PATENT OFFICE
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`JAPANESE GOVERNMENT
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`This is to certify that the annexed is a true copy of
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`the following application as filed with this Office.
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`Date of Application:
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`August 20, 1987
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`Application Number:
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`Patent Application No. 207224/1987_
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`Applicant:
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`Nissan Chemical Industries Ltd.
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`October 7, 1988
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`Fumitake-Yoshida
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`Director—General, Patent Office
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`Sawai Ex 1015
`Page 1 of 40
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`International Patent Classification
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`C07D
`215/00
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`PETITION FOR PATENT APPLICATION
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`August 20, 1987
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`To: Director-General, Patent Office:
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`Kunio Ogawa
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`1. Title of the Invention:
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`QUINOLINE TYPE MEVALONOLACTONES
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`2.
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`Inventor(s):
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`Name:
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`Address:
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`Yoshihiro Fujikawa
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`(and four others)
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`' Nissan Chemical Industries Ltd;
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`Chuo Kenkyusho, 722~l, Tsuboi-cho,
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`Funabashi—shi, Chiba-ken
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`3. Patent Applicant:
`Name:
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`(398) uiéiah dhefiical Industries Ltd.
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`Representative: Takeoségiai‘
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`751; Bachofie, Kanda~Nishiki—cho,
`‘Address:
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`Chiyoda~ku, Tokyo
`101
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`Please contact:
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`TEL. 0474-6541111
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`4. vList of Attached Documents:
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`"(ll Specification
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`(2) Duplicate of Petition
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`1 copy
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`1 copy
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`Page 2 of 40
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`5.
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`Inventors excegt above—mentioned:
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`Name:
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`Address;
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`Mikio Suzuki
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`Nissan Chemical Industries Ltd.
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`Chuo Kenkyusho, 722-1, Tsuboi—cho,
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`Funabashi—shi, Chiba—ken
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`Name:
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`Hiroshi Iwasaki
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`Address:
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`same as above
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`Name:
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`- Mitsuaki Sakashita
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`Address:
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`Nissan Chemical Industries Ltd.
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`Seibutsukagaku Kenkyusho, 1470,
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`Oaza-shiraoka, Shiraoka-machi,
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`Minamisaitama-gun, Saitama-ken
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`Name:
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`I Masaki Kitahara
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`Address:
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`same as above
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`Sawai Ex 1015
`Page 3 of 40
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`NC-115 l/3 m/h
`(1573/1589)
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`1
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`_
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`SPECIFICATION
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`l.TITLE OF THE INVENTION:
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`QUINOLINE TYPE MEVALONOLACTONES
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`2.SCOPE OF THE CLAIM:
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`1.
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`A compound of the formula:
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`12"
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`(1)
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`Y-Z
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`wherein R1, R2, R3
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`are independently hydrogen, Cl_4
`and R
`alkyl, Cl_3 alkoxy, n-buto;§,
`i—butoxy, sec-butoxy,
`trifluoromethyl, fluoro,'g§Dro, bromo, phenyl, phenoxy or
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`4
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`5benzyloxyé or when looatedzfii the ortho position to each
`1
`2
`3
`4
`and R , or R
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`and R
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`together form
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`other, R
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`-cH=cH-cH=cH-; x is -CH2-,
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`-CHZCHZ-, —cH=cH-; -CH2-CH=CH-
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`or -CH=CH-CH2-: and Z is
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`01'
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`wherein R11 is hydrogen or Cl_3 alkyl, R12 is hydrogen,
`14R
`(wherein R14 is physioiogically hydrolyzable alkyl or
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`Sawai Ex 1015
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`Page 4 of 40
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`2
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`M (wherein M is NH4, a.meta1 capable of forming a salt
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`which is pharmaceutically acceptable, or an amine-H) and
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`R13 is hydrogen or Cl_3 alkyl) and R5 is hydrogen, Cl_6
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`alkyl, C3_6 cycloalkyl, phenyl-(CH2)m-
`(wherein m is 1,
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`or 3)..
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`2
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`3.DETAILED DESCRIPTION OF THE INVENTION:
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`[Industrial Field of Utilization]-
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`The present invention relates to novel
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`m valonolactones having a-quinoline ring, processes for
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`their production, pharmaceutical compositions containing
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`them and their pharmaceutical uses particularly as
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`hYP0lipoproteinemic and anti-atherosclerotic agents,
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`and intermediates useful for their production and processeg
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`for the production of such,&ptermediates.
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`_ [Prior Art and its Problem]
`'—."
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`some fermentation metagglic products such as
`:compactine, CS-514, Mevinofgp or semi-synthetic
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`derivatives or fully synthetic derivatives thereof are
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`known to be inhibitors against HMG-CoA reductase which is
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`a rate limiting enzyme for cholesterol biosynthesis;
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`(A.
