l-yl]ethyl]tetrahyd ro-4-
`hydroxy—2H-pyran-2-one.
`Particularly preferred compounds in accordance
`with the present invention are:
`trans—6-[2-[3,4-Dichloro-2-(4-flnorophenyl)-5-(1 -
`methylethyl)- 1H-pyrrol- l -yl] eth yl]tetrahy dro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[3,4-Dibromo-2-(4-fluorophenyl)-5-(1-
`meth ylethyl)— l H-py rrol- ] -yl] e1;hyl]tetrah ydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-(trif'1noromethyl)-1H-
`pyrrol-1-yl)ethyI]tetrahydro-4-hydroxy-2H-pyram
`2-one.
`
`trans-Dimethy] 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-Fluorophenyl-5-methyl-1H-pyrrol-1-
`yl]ethyljtetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4—Fluoropheny1-5-(1-methylethyl)-lH-
`pyrro1-1-y1]ethyl]tetrahydro-4-hydroxy-2H-pyran-
`2-one.
`
`trans-6-[2-[2-Cyclopropyl-5-(4-fluorophenyl)-1H-pyn
`rol-l-yl]ethyl]tetrahydro-4-hydroxy-2H—pyran-2-one.
`trans-6-[2-[2-(l ,1-Dirnethylethyl)-5-(4-flunrophenyl}
`IH-pyrrol-‘I-y]]ethy]]tetrahydro-4-hydroxy-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-Inethoxy-
`phenyl}-5-trifluorom eth yl— 1H-pyr rol-1 -yl]eth yl]-2H-
`2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy
`pheny1)-5-(1-methyIethy])-1H-pyrrol-l-yl]ethyl]-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy—6-[2-[2-methyl-5-(1-naph-
`thalenyl)->1H-pyrrol-l-yl]ethy]]-2H-pyran-2-one.
`
`15
`
`20
`
`25
`
`35
`
`45
`
`SD
`
`55
`
`{:5
`
`5ufl8
`
`PENN EX. 2194
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`

`
`9
`tt'ans—6-[2-(2-Bicyclo[2.2. l ]hep-5 -en-2 -yl-5-meth yl-l H-
`pyrrol- l-yl}eth y]]tetrah yd ro-4-h ydrox y—2 H-pyran—
`2-one.
`
`trans-6-[2-[2-(4-Fluorophen yl)-5-(1-methylphenyl)-I H-
`pyrrol- 1 —yl]propyl]tetrah yd ro-4-hyd roxy-2H-py ran-
`2—one.
`
`5
`
`Compounds of the present invention where R2 and
`R3 are hydrogen are prepared by the methods outlined
`in Reaction Sequence 1 or Reaction Sequence 2. As
`shown in Reaction Sequence 1, the aldehydes, V1, are
`reacted with the appropriately substituted vinylketones,
`VII, in the presence of the thiazolium salt, VIII, and a
`base such as triethylamine, to produce the diketones,
`IX. (See Aug. Chem. Int. Ed. 15: 639-712 (1976)).
`The diketones,
`IX, are reacted with an omega-
`aminoalkylnitrile
`(compound Roman numeral
`ten
`where the value of X is methylene, ethylene, or 1-
`rnethylethylene) in acetic acid to produce the disubsti—
`tuted pyrrole nitriles, XI.
`Treatment of
`the pyrrole nitriles, XI, with
`diisobutylaluminum hydride in an inert solvent such as
`dichloromethane produces the corresponding pyrrole
`aldehydes, XII.
`
`10
`
`15
`
`20
`
`4,647,576
`
`10
`
`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
`added to the mixture which is then cooled to a tempera-
`ture of preferably between about 0'’ C. and -78“ C.
`after which sodium borohydrideis added.
`After stirring this mixture for about one to two hours,
`the mixture is oxidized with basic hydrogen peroxide.
`The reaction produces the 7-(substituted-pyrrolyl)—3,5-
`dihydroxyheptanoic acids, XIV, in which the product
`contains a predominance of the desired R‘, R"‘ configu-
`ration 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 methods
`or, alternatively. cyclized to the 6-[2-(substituted-pyn
`rol-l-yl)alkyl]pyran-2-ones,
`I, by dehydration in an
`inert solvent such as refluxing toluene with azeotropic
`removal of water. This cyclization reaction is found to
`produce material containing from 35-90% of the de-
`sired active trans-configuration of the 4-hydroxy group
`relative to the 6-(substitutedpyrrolybalkyl group on the
`pyran-2-one lactone ring.
`
`REACTION SEQUENCE l
`
`o
`II
`R1CC1
`vi
`
`o
`o
`o
`II
`II
`(E-I5Cg)3N
`II
`RgCCl~i=CH; fife R.|CCH;:CH1CR.1
`vn
`Ix
`
`HOAC
`”=N‘X‘C“
`x
`
`RI
`
`X—CN
`
`N
`/ /
`
`R2
`
`xi
`
`H c
`3 / 5 Cr
`-*/N J vnt
`tfJH;IC
`
`.
