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.3, 1988
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`Application Number:
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`Patent Application No. 193606/1988
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`Applicant:
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`Nissan Chemical Industries Ltd.
`1
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`November 14; 1933
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`Fumitake Yoshida
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`Director—Genera1, Patent Office
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`Sawai Ex 1013
`Page 1 of 98
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`(Internal priority claimed under Patent Law
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`Article-42-2-l)
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`(Filing Date of the earlier application
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`.August 20, 1987)‘
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`;(App1ication Number of the earlier application
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`207224/1987)
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`(Filing Date of the earlier application
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`.January 26, 1988)
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`(Application Number of the earlier application
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`015585/1988)
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`International Patent Classification
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`CQ7D
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`PETITION FOR PATENT APPLICATION
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`215/00
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`Director—General, Patent Office:
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`Title of the Invention:
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`I
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`August 3, 1988
`Fumitake Yoshida
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`QUI NOL INE TYPE MEVA LONOL ACTONES
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`Number of Inventions stated in Claims:
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`34
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`Inventorts):
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`'Name: ”
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`Address:
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`T g‘?-
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`Yoshihirofifiujikawa
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`(and four others)
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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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`Patent Applicant:
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`Name:‘
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`1398) Nissan Chemical Industries Ltd.
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`_ Representative:
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`Takeo Nakai
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`Address:
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`7-1, 3-chome, Kanda-Nishiki-cho,
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`Chiyodaéfifl, Tokyo
`101
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`Please contact:
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`TEL; 0473-65-1111
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`'——p
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`of Attached Documents:
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`Specification
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`Duplicate of Petition
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`§_
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`a
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`1 copy
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`1 copy
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`Sawai Ex 1013
`Page 2 of 98
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`6.
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`Inventors excegt above-mentioned:
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`Name:
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`Address:
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`Name:
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`Address:
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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 Kenkypsho, 722-1, Tsuboi—cho,
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`" Funabashi-shi, Chiba-ken‘
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`Hiroshi Iwasaki
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`same as above
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`Mitsuaki sakashita
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`Nissan Chemical Industries Ltd.
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`Seibutsukagaku Kenkyusho, 1470,
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`Oaza-shiraoka, Shiraoka—machi,r
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`Minamisaitama-gun, Saitama-ken-
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`Name:
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`Masaki‘Kitahara
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`Address:
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`same as above
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`Sawai Ex 1013
`Page 3 of 98
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`4
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`.
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`-,
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`1
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`'2-115 3/3 m/h
`(1573/1589)
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`éééoxrxcawxou
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`1.TITLE OF THE INVENTION:_
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`QUINOLINE TYPE MEVALONOLACTONES
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`2.SCOPE OF THE CLAIMS:
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`1.
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`A compound of the formula:
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`3"
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`\\R R
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`4
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`Y-Z
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`( I)
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`R’
`N
`'
`i
`R‘
`wherein R1, R2, R3, R4 and R6 are independently hydrogen,
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`Cl_6 alkyl, Cl_6 cycloalkyl, Cl_3 alkoxy, n-butoxy,
`i-butoxy, sec-butoxy, R7ReN- (wherein R7 and R8 are
`independently hydrogen or Cl_3 alkyl),
`trifluoromethyl,
`trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo,
`phenyl, phenoxy, benzy1oxy,2hydroxy,
`trimethylsilyloxy,
`19
`.diphenyl-t-hutylsilyloxy,lhégroxymethyl or -OfiCH2)zOR
`19 is hydrogen'orEg1_3 alkyl, and 2 is 1, 2 or
`:(wherein-R
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`3); or when locatedfiat the ortho position to
`l
`2
`3
`4
`each other, R
`and R.,-or R
`and R
`together form
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`~CH=CH—CH=CH-; or when located at the ortho position to
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`1
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`and R
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`2
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`together form -OC(R15)(R
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`1s)o_
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`each other, R
`15
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`(wherein R
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`‘and R
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`16
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`are independently hydrogen or ¢l_3
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`alkyl); Y is -CH2-,,-CHZCH2-,
`-CH=CH-,
`- _
`.