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`Endo J. Med.chem., 28(4) 401 (1985))
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`CS-514 and Mevinolin have been clinically Dioved to be
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`potentially useful anti—hyperlipoproteihemic agents, and
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`they are considered to be'§ffective for curing or‘
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`2
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`preventing diseases of coronary artery sclerosis or"
`atherosclerosis.
`(IXth In€:'§ymp. Drugs Affect. Lipid
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`Metab., 1986, P30, p31, pséi
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`Sawai Ex 1015
`Page 5 of 40
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`-3...
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`However, with respect to fully synthetic derivatives,
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`particularly '_heteroc:,'rc_1ic‘ derivatives of inhibitors
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`against '1-IMG-CoA reductase,
`there h35_-been di5C.1°5‘3d
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`limited information.
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`The present inventors have found that mevalonolactone
`the corresponding
`derivatives having a euinoline ring,
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`dihydroxy carboxylic acids and salts and esters thereof
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`have high inhibitory activities against.HMG‘C°A f5dUCta5E.
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`The present invention has been accomplished on the basis of
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`this discovery.
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`The novel mevalonolactone derivatives of the present
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`invention having high inhibitory activities agaihgt
`HMG—CoA reductase are represented by the'follofiing formfila
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`-I:
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`R2
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`R1
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`wherein R1, R2, R3 and R4 are independently hydrogen,'C1_4
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`alkyl, C1_3 alkoxy, n—bute§y,
`i-butoxy, sec-butoxy,
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`trifluoromethyl,
`fluoporf§E%9ro, bromo, phenyl, phenoxy or
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`benzyloxy,_or when locatedgat
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`R
`1 and R2; or R3
`tog'-ether form —cH=cH-CH--CH-; Y is -CH2-
`and R?‘
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`.t
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`Sawai Ex 1015
`Page 6 of 40
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`-CHZCHZ-, ~CH=CH-,
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`-CH2'CH=C$- or -CH=CH-CH2-; and Z 15
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`RI!
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`-ca-cuzg-cH=—C0=R"
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`.i
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`on
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`an
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`R1:
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`H0-
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`12
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`is'hydrogen,
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`11
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`is hydrogen or C143 alkyl, R
`wherein R
`Rl4(wherein R14 is phy$o$§m§uy hydrolyzable alkyl) or
`M (wherein M is NH4,_a metal capable of forming a salt_
`which is pharmaceutically acceptable or an amine.fl) and
`13R
`is hydrogen or Cl_3 alkyl; and R5 is hydrogen, Cl_6
`.
`._=_,
`.,1ky1, 03-5 cycloalkyi or §heny1-<cH2)m- (wherein m is
`1f 2
`‘'
`.:'--‘:-’;!-'I;-—'-‘’
`ll‘
`‘
`--
`” Variofis substituentsiifilthe formula I will be
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`described in detail with reference to specific examples.
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`‘91—4 alkyl for R1, R2, R3 and. R4includes,.for
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`example, methyl. ethyl, n-propyl,
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`i—propy1, n-butyl,
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`cl_3 alkoxy for R1, R2,
`i-bUtYl. 5eC"butYl and t-butyl.
`4
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`R3and ‘R
`includes, for example, methoxy, ethoxy
`fl‘Pr0poxy and i-prop0xy_
`‘ i
`c _
`alkyl 5
`11
`inclfies, for example, methyl,
`or R
`1 3
`ethyl» n-Propyl and i—prop§1,.
`-
`cl"3 alkyl f°‘ Rla in°f3de5, for example, methYl I
`ethyl. n-propyi and i—propy1
`-
`Alkyl for R14 -
`1 d
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`inc u es, for example, methyl, ethyl,
`i'Pr°Pyl. n-butyl and i-butYl
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`”"PF°PY1:
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`Sawai Ex 1015
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`Page 7 of 40
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`' A metal capable of forming a pharmaceutically
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`acceptable salt for M
`includes, for example, sodium afid
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`potassium.<
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`CO2M includes, for example,
`-CO NH4 and'—CO2H-'
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`2
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`(primary to tertiary lower alkylamine such as
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`trimethylaminel,
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`Cl_5 alkyl for R5 includes, for example, methyl,
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`eFhY1¢ H-propyl,
`i-propyl, n-butyl,
`i—butyl, SeC*bUtY1;
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`t—butyl, n-pentyl-and n-hexyl.
`5
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`includes, for example,
`C3_6 cycloalkyl for R
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`Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
`5
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`includes, for example, benzyl,
`Phenyl—(CH2)m— for R
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`6-phenylethyl and y~phenylQ£OPY1-
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`The mevalonclactones cfigthe formula I can be prepared
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`by the following reaction:s;%eme.