`Diisabutylaluminum
`hydride
`
`5
`
`R1
`
`X—CHO
`
`N
`
`R2
`
`Jot
`
`R1
`
`xrn
`
`0
`ll e
`9
`NaLi(cHzc—cH—_coocn,)
`
`0
`
`on
`l
`CH2CH2CHCH;CCH2COOCH_;
`
`N
`
`R,
`
`H onas
`
`
`I Tribut lborane
`(2) Sodium iiorohydride
`(3) H202. on -
`
`
`
`RI
`Z
`
`H,
`1,,
`N—CHgCH;
`
`K
`‘*0
`
`0
`
`R}:
`
`I
`
`R]
`
`xiv
`
`/cH;cH\\gcH,§cH;cooH
`.\\>“
`x\“ i
`H OH};
`OH
`
`N
`
`R2 _
`
`Reaction of the pyrrole aldchydes, 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-
`
`-6ofl8
`
`PENN EX. 2194
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`
`

`
`11
`
`4,647,576
`
`12
`by starting with compounds of formula XIX. In this
`latter instance, the hydroxy functionality of compounds
`of formula XIX is convened to the p-tolueriesulfonate
`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 Sequenoe 1 above.
`Starting materials and intermediates employed in
`Reaction Sequences l 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 trirnethylsilylethene, XXIV, in the pres-
`ence of anhydrous aluminum chloride in diehlorometh-
`ane.
`
`5
`
`l0
`
`I5
`
`20
`
`In the alternative method of preparing the vinyl ke-
`tones, VII, which is preferred when R; is an aromatic
`substituent such as phenyl or substituted phenyl, the
`
`REACTION SEQUENCE 3
`
`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
`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 SEQ LTENCE 2
`
`ii
`‘ii
`in’
`if
`R1CCH2X + R2CCH2COOC2I-I5 -—>R|OCH2!i_IHCR.3
`(X = halogen)
`c00C._,H5
`XV
`XVI
`\I/
`
`Rt
`
`/H
`
`R2
`
`/ N
`
`XVIII
`
`Ninoac
`Q-I-_I-d-K6-—
`
`O
`0
`II
`II
`R]CCH;:_CHgCR-_i
`
`IX
`
`(1) NaH
`(2) Br—X—CH(UCH3}3
`(3) H ‘l’, H30
`(Km
`
`R]
`
`
`
`/X—CHO
`
`N
`
`H3N—X—OH
`
`(XVIII)
`
`R]
`
`/X--CN
`
`/ N
`
`R2
`
`XX
`
`R2
`
`(XXII in Rction Sequence 1}
`
`(XIII in Reaction Sequence 1)
`
`(1) Tosyi chloride
`(2) CN‘
`
`REACTION SEQUENCE 3
`
`0
`0
`||
`AICI3
`II
`RCCI -:— CH2=CH5i(CH3)3 R—C—CH=CH2
`XXIII
`xxlv
`v11
`
`0
`
`0
`ll H :[CH_i)gNH.HCl II H HNCU
`
`ArCC 3
`(CHZOJN
`AICC 2C 3
`{ H3);
`xxv
`' XXVI
`
`ll)CH3I
`(2}NaHOC‘.'3
`
`0|
`
`VII
`
`|
`ArCCH=CH;~
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`_._..........._.....%
`D‘ H;N—x-«oi-1
`XVIII
`
`Rt
`
`/X—OH
`
`/ N
`
`R2
`
`XIX
`
`known methyl aryl ketones, XXV, are converted to
`(dimethylaminoethyl)aryl ketones, XXVI. and then by
`deamination to the vinyl ketones, VII.
`The compounds of the present invention of formula I
`where the groups R; 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
`An alternative for this step, preferred when R] and-
`R; and R3 are both halogen can be prepared by the
`/or R4 are sterically bulky groups, involves reaction of
`haloge-nation of the unsubstituted compounds with N-
`the diketones, IX, with an omega-hydroxyalkyl amine
`halosuceinirnide in a three-step process involving the
`(compound XVIII where X is methylene, ethylene,
`1_methy1,_._thy]¢ne), to produce the N_(omega_hyd,°xy_ 55 prior protection of the 4-hydroxy group of the lactone
`alky])_2’5_disub5mutedpy,-mics, XIX
`ring. Thus, for example, the 2,5-dIsubstItutedpyrrol-1-yl
`The 2,5-disubstitutedpyrroles, XVII, are converted
`compounds. XXVII. are first converted to the oom-
`to the omega-(substitutedpyrrolyhaldehydes, XX, by
`5P0“d1TlS I-51’t'l311tY1'dim91hYl5i]Y1 5th’-’-‘1'5» XXVI“ The
`sequential reaction with sodium hydride, a l,1-dime-
`protected compounds and then chlorinated with N-
`thmgy-omega.b;mmoa]kane (compound XX] where X is 59 chlorosuecinimide in a polar solvent such as dimethyl-
`methylene, ethylem;
`|-methy1ethy]ene, or vinyl), and
`formamide to produce the silylated 3,4-dichloro com-
`then acid. The aldehydes, XX, are subsequently used in
`Pounds» XXIX The Prmecting Sllyl ether ET01-113 I5 1115“
`the preparation of compounds of formula I of this in-
`subsequently removed by reaction with a buffered fluo-
`vention as illustrated above in Reaction Sequence ].