`~
`12
`-CH—CH-CH2—; and z 15 -Q:§d2yCH2-COZR ,
`R11
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`-CH2-CH=CH- or
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`-Ho OI‘
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`Sawai Ex 1013
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`Page 4 of 98
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`-c(oR13)2— or ~cH(oH)—; w is -c(o)—,
`(wherein Q is —c(o)-,
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`l3)2- or -C(R11)(OH)-; R11 is hydrogen or Cl_3 alkyl;
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`~C(OR
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`14
`'14
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`is hydrogen or R
`(wherein R
`is physiologically
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`12
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`R
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`hydrolyiable alkyl or M {wherein M is NH4, sodium,
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`potassium, l/2 calcium or a hydrate of lower alkylamine,
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`di-lower alkylamine or tri-lower alkylamine)):
`two R13 are
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`independently primary or secondary Cl_6 alkyl; or two R13
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`R17 and R18 are
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`together form —(CH2)2- or —(CH2)3—:
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`independently hydrogen or C1_3 alkyl; and R5 is
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`‘hydrogen, C1_6 alkyl, C2_3 alkenyl, C3_6 cycloalkyl,
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`..
`R9
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`_
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`—<:j;'
`(wherein R9 is hydrogen, C1_4 alkyl, Cl_3'
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`alkoxy, fluoro, chloro, bromo or trifluoromethyl),
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`phenyl—(CH2)m— (wherein m is l,
`2 or 3),
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`.-(CH2)nCH(CHé)—phenyl or pégnyl-(CR2)nCH(dH3)s (wherein n
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`:3 i‘-"'_.
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`_’::‘zr -
`1 or 2).
`is O,
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`‘-2.’ The compound according to Claim l, wherein in the
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`2
`1
`6
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`formula I, R , R
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`and R
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`are independently hydrogen,
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`fluoro, chloro, bromo, Cl_3 alkyl, Cl_3 alkoxy, C3_6
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`cycloalkyl, dimethylamino, hydroxy, hydrogymethyl,
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`hydroxyethyl,
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`trifluoromethyl,
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`trifluoromethoxy,
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`hydrogen, R
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`difluoromethoxy, phenoxy or benzyloxy: or when R6 is
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`1
`2
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`together form methylenedioxy: when R4
`and R
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`3
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`is hydrogen, R
`is hydrogeé%_3'—fluoro, 3'-chloro,
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`3M
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`3'—methyl, 4'-methyl, 4'-cfiloro or 4'-fluoro; Or R
`and_R4
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`together represent 3'~meth§l—4'-chloro, 3',5'~dichloro,
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`3',5‘-difluoro, 3',5'-dimethyl or 3'~methyl—4'—fluoro; R5
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`is primary or
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`Sawai Ex 1013
`Page 5 of 98
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`secondary Cl_6 alkyl or C3_6 cycloalkylz and Y is —CH2—CHf-
`or —CH=CH~; and Z is
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`H0
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`-CH(0H)CH2C(0)CH2C02R12 or
`12,
`-cH(oH)cH2cH(oHicH2co2n
`-CH(OH)GH2C(0R13)2GH2CO2Rl2.
