United States Patent
`
`
`
`
`
`Hoefle et al.
`
`[193
`
`
`_[11] Patent Numbef:
`
`
`
`
`
`[45] Date of Patent:
`
`
`
`
`4,647,576
`
`Mar. 3, 1987
`
`
`
`
`[54] TRANS.6-[2.(SUBSTITU'I‘EDPYRROL.1.
`
`
`YL)ALI(YL]_pYRAN.2_oNE INHIBITORS OF
`CHOLESTEROL SYNTHESIS
`
`
`
`
`
`
`
`
`
`
`
`
`
`[75]
`
`
`[63]
`
`
`Inventors: Milton L. Hoefle; Bruce D. Roth;
`
`
`
`
`Charlotte D, Stratton, all of Ann
`
`Arbor, Mich.
`
`
`[73] Assignee: Warner-Lambert Company, Morris
`
`
`
`
`
`P131115: N-1
`
`
`[211 APPL N0-‘ 679157‘
`
`
`
`
`[221 Filed‘
`Dec‘ 109 1984
`
`
`
`
`
`Related US. Application Data
`
`
`
`
`
`
`
`Continuation-in-part of Ser. No. 653,798, Sep. 24, 1984,
`abandoned.
`‘
`
`
`
`
`
`
`
`
`[51]
`Int. Cl.4 .................. .. C07D 405/06' A61K 31/40
`
`
`
`
`
`
`
`
`[52] 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
`
`
`
`
`
`[58] Field of Search ................ 548/517, 562; 514/422,
`
`
`
`
`
`
`
`514/343; 546/281
`
`
`
`[56]
`
`
`
`_
`
`References cued
`
`
`
`
`
`U.S. PATENT DOCUMENTS
`3983140 9/1976 Endo et a1.
`.......................... 549/292
`
`
`
`
`
`
`4/1980 Mistui et al.
`4,193,425
`514/460
`
`
`
`
`
`
`
`4,219,560
`8/1980 Houlihan
`544/372X
`
`
`
`
`
`4,248,889
`2/1981
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`549/292 X
`4,255,444
`3/1981 Oka et al.
`
`
`
`
`
`549/292
`4,308,378 12/1981 Stokker
`514/415
`3/1982 Humans et a1
`4,343,811
`
`
`
`
`
`
`
`
`
`514/460
`4,351,844
`9/1982 Patcheti Cl 31.
`..
`549/292 X
`3/1983 Willard et al.
`4,375,425
`
`
`
`
`
`549/292
`3/1983 Lam .........
`4,376,863
`
`
`
`
`
`4,440,927 4/1934 Prugh .................................. 549/292
`
`
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`
`
`4/1933 Belgium .
`395445
`
`
`
`OTHER PUBLICATIONS
`
`
`Hulcher, Archives of Biochemistry and Biophysics,
`
`
`
`
`
`146, (1971), pp. 422-427.
`
`
`
`
`
`Primary Examiner—Donald G. Daus
`
`
`
`
`
`
`Assistant Examiner—~Wi1liam A. Teoli, Jr.
`
`
`
`
`
`Attorney, Agent, or Firm—Jerry F. Janssen
`
`
`
`ABSTRACT
`[57]
`
`
`
`
`6-[2-(Substituted-—pyrroLI-yI)aklyl]pyran-2-ones ancl the
`corresponding ring-opened hydroxy-acids derived
`
`
`
`
`therefrom are potent
`inhibitors of the enzyme 3~
`
`
`
`
`
`
`
`hydroxy—3-methylglutarylcoenzyme
`reductase
`A
`
`
`
`(HMG-CoA reductase), and are thus useful hypolipi-
`
`
`
`
`
`
`
`demic and hypocholesterolemic agents. Pharmaceutical
`
`
`
`
`
`
`
`
`
`
`compositions containing such compounds,
`and a
`m°‘h°d °f ‘“°"“““’“‘ “"‘P1°Yi“g S“°h Ph“‘“a“°““°a1
`
`
`
`
`
`°°mP°51“°“5 are 3150 ‘1‘5°1°5°d~
`
`
`
`
`
`19 Claims, No Drawings
`
`
`
`
`
`Sawai Ex 1032
`Page 1 of 19
`
`

`
`1
`
`
`4,647,576
`
`
`
`TRANS-6-[2-(SUBSTITUTEDPYRROL-1-YL)AL-
`
`KYL]-PYRAN-2-ONE INHIBITORS OF
`
`
`CHOLESTEROL SYNTHESIS
`
`
`
`2
`
`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
`
`
`
`
`
`
`
`
`hal"
`
`
`
`
`
`R5
`+/N
`
`I
`
`
`\
`
`10
`
`20
`
`25
`
`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 R; 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. R;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and R3 may also, when taken together with the carbon
`atoms to which they are attached, form a ring denoted
`
`
`
`
`
`
`
`
`by
`
`
`
`
`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.