`‘A-.?_
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`Page 8 of 40
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`as.—
`use
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`_'—:u-
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`Sawai Ex 1015
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`Page 11 of 40Page 11 of 40
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`2
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`In the above reaction scheme, R1, R , R . R4: 3
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`12
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`and R
`are as defined above with respect.to the formula
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`1, and R21 rePresents Cl_4 lower alkyl such as methYl,
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`i-Pr°PY1 °' “*b”tY1'
`e£hYl..n-propyl.
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`5
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`' Step A represents a reduction reaction of the ester to
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`a primary alcohol.
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`Such reduction reaction can be
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`conducted by using various metal hydrides, preferably
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`diisohutylaluminium hydride,
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`in a solvent such as
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`tetrahydrofuran or toluene at a temperature of from -20 to
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`20°C, preferably from -10 to 10°C.
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`[Step B represents an oxidation reaction of the primary
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`alcohol to an aldehyde, which can be conducted by using-
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`the reaction can be
`gvarious oxidizing agents} greferably,
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`,conducted by using pyridifié§;‘chlorochromate in methylene
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`‘chloride'at a temperature o?;from 0'to 25°C, or by_using
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`oxglyl chloriqe and dimethyl sulfoxide(SWern °Xid3ti°nL
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`istep C represents a synthesis of a hydroxyvinyl ether,
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`which can be prepared by reacting a compound y to lithium
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`compound which has been preliminarily formed by treating
`cis—l-ethoxy-2-(tri-n—buty1stannyl)ethylene with butyl
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`lithium in tetrahydrofuran.
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`As the reaction temperature, it is preferred to employ
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`a low temperature at a 1eve;:of from -60 to -78°C;
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`Step D represents a synthesis of an enal by acidic
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`hydrolysis.
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`As the acid catalyst, it is preferred to
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`employ p-toluene sulfonic acid, hydrochloric acid or
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`sulfuric acid,'and the reaction may be conducted in a
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`solvent mixture of water and tetrahydrofuran or ethanol at
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`a temperature of from 10 to 25°C.. The hydroxyvinyl ether
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`obtained_in Step C
`can be used in Step D without purification
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`i.e. by simply removing tetra—n-butyl tin formed simultaneously
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`Step E represents a double anion condensation reaction
`between the enal
`IV and an acetoacetate.
`Such
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`condensation reaction is preferably conducted by'using
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`-sodium hydride and nEbutyl lithium as the base in
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`-78°C.
`tetrahydrofuran at
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`Step F represents a're§Ection reaction of the carbonyl
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`group, which can be conudg§§d.by using.a metal hydride,
`5preferably sodium borohydrfde in ethanol at a temperature
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`of from -10 to 25°Cy_preferably from -10 to 5°C.
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`Step G is a step_for hydrolyzing the ester.
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`The
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`hydrolysis can be conducted by using an equimolar amount
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`of a base, preferably potassium hydroxide or sodium
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`hydroxide,
`in'a solvent mixture of water and methanol or
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`,Ethanol at a temperature of from 13 to 25°C.
`The free
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`acid her9bY Obtained may béébonverted to a salt with a
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`suitable base.
`I f :1
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`5teP H is a Step for fé§fiihg"a mevalonolactone by the
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`dehydration reaction of thetfree hydroxy acid I-2.
`The
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`dehydration reaction can be conducted in benzene or‘
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`toluene Under reflux while removing the resulting water or
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`by adding a suitable dehydrating agent such as molecular
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`sieve.
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`Sawai Ex 1015
`Page 13 of 40
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`Step J-represents a reaction for hydrogenating the
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`- double bond connecting the mevalonolactone moiety and the
`quinoline ring. This hydrogenation reaction can be
`conducted by using a catalgtic amount of palladium-carbon
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`or rhodium-carbon in a solvent such as methanol, ethanol,
`
`tetrahydrofuran or acetonitrile at a temperature of from 0
`to 50°C, preferably from 10 to 25°C.
`
`’In addition to the compounds disclosed in Examples
`given hereinafter, compounds of the formulas I-2
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`given in Table‘1 °a“ be Prepared by the Process of the
`Present invention.
`
`Table 1
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`Sawai Ex 1015
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`Page 14 of 40
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`H2HCLUP
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`Sawai Ex 1015
`Page 15 of 40
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`Further, pharmaceutically acceptable salts such as
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`_sodium salts or esters such as ethyl esters or methyl
`esters of'these compounds can be prepared in the same
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`‘manner.
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`invention exhibit high
`The compounds of the present
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`inhibitory activities against the cholesterol biosynthesis
`wherein HMG-Coa reductase acts as a rate limiting enzyme,
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`as shown by the test results given hereinafter, and thus
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`are capable of suppressing or reducing the amount of
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`cholesterol” Thus, the COmpound5of the Present invent,ion
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`are useful as curing agents against hyperlipoproteinemia and
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`atherosclerosis.