`3.’-Compoudd according to dlaim 2, wherein when R
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`2
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`and R
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`6
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`are both hydrogen, R1 is hydrogeh, 5-fluoro, 6-fluoro,
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`7+fluoro, 8-fluoro, 5-chloro, 6—ch1oro, 7-chloro,
`8-chloro, 5-bromo, 6-bromo, 7—bromo, 8-bromo, 5-fiethyl,
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`6-methyl, 7-methyl, 8-methyl, 5-methoxy, 6—methoxy,
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`7—methoxy, 8-metroxy, 5-trggluoromethyl,
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`romethyl, 8-triflfioromethyl,
`’6-trifluoromethyl, 7~triflfib
`-:e¥r¥
`-
`_6~trifluoromethoxy, Sfdiflqgromethogfi, 8-hydroxyethyl,
`5-hydroxy, 6-hydroky, 7—hydroRy, 8-hydroxy, 6~ethy1,
`6
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`6-n-butyl or 7-dimethylamino; when R
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`is hydrogen, R
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`1
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`and
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`R2 together represent 6-chloro-8-methyl,
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`§~bromo—7-methoxy, 6-methyl—7—chloro, 6—chloro—8—hydroxy,'
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`5-methyl—2~hydroxy, 6-methoxy—7-chloro,
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`6-ch1oro—7~methoxy, 6-hydroxy-7-chloro,
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`6-chloro-7—hydroxy, 6~chlo§p-8-bromo, 5—ohloro-6-hydroxy,
`6-bromo-8—chloro, 6-bromo-géhydroxy, 5-methy1;8—chloro,
`7-hydroxy-8-chloro,'6~brom%?B4hjEroxy, 6-methoxy—7-methyl,
`6-chloro-8-bromo, 6—methyl;§-bromo, S,7—difluoro,
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`Sawai Ex 1013
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`Page 6 of 98
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`6,8—difluoro, 6,7-methylenedioxy, 6,8-dichloro,
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`5,8~difiéthyl, 6,B4dimethyl, 6,7-dimethoxy, 6,7-diethoxy,
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`6,7—dibromo or 6,8edibromor or Rl,iR2 and R6 together
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`represent 5,7-dimethoxy—B—hydroxy, 5,8—dioh1oro-6-hydroxy,
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`6,7,8fitrimethoxy, 6,7,d-trimethyl, 6,7,8-trichloro,
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`5—fluoro-6,8-dibromo or 5-chloro-6,B=dibromo; when R3 is
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`4 is hydrogen, 4'-methyl, 4'—chloro or
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`3
`4'—flfioro; or when both R
`and R4.are not hydrogen,
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`they
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`hydrogen, R
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`represent 3',5'-dimethyl or 3'-methyl-4'-fluoro; and Y is
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`(E)--CH=CH—.
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`>-CH2-CH2- or
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`4.- The compound.according to Claim 3, wherein when both
`2
`1
`and R6 are hydrogen, R
`is hydrogen, 6-methyl, 6-ethyl,
`R
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`6—nrbutyl, 6-trifluoromethyl, 6-chloro, 6—bromo,
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`6-hydroxy, 6-methoxy or 7-dfimethylamino; or when R6 is
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`1
`2
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`togethggzgepresent 6,8—dich1oro,
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`;5,8—dimethyl, 5,8—dimethyl:;6,7-dimethoxy, 6,7—diethoxy,
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`lhydrogen, R
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`and R
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`6,7—dibromo, 6,B—dibromo, 6,7~dif1uoro or 6,8-difluoro;
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`when R
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`4'-chloro; or R
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`3 is hydrogen, R4 is hydrogen, 4'-fluoro or
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`4
`3
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`and R 'together represent
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`3'—methyl-4'—fluoro; R5 is ethyl, n—propyl,
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`i—propyl or
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`cyclopropyl; and Y is (E)——CH=CH~.
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`5._ The compound according to Claim 3, wherein when both
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`1
`2
`6
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`Eds hydrogen, 6—methy1 or
`R
`and R
`are hydrogen, R
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`1
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`and R2 together
`6
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`is hydrogen, R
`6~chloro; or when R
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`represent 6,7—dimethoxy; wEEn.R3 is hydrogen, R4 is
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`5
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`hydrogen, 4'—chloro or 4'—f1uoro: R
`is i—propyl or
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`'cyclopropyl; and I is (E)--CH=CH—.
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`Sawai Ex 1013
`Page 7 of 98
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`6.