`
`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-1-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
`
`
`
`
`
`
`
`35
`A.rsaciatt'0n (1984) 251, No. 3, 351-374).
`
`
`
`
`
`Moreover,
`is known that certain derivatives of
`it
`
`
`
`
`
`
`
`
`
`
`
`mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid)
`and the corresponding ring-closed lactone form,
`
`
`
`
`
`
`mevalonolactone, inhibit the biosynthesis of cholesterol
`
`
`
`
`
`(cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med.
`
`
`
`
`
`
`
`
`
`
`(1959), 102, 270) and F. H. Hulcher, Arch. Biochem.
`
`
`
`
`
`
`
`
`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-
`
`
`
`
`
`ky1]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).
`
`
`
`
`
`where n is three or four; a ring denoted by
`
`
`
`
`
`
`/ \
`
`
`
`
`
`
`
`
`
`a ring denoted by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sawai Ex 1032
`Page 2 of 19
`
`

`
`3
`
`where Rg is hydrogen, alkyl of from one to six carbon
`
`
`
`
`
`
`
`atoms, phenyl, or benzyl; or a ring denoted by
`
`
`
`
`
`
`4,647,576
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`I above by (a) first reacting a substituted [(pyrrol-1-
`
`
`
`
`
`
`
`yl)alkyl]aldehyde compound of formula III
`
`
`
`
`
`
`
`
`
`
`
`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—C}_iO
`
`R1 / N/
`
`
`
`R3
`
`R4
`
`
`
`
`
`
`
`
`
`where X, R1, R2, R3, and R4are as defined above, with
`
`
`
`
`
`
`
`
`the alkali metal salt of the dianion of methyl acetoace-
`
`
`
`
`
`
`
`
`
`tate to form a compound of structural formula IV
`
`
`
`
`
`
`.0
`on
`
`
`II
`I
`X—CHCI-I2CCH2COOCH3
`
`
`
`
`
`R
`
`‘
`
`
`R2 2 N/
`
`R:
`
`
`
`R4
`
`
`where X, R1, R2, R3, and R4 are as defined above, then
`
`
`
`
`
`
`
`
`successivly (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
`
`
`
`
`
`
`
`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, 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 —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-
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sawai Ex 1032
`Page 3 of 19
`
`

`
`4,647,576
`
`
`
`
`
`
`
`10
`
`
`
`where n is three or four; a ring denoted by
`
`
`
`
`
`
`0
`\\
`
`Rg—'N
`
`//o
`
`/
`
`\
`
`5
`
`kanoyloxy of from two to eight carbon atoms, or where
`
`
`
`
`
`
`
`
`
`
`
`
`
`R] is 1-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
`
`
`
`
`
`
`
`
`/ \
`
`where n is three or four; a ring denoted by
`
`
`
`
`
`
`20 where R3 is hydrogen, or alkyl of from one to four
`
`
`
`
`
`
`
`carbon atoms; or a ring denoted by
`
`
`
`
`
`
`
`/ \
`
`
`
`
`
`
`
`
`
`a ring denoted by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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- 55
`
`
`
`
`
`
`
`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- 60
`
`
`
`
`
`
`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 65
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`where R9 and Rm 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 1 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. 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
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`Sawai Ex 1032
`Page 4 of 19
`
`

`
`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:
`trans-6-[2-[2-Cyclobutyl-5-(4-t1uorophenyl)- 1 H—pyrrol-
`1-yl]ethyl]tetrahydro-4—hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-Cyclohexyl-5-(4-fluorophenyl)-lH-pyrrol-
`1-yl]ethyl]tetrahydro-4-hydroxy-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-(2-methy1-5-phenyl-
`lH-pyrrol-1-yl)ethyl]-2H-pyran-2-one.