`J
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`These active components may be formulated into various
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`.suitable formulations depending upon the manner of Eh:
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`administration.
`The compeuids of the present invention
`in the
`may be administered in theégpgm of firee acids or
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`Jform of physiologically hy&;elyzable and acceptable esters
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`or lactones, or pharmaceutically acceptable salts.
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`The pharmaceutical composition of the present
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`invention is preferably administered orally in the form of
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`the compound of the present invention per se or in the
`form of powders, granules,
`tablets or capsules formulated'
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`by mixing the compound of the present invention with a
`suitable pharmaceutically‘éiceptable binder such 35
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`-_—
`syrup, gum arabic, gelatin,7§orbitol,
`tragacanth gum-or
`'_,1
`.
`...
`,.-.
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`L3
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`Sawai Ex 1015
`Page 16 of 40
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`

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`'1'‘
`rd "'t'h
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`as lactose, sugar’ corn
`po yvinyl pyrro 1 one’an excipien suc
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`starch, calcium phosphate, sorbitol or 9lYcine,a
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`a lubricant such as magnesium stearate,
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`talk, polyethylene glycol or silica, and a disintegrator
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`such as potato'starch.
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`However,
`the pharmaceutical composition of the present
`-invention is not limited to such oral administration and
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`For
`it is applicable for parenteral administration.
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`example, it may be administered in the form of e.g. a
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`suppository formulated by using oily base material such as
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`cacao butter, polyethylene glycol,
`lanolin or fatty acid
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`«=-
`.-u......-
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`triglyceride.
`Furthef:
`thé COWPOUHQS-gf the present invention may be
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`-'_..x'.u'_""-»
`-
`-
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`.
`a-y...,..._ -
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`F°mPined Hith bafiic
`ani6n€Exchange_resins which are capable
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`of binding bile acids and yet not being absorbed in
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`gastraintestinal tract.
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`The daily dose of the compound of the formula I
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`is
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`from 0.05 to 500 mg, preferably from 0.05 to 30 mg fcf an
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`It is administered from once to three times per
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`adult.
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`‘day;
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`The dose may of course be varied depending upon the
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`- age,
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`the weight or the condition of illness of the’
`a—
`n2.
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`patient.
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`.
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`"I 7-
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`are novel, and
`The compounds of the fogmulas“II to_VI
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`they are important intermediates for the preparation of
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`the compounds of the formula I. Accordingly,
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`the present
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`invention relates also to the compounds of the formulas II
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`to VI
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`and the processes for their production.
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`Sawai Ex 1015
`Page 17 of 40
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`

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`[Examples]
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`the present invention will be described in
`Now,
`further detail mith reference to Test Examples for the
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`pharmacological activities of the compounds of the present
`"invention, their Preparation Examples and Fcrmulationl
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`Examples, However, it should be understood that the
`present invention is by no means restricted bv such
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`specific.Examples.
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`Test A:
`22Qi2i3i22_2E_2Q2AseEss2l_2i2s22£nesia_££2m
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`-
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`acetate in vitro
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`Enzyme solution was prepared from live! 05 male Wi5t3r
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`duct ‘and dis charged
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`. rat (weighing from 200 to 250 g.) canziulated‘ to.the.bi1e-
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`bile for over 24 hours.‘ Liver was cut out at mid-dark and
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`mic_os6me and 105mm xg supernatant fraction which was
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`PreciPitabLe'witE 4o-3o%4of§Eturation of ammonium sulfate
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`_.
`‘
`'
`t
`::d'c1’
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`(sup fraction) were P§e?3f§g§§£°m 1LV$'_h°m09e3a 9 ac 9‘ 1“-
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`to the modified method of xieueeet el-:_Kur6da. M., et. a1,,
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`Biochim- Biophys. Acta, 489, 119 (1977);
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`By the cannulation to the bfle'-duct of rats ,.
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`it has been.confirmed that the ability for
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`ch°l§5te‘°1.biP5Ynthé5iS is increased from a few to 10
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`The measurement of the ability fcr cholesterol
`‘times.
`bi°5Ynthe5iS was-conducted in accordance with a method of
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`Endo, The Metabolism, 16, lit: (1979)_ Namely’ microsome
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`(°'l mg ?”°tei“’ and SUP fr§ction~(1.o mg Protein) were
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`incubated for_2 hours at 379C in 200 pl of reaction mixture
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`6 mM and GL2 mM [2—14c1
`Containing ATP: 1 mM, Glutathione;
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`‘sodium acetate (0.2 pci) with 4 pl of test compound solution
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`Sawai Ex 1015
`Page 18 of 40
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`To Sum
`in water or dimethyl sulfoxide_jDMSO).