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`The compound according to Claim 1, which is
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`(E)-3,5~dihydpoxy47-[4f-<4-I—£1uo:opheny1)—2'-(1"—
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`methylethyl)-quinolin-3'-yl}—hept~6—enoic acid, a lactone
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`formed by the condensation of the carboxylic acid with
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`hydfoxy at the 5-position, ot a sodium salt or Cl_3 alkyl
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`ester of the.carboxylic acid.
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`7.
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`The compound according to Claim 1, which is
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`(E)-3,5~dihydroxyw7—[4'-(4"-fluorophenyl)—2'-(l"-
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`methylethYl)—6'-chloro—quino1in—3'-yl}-hept-6-enoic acid,
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`a lactone formed by the condensation of the carboxylic
`acid with hydroxy at the Séposition, or a sodium salt or
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`Cl_3 alkyl ester of the carboxylic acid.
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`‘The compound according to Claim 1, which is
`8.
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`(E)-3,5-dihydroxy-7-[4'-(4ff-fluorophenyl)-2'-(l"-
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`"methylethyl)-6'-methyl—qqifi3lin-3'jyl]—hept-6—enoic acid,
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`;a 1actone.formed by the cofifiensation of the carboxylic
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`acid with hydroxy at the 5-position, or a_sodium salt or
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`Cl_3 alkyl ester of the carboxylic acid.
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`The compound according to Claim 1, which is
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`_ 9.
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`(E)~3,5—dihydroxy-7-[4'—(4"-fluorophenyl)—2'-(l"-
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`methylethyl)—6',7‘-dimethoxy-quinolin—3'-yllahept-6—enoic
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`-acid, a lactone formed by the condensation of the
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`carboxylic acid with hydtogy at the 5—position, or a
`sodium salt or Cl_3 alhyl Site: of the carboxylic acid.
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`10. The compound accordingigo Claim 1, which is
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`(E)-3,5—dihydroxy-7-{4}-i4::—fluorophenyl)—2‘-cyclopropyl—
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`quinolin—3'-yl]-hept—6—enoic acid, a lactone formed by the
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`Sawai Ex 1013
`Page 8 of 98
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`_ Q _
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`condensation of the carbcxylic acid with hydroxy at the
`Ssposition, or a sodium salt or Cl_3 alkyl ester of the
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`carboxylic acid.‘
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`ll. The compound according to Claim 1, which is
`(E)43,5-dihydroxys7-[4'—(4"—fluorophenyl)-2'—cyclopropyl—
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`6'—chloro—quinolin—3'-y1]—hept-6—enoic acid, a lactone
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`formed_by the condensation of the carboxylic acid with
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`
`
`
`
`
`hydroxy at the 5—position, or a sodium salt or Cl_3 alkyl
`
`ester of the carboxylic acid.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l2. The compound according to Claim 1, which is
`
`
`
`
`(E)-3,5-dihydroxy-I-[4'—(4"-fluorophenyl)-2'—cyclopropyl-
`
`
`
`
`
`
`a lactone
`6'-methy1jquino1in—3'fiylj-hept—6-enoic acid,
`formed by the condensation of the carboxylic acid with
`
`
`
`
`
`
`
`
`
`hydroxy at the 5-positiontfor a sodium salt or Cl_3 alkyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.—..._._.
`Alester of the carboxylic ac;gi_
`
`
`;l3. The compound accordingitb Claim 1, which is"
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)—3,5-dihydroxy—7L{4'~(4"—fluorophenyl)-2'—cyclopropyl-
`
`
`
`
`
`6‘,7‘—dimethoxy-quinolin—3'-ylI—hept~6-enoic acid, a
`lactone formed by the condensation of the carboxylic acid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Qith hydroxy at the 5—position} or a sodium salt or Cl_3
`
`
`
`
`
`
`
`alkyl ester of the carhoxylic acid.