`trans-6-[2-[2-(4-Chlorophenyl)-5-methy1-1H-pyrrol-1-
`yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(4-methoxy-
`phenyl)-5-methy1- lH-pyrrol-1-y1]ethy1]-2H-pyran-
`2-one.
`
`trans-6-[2-[2-([1,1'-Biphenyl]-4-yl)-5-methyl-lH-pyrrol-
`1-yl)ethy1]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-[3-(tri-
`1luoromethyl)phenyl]- 1H-pyrro1- l-yl]ethyl]-2H-
`pyran-2-one.
`trans-6-[2-[2-(2,S-Dimethylphenyl)-5-(1-methylethy1)-
`lH-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-
`pyran-2-one. _
`trans-6-[2-[2-(2,6-Dimethoxyphenyl)-5-(1-methylethyl)-
`lH-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(2-naph-
`thalenyl)-lH-pyrrol-1-y1]ethyl]-2H-pyran-2-one.
`trans-6-[2-(2-(Cyclohexy1-5-trifluoromethy1-lH-pyrrol-
`1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)—3,4—dimethyl-5-( l -
`methylethy1)-1H-pyrrol- l-yl]ethyl]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-yl)ethyl]-1 H-
`pyrrole-3,5—dicarboxyliC acid.
`trans-2-(4-Fluorophenyl)-N3,N3,N4,N4-tetramethyl-5-
`(1-methylethyl)-1-[2-(tetrahydro-4—hydroxy-6-oJEo-
`2H-pyran-2-y1)ethyl]-1H-pyrrole-3,4-dicarboxamide.
`trans-6-[2~[3,4-Dichloro-2-(3-fluorophenyl)-5-(1-
`methylethyl)- 1H-pyrro1= 1-y1]ethy1]tetrahydro-4»
`hydroxy-2H-pyran-2-one.
`trans-2-(4-Fluoropheny1)-5-(1-methylethyl)-l -[2-(tet-
`rahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethy1]- 1 H-
`pyrro1e-3,4-dicarbohitrile.
`trans-6-[2-[3,4-Diacetyl-2-(4-fluorophenyl)-5-(1 -
`methylethy1)- lH-pyrrol- 1-y1]ethyl]tetrahydro-4-
`hydroxy-2H—pyran-2-one.
`trans-Diethyl
`2—(4-Fluorophenyl)-l-[2-(tetrahydro)-4-
`hydroxy—6-oxo—2H-pyran-2-yl)ethyl]-5-(trifluorome-
`thy1)-1H-pyrrole-3,4-dicarboxylate.
`trans-Bis( 1-methylethyl)
`2-(4—F1uoropheny1)-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-Diethy1-2-(4-fluorophenyl)-5-(1-
`methylethy1)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans—6-[2-[2-(4-F1uoropheny1)-3,4-bis(hydroxymethyl)—
`S-(1-methylethyl)-1H-pyrrol-1-y1]-ethy1]tetrahydro-
`4-hydroxy-2H-pyran-2-one.
`
`4,647,576
`
`15
`
`8
`.
`trans- l-Meth ylethyl 4-Chloro-2-(4-fluorophenyl)-S-( 1-
`methylethyl)- I -[2-(tetrahydro)-4—hydroxy-6-oxo-2H-
`pyran-2-yl)ethy1]-1H-pyrrole-3-carboxylate.
`trans-6-[2-[4-(4-Fluorophenyl)-6-( l -methy1ethyl)- 1 H-
`furo[3.4-c]pyrrol-5(3I-I)-yl]ethy1]tetrahydro—4-
`hydroxy—2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-( l —methylethyl)-3,4-
`bis[[[(phen ylamino)carbon yl]oxy]methyl]- lH-pyrrol-
`1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
`trans-1-Methylethyl 4-Chloro-5-(4-fluorophenyl)-2-(1-
`methylethy1)- 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]ethyl]tetrahydro-4-hydroxy-
`2H-pyran—2-one.