`ride reagent Such 33 '£811‘3bUlY13m1T10ni11m fluoride in 3
`The 2,5-disubstituted pyrroles, XVII, are convened 55 mixed acetic acid/tetrahydrofuran solvent system to
`to the eorrespondin g (2,5-disubstitutedpyrrolyl)nitriles,
`produce the dichloro compounds, XXX.
`XXII (when X is ethylene), by reaction with acryloni-
`Alternatively, as detailed in Reaction Sequence 5,.the
`trile or, alternatively (when X is other than ethylene),
`(2,5-disubstitutedpyrrol-l-yl)alkyl nitriles, XI (see Re-
`
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`13
`action Sequence 1) are halogenated by employing an
`N—halosuccinimide in dimethylformamide to provide
`the 2,5-disubstituted—3,4-dihalopyrroles, XXX].
`(See
`Aiello, et al., J’. Her. Chem., 19: 97')‘ (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., Aug. Chem. Int. Ed., 3: 136 (1964). In I0
`this procedure, detailed in Reaction Sequence 6, an
`
`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, XXXVI]. 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.
`
`_
`Hflgyflf
`
`REACTION SEQUENCE4
`.
`-
`_
`t—Buty1(Me)1SiC]
`¢O mzfi I Eu(Me)25IO;;y,{
`
`0
`
`R4
`
`‘
`
`R1
`
`N
`
`XXVI]
`
`RI.
`
`N
`
`.11..
`
`XX\«"lll
`
`DMF
`
`Ll__--Chloro-
`succinimide
`
`¢()
`
`0
`
`éo
`0
`
`in
`
`Cl
`
`H0’/4'3
`
`éo
`O
`
`Tetrabutyl—
`{ammonium fluoride
`HOACKTHF
`
`_
`-
`I Bulmehslo/’5'/I
`
`12.:
`
`CI
`
`XXIX
`
`45
`
`RI:
`
`C1
`
`XXX
`
`CR4
`
`Cl
`
`REACTION SEQUENCE 5
`
`C”
`
`2 fl“-Chloro- or _l‘~i--Bromo-
`N
`Rd
`succinirnide
`\E I Dirnethylforlnarnide
`
`R1
`
`;
`
`XI
`
`Preferred substituents for the substituted acetylenic
`compounds in this method of making compounds of the
`so present invention include carboalkoxy groups, phenyl
`groups, alkanoyl groups, alkyl groups and cystic
`groups. The reaction between the disubstituted acety-
`lene compound and the N-acyl-N-all-tyl aminoacids,
`XXXIV, generally proceeds smoothly; for example, the
`55 dicarbomethoxy acetylene reacts smoothly at 25" C.
`
`CN
`(I
`
`N
`
`R‘
`
`However, when only one activating group is attached
`to the acetylene, the reaction mixture must generally be
`warmed to ':'0°—1l0" 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
`N-all-:yl-N-acylamino acid is treated with an acid anhy-
`example, as shown in Reaction Sequence 7, reduction of
`dridc and a substituted acetylenic compound to produce
`a pyrrole. For example, Reaction Sequence. 6 shows 6S_ XXXVI with a reducing agent such as lithium alumi-
`how reaction of an alpha-halo ester, XXXII, with 2-(l-
`num hydride results in the bis(l1ydroxymethy1)pyrrole
`(2~aminoethyl))—1,3-dioxalane in triethylamine provides
`which can be subsequently further reduced to the di-
`the N-alkyl-alpha-aminoester, XXXIII. The arninoester,
`methyl compound,
`
`RI
`
`(Eric;
`
`I I
`l
`
`xxx:
`
`CERT) 60
`
`3 Of 13
`
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`

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`
`«
`
`15
`
`REACTION SEQUENCE 6
`
`1'31‘
`R1CI-ICO0CH_1
`
`.
`.
`|
`COOCH3
`T .
`0”‘-'1' “"“'“°NH} RICHNH
`
`/"'\
`
`o
`
`0
`
`16
`XXXVIII, by means of triethylsilane and trifluoroacctic
`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 allay]-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 biswialkylamides). XL.
`Alternatively,
`reaction of XXXVI with primary
`amines, followed by thermal cyclizationfi 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(hyd1'oxymethyl)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: 97? (1979)).
`The acids, XLII1, 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(all<anoyl)pyrro1es,
`XLVI, can be derived from the bis(nitrilo)pyrroles by
`reaction in the convention manner with the appropriate
`Grignard reagents.
`The ring-opened dihydroxy-acids of structural for-
`mula II above are intermediates in the synthesis of the
`lactone compounds in accordance with