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`reaction and saponify, l ml of 15% EtOH-KOH was added to
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`the reactions and heated at i5°C for l'hour.
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`_Nonsagonifiable lipids were extracted with petroleum ether
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`and incorporated 14C radioactivity was counted.
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`Inhibitory activity of compounds was indicated with IC50L'
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`which is the concentration for inhibiting radioactivitY
`-—
`'11:
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`--
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`incorporated in the nonsaP°n1f13b1e 11Pld5 at the
`eve
`°
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`50%.
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`Test B=
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`culture cells
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`Human liver cancer cells (He; G2 cells)at
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`from several to several
`t8nSPE$mge were seeded to 5
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`well plates-and incubated with Dulbecco's modified
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`'Eag1¢ (DME) medium containidgflloé of fetal
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`bovine serum (EES) at3?°C;#%§TEo2 until cells were cgnfluent
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`for about % days. C§llS were exposed to the DME medium
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`containing 5% of
`lipoprotein deficient gerum (Lpos)
`Pre9ére§QbYUltracentrifugation method and the incubation
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`was continued.
`By changing the EBS containing medium to
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`the LpDs containing medium, it has been confirmed that the
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`ability for cholesterol biosynthesis in vivo increases
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`about l.4 times. After 24 hrs
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`incubation the medium was
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`removed, 0.5 ml of DME mediuE;containing 5% LQDS was added
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`fresh and1 5 pl of test compound solution dissolved in
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`a
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`0E5_ uCi of [2—14c]sodium
`water or DMSO was- added.
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`Sawai Ex 1015
`Page 19 of 40
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`-acetate W35 added at 0 hr{E—l) or 4 hrs(B—t) after
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`addition of compounds. Afte: 4 hrs further incubation
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`14
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`with [2-
`Clsodium acetate, medium was removed and cells
`were washed with phosphate buffered saline(PBS) chilled at
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`4°C three times. Cells were scraped with rubber.policeman
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`and collected to tdbes._ To the resulting cell pellet} 200
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`pl of 0.5 NKOH was added and the cells were digested by
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`Aliquot of-the digestion was_saponifi'ed
`heating them overnight.
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`wfih l5%EnOH—KOH._3B-Hydroxysterol was
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`separated from the resulting nonaaponifiable lipids by
`precipitation method with digitonin in accordance with the
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`method of Sperry el al., .,J-.5531" chemf, 137, 97 (1950).
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`on the other hand,
`the afigunt
`'
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`I
`.
`...
`_$#£__
`_
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`of the protein was measuredshy using the remaining of the
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`The ability of cholesterol biosynthesis”
`cell digestion.
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`was indicated with DPM/mg cell protein,
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`Inhibitory
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`activity of compounds was indicated with ICSO, which is
`the concentration for inhibiting radioactivity incorporated" in the
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`digitonide at the level of 50%.’
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`'
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`I
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`with respect to the compounds of the present
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`inwention,
`the inhibitory activities against HMG—coA ‘
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`‘reductase were measured by tE§.above Test
`_A and B;
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`0
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`The results are shown in Table —
`2-
`‘.4n...
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`Sawai Ex 1015
`Page 20 of 40
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`

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`fable 2: Inhibitory activities by Test A
`
`Compound
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`(molar concentration}
`
`50
`
`(Compounds
`of.the present
`invention)
`
`I7. 51
`
`1- 52
`
`1- 53
`
`1- 13
`
`(Reference
`compounds)
`
`Mevinolin
`
`CS-514
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`Sawai Ex 1015
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`Page 21 of 40
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`

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`'—19'—
`
`Structures of reference compounds:
`
`(1) Mevinolin
`
`CH3
`
`H
`
`CH3
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`SC /
`
`Hgcé
`
`(2) CS-514
`
`
`
`an-_‘
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`Sawai Ex 1015
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`Page 22 of 40
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`

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`_. _.2O _
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`....:._i-...
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`-Table 3: Inhibitory activities by Test B41
`
`
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`Compound
`
`-
`
`I050 (molar concentration)
`
`‘(Compound
`of the present
`invention)
`
`I-51
`
`.
`
`‘
`
`~
`
`1
`
`x 10
`
`(Reference
`compound)
`
`3.5 x 10‘
`,
`.
`.
`cs-514
`
`
`g. .
`
`The compounds of the presé§f71nvention‘exhibited
`gr-
`
`‘activities similar to the reference compound such as
`CS—514 or Mevinolin in Test A, and exhibited activities_
`
`superior to CS-514 in Tests 3
`EXAMPLE 1
`.