`trans—4-(4-F1uorophenyl)-2-methyl-6-(1-methylethyl)-5-
`[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y1)e-
`thyl]-pyrrolo[3,4-c]pyrrole-1;3(2H,5H)-dione.
`trans-6-[2-[1-(4-F1uorophenyl)-5,6-dihydro-3-(1-
`methy1ethyl)pyrrolo[3,4-c]pyrro1-2(4H)-yl]ethyl]-tet-
`rahydro-4-hydroxy-2H—pyran-2-one.
`trans-6-[2-[1-(4-F1uorophenyl)-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-Chloro-5-(4-fluorophenyl)-2-(1-methyle-
`th yl)-4-phenyl-lH-pyrrol-1-yl]ethyl]tetrahydro-4-
`hydroxy-21-I-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3,4—
`diphenyl- lH-pyrrol- 1-yl]ethy1]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)- lH-pyrrol- 1 -yl] ethy1]tetrahydro-4-
`hydroxy-2H—pyran-2-one.
`trans-6—[2-[3,4—Dibromo-2-(4-fluoropheny1)-5-(1-
`methylethyl)- 1 H—pyrrol- l -yl]ethyl]tetrahydro-4-
`hydroxy-2H-pyran-2-one.
`trans-6-[2-[2-(4-Fluorophenyl)-5-(trifluoromethyl)— 1 H-
`pyrrol—1-yl)ethyl]tetrahydro-4—hydroxy-2H-pyran-
`2-one.
`trans-Dimethyl 2-(4-Fluorophenyl)-5-(1-methy1ethy1)-
`1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-y1)e-
`thyl]-1H-pyrrole-3,4-dicarboxylate.
`trans-6-[2-[2-(4-Fluorophenyl-5-methyl-1H-=pyrrol-1-
`yl]ethylltetrahydro-4-11ydroxy-2H-pyran-2-one.
`trans-6-[2=-[2-(4«F1uoropheny1-S-(1-methylethyl)-1H-
`pyrrolu1-yl]ethy1]tetrahydro-4—hydroxy-2H-pyran-
`2-one.
`trans-6-[2-[2-Cyclopropyl-5-(4-fluorophenyl)- lH-pyr-
`ro1=-1-y1]ethyl]tetrahydro-4-hydroxy—2H-pyran-2-one.
`trans-6-[2-[2-(1 , 1-Dirnethy1ethy1)-5-(4-fluoropheny1)-
`lH-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-
`pyran-2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-
`pheny1)-5-trifluoromethy1-lH-pyrrol-1-yl]ethyl]-2H-
`2-one.
`trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-
`phenyl)-5-(1-methylethyl)-1H—pyrrol-1-yl]ethyl]—2H-
`pyran-2-one.
`trans-Tetrahydro-4»hydroxy-6-[2-[2-methyl~5-(1-naph-
`thaleny1)— lH-pyrrol- 1-y1]ethyl]-2H-pyran-2-one.
`
`Sawai Ex 1032
`Page 5 of 19
`
`

`
`
`
`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 borohydride is 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-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 reaction is found to
`
`
`
`
`
`
`produce material containing from 85-90% of the de-
`
`
`
`
`
`
`
`
`
`
`
`
`
`sired active trans-configuration of the 4-hydroxy group
`relative to the 6-(substitutedpyrro1yl)a1kyl group on the
`
`
`
`
`
`pyran-2-one lactone ring.
`
`
`
`
`9
`
`
`
`trans-6-[2-(2-Bicyclo[2.2.1]hep—5—en—2-yl-5-methyl-lH-~
`
`pyrrol- l -yl)eth yl]tetrahydro-4-hydroxy-2H-pyran-
`2-one.
`
`trans-6-[2-[2-(4-Fluorophenyl)-5-(1-methylphenyl)-1H-
`pyrrol-l-yl]propy1]tetrahydro-4-hydroxy-2H-pyran— 5
`2-one.
`
`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, VI, 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 Ang. 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-
`
`
`
`
`
`
`
`methylethylene) in acetic acid to produce the disubsti-
`
`
`
`
`
`
`tuted pyrrole nitriles, XI.
`
`
`
`
`with 20
`Treatment of
`the pyrrole‘ nitriles, XI,
`
`
`
`
`
`
`
`diisobutylaluminum hydride in an inert solvent such as
`
`
`
`
`
`
`
`
`
`
`
`dichloromethane produces the corresponding pyrrole
`aldehydes, XII.
`
`
`
`
`
`
`
`
`
`4,647,576
`
`
`
`REACTION SEQUENCE l
`
`
`
`0
`I
`(H5C3)3N
`II
`
`
`
`1-—OH—-—% R1CCH3CH2CR2
`
`
`0I
`
`S Cl‘
`I-I3C Z
`
`
`VIII
`+N=/
`
`
`/
`¢H2C
`
`
`
`
`Diisobutylaluminum
`
`
`hydride
`
`
`
`E
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`O
`H
`H
`
`
`R1CCI + R2CCH=CH2
`
`
`VI
`VII
`
`
`
`
`
`
`
`
`
`
`
`
`
`lborane
`1 Tribut
`
`
`
`(2) Sodium borohydride
`
`
`(3) H202. OH‘
`
`
`
`
`
`
`
`R
`
`0
`e H e
`
`
`NaLi(CH2C—CH—.COOCH3)
`
`OH
`I
`I
`
`‘
`Cl-I2CH2CHCHgCCH2C00CH3
`
`
`
`/N/
`
`
`
`
`
`0I
`
`
`
`
`
`
`
`
`
`
`
`
`/ N-CH2CH2
`
`R2
`
`
`
`I
`
`
`0
`
`
`
`
`\
`/ N
`\0
`
`<-—-
`
`
`
`
`XIV
`
`
`\
`
`.\\\
`H
`‘OH
`
`
`\
`Hz CHZCOOI-I
`
`\\‘\\
`H
`I-‘lo
`
`
`
`
`
`
`R
`
`1.
`
`
`Reaction of the pyrrole aldehydes, XII, with the
`
`
`
`
`
`
`
`dilithium or lithium sodium salt methyl acetoacetate
`
`
`
`
`
`
`
`
`produces the 7-(substitutedpyrrolyl)-5-hydroxy-3-oxo-
`heptanoates, XII_I. The heptanoates, XIII, are dissolved
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Alternative procedures for preparing compounds of
`formula I of this invention where R; and R3 are hydro-
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`Sawai Ex 1032
`Page 6 of 19
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`12
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`by starting with compounds of formula XIX. In this
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`latter instance, the hydroxy functionality of compounds
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`of formula XIX is converted to the p-toluenesulfonate
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`by conventional means, and the tosylate group is subse-
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`quently displaced by cyanide ion to produce the nitriles
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`of formula XXII. The compounds of formula XXII are
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`subsequently used in the preparation of compounds of
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`formula I of this invention by methods detailed in Reac-
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`tion Sequence 1 above.
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`Starting materials and intermediates employed in
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`Reaction Sequences 1 and 2 above may be prepared by
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`the general methods outlined in Reaction Sequence 3.
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`For example, as shown there, the vinyl ketones, XII, are
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`prepared by either of the two methods illustrated. In
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`one method, the known acid chlorides, XXIII, are re-
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`acted with the trimethylsilylethene, XXIV, in the pres-
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`ence of anhydrous aluminum chloride in dichlorometh-
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`ane.
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`In the alternative method of preparing the vinyl ke-
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`tones, VII, which is preferred when R1 is an aromatic
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`substituent such as phenyl or substituted phenyl, the
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`REACTION SEQUENCE 3
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`REACTION SEQUENCE 3
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`0
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`0
`o
`ll
`AlCl3
`,
`II
`RCCI + CH2=CI-ISi(CI-I3); R—C—CH=CH2
`XXIII XXIV
`VII
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`0
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`II H (Cl-l3)2NH.HCl
`___:__.%
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`ArCC 3
`(CHZOM
`XXV
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`NCH
`II H
`ArCC 2CH2 (
`XXVI
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`3);
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`(I) CH3I
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`(2) Na]-ICO3
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`0l
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`l
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`ArCCH=CH2
`VII
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`known methyl aryl ‘ketones, XXV, are converted to
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`(dimethylaminoethyl)aryl ketones, XXVI, and then by
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`deamination to the vinyl ketones, VII.