`
`Ethyl (E)-3,5-dihgdroxy-7—!4'-(4"-fluoropheny1)-2'-
`
`(1"-methgleth2l)~auinolin-3'-yl]-hept—6-enoate (compound
`
`I111)
`
`(prepared by steps o£.Examole 1-a through Example
`
`
`I-a).
`
`5 ii
`
`rxampnz 1-a: Ethyl 4—(4'-sihoroghengi)-2-(1--
`methvlethvl)-guinolin-3-glééarboxvlate,(compound VII—l)
`
`The synthesis was conducted in accordance with the
`
`method disclosed in J. Org. Chem., 2899 (1966).
`
`Sawai Ex 1015
`
`Page 23 of 40
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`

`
`6.45 g (0.03 mol) of 2-amino-4'-fluorobenzophenone,
`5.53 g (0.035 mol) of ethyl-isobutyrylacetate and 0.1 ml
`
`of conc. sulfuric acid were dissolved in 30 ml of glacial
`acetic acid, and the mixture was heated at 100°C for about
`
`10 hours. After confirming the substantial disappearance
`
`of 2—amino—4'-fluorobenzophenone by thin layer
`
`the reaction solution was cooled to room
`chromatography,
`temperature, and gradually added into A mixture solution‘
`
`of 45 ml of cone. aqueous ammonia and 120 ml of water
`cooled with ice,’
`A separated oilf substance was solidified
`when left to stand overnight
`in a refrigerator. This
`
`solid was recrystallized.from a small amount of ethanol to
`
`"obtain 6.47 g (b5%) of whit§_powder. Melting point:
`
`-as-7o.5°c
`
`1)-3—fi:arax meth 1-2—(1--
`_EXAMPLE 1:b='4—(4v-s1uora"E€fi
`methglethyl)-auinoline (compound VIrl)
`
`5.4 g (0.016 mol) of compound VII-l was dissolved in
`
`dry toluene under a nitrogen atmosphere and cooled in ice
`
`bath to 0°C.
`
`To this solution, 40 ml of a 16 wt%
`
`diisobutylaluminium hydride—to1uene solution was dropwise
`
`added, and the mixture was stirred at 0°C for two hours.
`
`After confirming the compiqte disappearance of compound
`VlI-1 by thin layer chromatggraphy, a saturated ammonium
`chloride solution was addedéthereto at 0°C to terminate the
`reaction. Ethyl ether was added to the reaction mixture,
`
`and the organic layer was separated.
`
`A gelled product was
`
`Sawai Ex 1015
`
`Page 24 of 40
`
`

`
`
`
`
`
`L 22 _
`
`
`dissolved by an addition of an aqueous sodium hydroxide
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`solution and extracted anew with ethyl ether.
`The ethyl
`
`
`
`
`
`
`
`
`
`
`
`
`ether extracts were put together} dried over anhydrous
`magnesium sulfate and filtered.
`The solvent was distilled
`
`
`
`
`
`
`
`off.- The residual oil underwent crystallization when left
`
`
`
`
`
`
`
`to stand.
`It was recrystallized from ethyl
`
`
`
`
`
`acetate—n-hexane to obtain 3-3 9 Of White CFY5ta15-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`rieia: 70%. Melting point: 136—137°c.
`
`
`
`EXAMPLE l—c: 4-(4'-fluoroghenyll—2-(l'-methvlethvl)-
`
`
`
`guinolin-3—yl—carboxyaldehyde (comoound V-1)
`
`2.§ g (9.3 mmol) of pyridinium chlorochromate and 0.4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`g of anhydrous sodium acetate was suspended in 10 ml of
`
`
`
`
`
`
`
`To this suspension, a solution
`
`
`
`
`
`
`
`
`
`
`
`
`-obtained by dissolving l g_i§.4 mmol) of compound VI-1 in
`
`
`dry dichloromethane.
`
`
`
`
`
`
`
`
`
`10 ml of dry dichloromethafiéfi was immediately added at
`
`
`
`
`
`
`
`
`.—nv_-
`
`
`
`
`
`
`
`The mixture was stirred for one hour.
`
`
`room temerature.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Then, 100 ml of ethyl ether was added thereto, and the
`
`
`
`
`
`
`
`
`mixture wasthcroughlymixed.
`The reaction mixture was
`
`
`
`
`
`
`
`
`
`
`filtered under suction through a silica gel layer.
`
`
`
`The
`
`
`
`
`
`
`
`
`filtrate was dried under reduced pressure.
`
`
`
`
`The residue
`
`
`
`
`
`
`
`
`
`
`
`was dissolved in the isopropyl ether, and insoluble
`substances were filtered ogf.