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`The compounds of the present invention of formula I
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`where the groups R2 and R3 are other than hydrogen or
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`halogen can be synthesized by the methods detailed in
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`Reaction Sequences 4-8.
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`Employing the method detailed in Reaction Se-
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`quence 4 the compounds of the present invention where
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`R2 and R3 are both halogen can be prepared by the
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`halogenation of the unsubstituted compounds with N-
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`halosuccinimide in a three-step process involving the
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`prior protection of the 4-hydroxy group of the lactone
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`ring. Thus, for example, the 2,S-disubstitutedpyrrol-1—yl
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`compounds, XXVII, are first converted to the corre-
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`sponding tert-butyl-dimethylsilyl ethers, XXVIII. The
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`protected compounds and then chlorinated with N-
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`chlorosuccinimide in a polar solvent such as dimethyl-
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`formamide to produce the silylated 3,4-dichloro com-
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`pounds, XXIX. The protecting silyl ether group is then
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`subsequently removed by reaction with a buffered fluo-
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`ride reagent such as tetrabutylammonium fluoride in a
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`mixed acetic acid/tetrahydrofuran solvent system to
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`produce the dichloro compounds, XXX.
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`Alternatively, as detailed in Reaction Sequence 5,.the
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`(2,5-disubstitutedpyrrol-1-y1)a1kyl nitriles, XI (see Re-
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`4,647,576
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`11
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`gen, and for preparing intermediates, are illustrated in
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`Reaction Sequence 2. As shown in Reaction Sequence
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`2, the diketones, IX, can be prepared by reacting the
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`known alpha—haloketones, XV, with the sodium salt of
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`known beta-ketoesters, XVI, followed by hydrolysis 5
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`and decarboxylation in the conventional manner. The
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`diketones, IX, are reacted with ammonium acetate in
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`acetic acid to produce the cyclized 2,5-disubstituted
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`pyrroles, XVII.
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`REACTION SEQUENCE 2
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`if
`if
`if
`ii’
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`R1CCI-I2X + R1CCH2COOC2H5 %R1CCH2CHCR;z_
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`I
`(X = halogen)
`CO0Cp_H5
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`l
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`XVI
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`15
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`50
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`0
`0
`H
`II
`NH4OAc
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`R]CCH2CHgCR2
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`E HOAc
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`IX
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`(1) NaH
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`(2) Br—X—CH(OCI-I3);
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`(3) H4’, H30
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`(XXI)
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`XVIII
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`HgN—x—oH
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`(XVIII)
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`(XXII in Reaction Sequence 1)
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`(X111 in Reaction Sequence 1)
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`(1) Tosyl chloride
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`(2) CN”
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`__...._..X
`‘X H2N—X—OH
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`XVIII
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`R1
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`/N
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`X— OI-I
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`R2
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`XIX
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`An alternative for this step, preferred when R1 and-
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`/or R4 are sterically bulky groups, involves reaction of
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`the diketones, IX, with an omega-hydroxyalkyl amine
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`(compound XVIII where X is methylene, ethylene,
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`1-methylethylene), to produce the N-(omega-hydroxy-
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`alkyl)-2,5-disubstitutedpyrroles, XIX.
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`The 2,5-disubstitutedpyrroles, XVII, are converted
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`to the omega-(substitutedpyrrolyl)aldehydes, XX, by
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`sequential reaction with sodium hydride, a 1,l-dime-
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`thoxy-omega-bromoalkane (compound XXI where X is
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`methylene, ethylene, 1-methylethylene, or vinyl), and
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`then acid. The aldehydes, XX, are subsequently used in
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`the preparation of compounds of formula I of this in-
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`vention as illustrated above in Reaction Sequence 1.
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`The 2,5-disubstituted pyrroles, XVII, ar