`The filtrate was again
`
`
`
`
`
`
`
`
`
`dried under reduced pressu3$§ and the residue was
`
`
`
`
`
`
`
`
`recrystallized from diisopfiopyl ether to obtain 0.7 g
`
`
`
`
`
`
`
`
`(Yield: 70%) of slightly yéilow prism crystals. Melting
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`point: 124-125°C.
`
`
`
`'
`
`Sawai Ex 1015
`Page 25 of 40
`
`

`
`
`
`
`
`
`
`'
`NHR 6PDm(inCDt!£ Q)
`
`
`
`
`
`
`J='THz.
`L1 (t,
`.I='?Hz.
`3‘Hl 1.3m,
`
`
`
`
`
`3.7.(fi.
`3.7-(q.
`1H)
`J=7Hz. 2H)
`
`
`
`
`
`
`
`
`
`
`
`en)
`
`
`
`
`
`¢l.75(t, mug, 1n)
`
`
`
`
`5.7(m.
`
`
`1H)
`
`
`
`5.95(m.
`
`
`1H)
`
`
`
`
`8H)
`7.o5—~3.2 cm.
`
`
`
`EXAMPLE 1-d: 3-(3'-ethox -1‘-h drox -2'— ro en 1)-4-(4'-
`
`
`fluoroEhengl)j2—(l'-methglethyl)-guinoline (comgound IV-1)
`
`
`
`
`
`
`
`
`
`
`‘1.13 g (3.13 mmol) of cis-l-ethoxy-2-(tri-n-
`
`
`
`H butylstannyl)ethylene was dissolved in 8 ml of dry
`
`
`
`
`
`
`
`
`
`
`
`tetrahydrofuran, and the solution was cooled to 278°C in a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘nitrogen stream.
`
`
`
`
`
`_To this solution,
`
`
`
`
`
`
`
`
`2 ml (3.2 mmol) of 6
`
`
`
`
`
`
`
`
`l5 wt% n-butyllithium-n-hexane solution was dropwise
`
`
`
`
`
`
`
`
`
`The mixture was stiired for 45 minutes.
`
`
`
`
`
`
`
`
`
`-solution prepared by dissqlfiang 0.76 g (2.6 mmol) of
`
`
`
`
`
`
`}compound V-l
`in 10 ml-of dr§Ltetrahydrofuran was dropwise
`
`The reaction mixture was stirred at -78°C
`
`
`
`
`
`
`
`added.
`
`
`
`added thereto,
`
`
`
`
`
`
`
`
`Then, a‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`for two hours. Then, 2 ml of a saturated ammonium
`chloride solution was added thereto to terminate the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The organic layer was extracted with diethyl
`reaction.
`
`
`
`
`
`
`
`
`
`
`ether, and the diethyl ether extract was washed with a
`
`
`
`
`
`
`
`
`
`
`saturated sodium chloride aqueous solution and dried over
`anhydrous magnesium sulfateé; The solvent was distilled
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`off under reduced oressure.§ The residue was separated
`
`—-— '
`‘
`
`
`
`
`
`> with nrhexane and acetonitfifile.
`
`
`
`
`The solvent was distilled
`
`
`
`
`
`Sawai Ex 1015
`Page 26 of 40
`
`

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`off under reduced pressure from the acetonitrile layer,
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`
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`
`
`
`
`
`
`
`and an oily substance thereby obtained was purified by
`
`
`
`
`
`
`
`
`silica gel column chromatography (eluent: 2.5%
`
`
`
`methanol-chloroform)
`
`
`
`to obtain 0.91 g of the desired
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`compound in a purified oily form.
`
`
`
`EXAMPLE l~e: (E)-3-[4'-(4"-fluorophenyl)“2'-(l"-
`
`
`methylethvl)-guinolin-3'vyl]propenaldehvde (compound
`
`
`
`III-1)
`
`
`
`‘
`
`
`
`
`
`
`
`
`
`
`
`
`0.91 g of compound IV-l was dissolved in 20 ml of_'
`
`
`
`
`
`
`
`
`
`
`
`tetrahydrofuran, and 5 ml of water and 100 mg of
`p-toluenesulfonic acid were added thereto.
`The mixture
`
`
`
`
`
`
`was stirred at room temperature for 24 hours;
`The
`
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`
`
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`
`
`
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`
`
`
`
`
`
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`
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`reaction solution was extracted with diethyl ether a few
`
`The extracts were dashed with a saturated sodium
`_times.
`
`
`
`
`
`
`
`
`
`
`
`chloride aqueous solution*§§§;dried'over anhydrous
`
`
`
`
`ihen, {HE solvent was distilled Off
`:ma§nesium sulfate.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The residue was purified by
`under reduced pressure.
`
`
`
`
`
`Silica gel column chromatography (eluent: chloroform)
`
`
`
`
`
`
`
`to obtain the desired Pr°d“Ct a5'”hite Prism °rY5ta15'
`O
`.
`
`
`
`
`
`
`
`
`0,4 g (50%). Melting point: 127-128 C-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EXAMPLE 1‘f= Ethzl (E)-7-I4'*(4"—fluorophenyl)~2'-(l"-
`
`
`
`
`_ methvlethyl)-guinolin+3’-yl]—5—hydroxy—3-oxoheEto—6-
`
`
`
`enoate (compound II-1)
`,j
`:5
`
`50 mg Of 50% Sodium hydride was washed with dry”.
`
`
`
`
`
`
`
`
`
`
`petr01eUm ether and dried finder a nitrogen stream, and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`then 5U5Pended in 5 ml of dry tetrahydrofuran.
`
`
`
`The
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`Sawai Ex 1015
`Page 27 of 40
`
`

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`‘-25-
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`
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`
`
`suspension was cooled to :l5°C in a nitrogen atmosphere.
`Then, 120 mg (0.92 mmol) of ethyl acetoacetate was
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`dropwise added thereto, and the mixture was stirred for 15
`
`
`
`minutes. Then, 0.6 ml
`
`
`
`
`
`(0.92 mmol) of a 15 wt%
`
`
`
`
`
`
`
`
`
`
`
`n-butyllithium—n-hexane solution was dropwise added
`
`
`
`. thereto, and the mixture was stirred for 30 minutes.
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Then, a solution prepared by dissolving 160 mg (0.5 mmol)
`of compound III-1 in dry tetrahydrofuran, was dropwise
`
`
`
`
`
`
`added thereto, and the mixture was stirred for one hour.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`' To the reaction mixture, 1 ml of a saturated ammonium
`
`
`
`
`
`
`
`
`
`chloride aqueous.solution was added at -15°C. Then,
`
`the
`
`
`
`
`
`
`
`
`
`
`mixture was extracted three times with diethyl ether.
`
`
`
`The
`
`
`
`
`
`
`
`
`
`
`
`diethyl ether solution was washed with a saturated sodium
`chloride aqueous solution'dfid dried over anhydrous
`
`
`
`
`
`
`‘magnesium sulfate. The-solution was evaporated to drpness
`
`
`
`
`
`
`--—_u
`.
`_I.u.-
`.
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`;under reduced pressure.
`
`
`
`
`
`
`
`-THE;residue was recrystallized
`
`
`
`
`
`
`
`
`
`
`from diisopropyl ether to obtain 130 mg (yield:
`
`white crystals. Melting point: 99—10l°C.
`
`
`
`
`
`
`
`
`
`59%} of
`
`
`
`
`
`
`
`EXAMPLE l-g: Ethvl (E)-3,5-dihgdroxg-7—[4'-(4"-
`
`fluorophenyl)—2'-(l"-methglethgl)-guinolin-3'-zl]—hept-
`
`
`
`6—enoate (compound I-ll)
`
`
`
`
`
`
`
`
`
`
`
`110 mg 10.245 mmol) of compound II—l was dissolved in
`
`
`
`
`
`
`
`
`
`
`5 ml of ethanol in a nitrogen atmosphere, and the solution
`
`
`
`
`
`
`
`
`
`
`
`
`éfinmg (0L263 mmol) of sodium
`was cooled to o°c_ Then,
`_-—.—'
`"'
`'.'
`
`
`
`
`
`Sawai Ex 1015
`Page 28 of 40
`
`

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`..—.26 _
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`
`
`borohydride was added, and the mixture was stirred for
`
`
`
`one hour. Then, l ml'of a 10% hydrochloric acid aqueous
`
`
`
`
`
`
`
`
`
`
`
`
`solution was added thereto, and the mixture was extracted
`
`
`
`
`
`
`
`
`three times with ethyl ether.‘ The ethyl ether solution
`
`
`
`
`
`
`
`
`was washed with a saturated sodium chloride aqueous
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_solution and dried over anhydrous magnesium sulfate.
`the solution was evaporated to dryness under reduced
`Then,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pressure.
`The residual oil was purified by silica gel
`column chromatography (eluent:
`5% methanol-chloroform)
`
`
`
`
`
`
`
`
`
`
`
`
`obtain the desired product as a pure colorless oily
`
`
`
`
`
`
`
`to
`
`
`
`
`
`
`substance.‘ 70 mg
`
`
`
`(Yield: 64%)
`
`6 ppm:
`H-ANMR (in CDCl3)
`
`
`
`1L3o(t,3H,J=3H:)'1.39 (d,J=8Hz,6H)1.4~l.8(m,2H)A
`
`
`3.0-3E§*(m,2HJ 3.S0(m,lH)
`2.42€d,J=7H$,2H)
`
`
`
`3.9-4.§(m,