`
`
`
`
`
`'14. The compound according to Claim 1, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)-3,5-dihydroxy—7-£4'f}4E:—chlorophenyl)-2'-(1"-
`
`
`
`methylethyl)-quinolin-3‘-yiflhept-6-enoic acid,
`a lactone
`
`
`
`
`
`
`formed by the condensationigf the carboxylic acid with
`
`
`
`
`
`
`
`
`hydroxy at
`the 5—position, or a sodium salt or C1_3 alkyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ester of the carboxylic acid.
`
`
`
`
`
`Sawai Ex 1013
`Page 9 of 98
`
`

`
`
`
`
`
`
`
`
`
`_ 7 _
`
`
`
`
`
`
`
`
`
`15. The compound according to Claim 1, which is
`
`
`
`
`(E)-3,5?dihydroxy-7-[4'-(4"—chlorophenyl)-2'-(l"-
`
`
`methylethyl)-6'—chloro-quinolin+3'-yllehept-6-enoic acid,
`
`
`
`' a lactone formed by the condensation of the carboxylic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘acid with hydroxy at the 5—position, or a sodium salt or
`
`
`
`
`
`
`
`
`
`Cl_3 alkyl ester of the carbogylic acid.
`
`16; The compound according to Claim i, which isi
`
`
`
`
`
`
`
`
`
`(E)-3,5-dihydroxy-7—[4'—(4"-chlorophenyl)-2'—(1"-
`methylethyli-6'—methyl-quinolin-3'-y1]-hept—6+enoic acid,
`
`
`
`
`
`
`
`
`
`
`
`
`a lactone formed by the condensation of the carboxylic
`
`
`
`
`
`
`
`
`
`
`
`
`acid.with hydroxy at the Séposition, or a sodium salt or
`
`C1_3 alkyl ester of the carboxylic acid.
`
`
`
`
`
`
`
`17. The compound according to Claim 1, which is
`
`
`
`
`
`
`
`
`(E)-3,5-dihydroxy—7-[4'~f4€f+ch1orophenyl)-2'—(l"~
`
`
`
`
`
`
`
`Imethylethyi)-6',7‘-dimethofiggguinoiin-3'-y1]—hept-6-enoic
`
`
`
`
`
`
`
`
`
`
`,acid, a lactone formed by £32 condensation of the
`
`
`
`
`
`
`
`carboxylic acid with hydroxy at the 5-position, or a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`sodium salt or Cl_3 alkyl ester of the carboxyiic acid.
`
`
`
`
`
`
`
`
`
`
`18. The compound according to Claim 1, which is
`
`
`
`
`
`
`
`
`
`(E)-3,5-dihydroxy—7-I4‘-(4"-chlorophenyl)—2'-cyclopropyl-
`
`
`
`
`
`
`
`quinoIin—3'—yl]—hept-6-enoic acid, a lactone formed by the
`
`
`
`
`
`
`
`
`
`
`'condensation of the carboxylic acid with hydroxy at
`
`
`
`the
`
`
`
`
`
`
`
`
`
`
`
`
`- 5-position, or a sodium shit or C1_3 alkyl ester of the
`nu:
`_
`
`
`carboxylic acid.
`‘Ctr
`‘
`‘ 19. The compound accordingéto Ciaim 1, which is
`
`
`
`
`
`
`
`
`(E)-3,5-dihydroxy—7—[4'—(4;'-chlorophenyl)-2'-cyclopropyl-
`
`
`
`
`
`
`
`6'-chloro-quinolin-3'-yl]-hept—6-enoic acid, a lactone
`
`
`
`Sawai Ex 1013
`Page 10 of 98
`
`

`
`_ 3 _
`
`
`
`
`
`
`
`
`
`formed by the condensation of the carboxylic acid with
`
`
`
`
`
`
`
`
`
`
`
`
`hydroxy at the 5-fiosition, or a sodium salt or Cl_3 alkyl
`
`ester of the carboxylic acid.
`I
`i
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`20. The compound according to Claim 1, which is
`
`
`
`(E)‘3,5-dihydroxy-7-[4'—(4"—ch1orophenyl)-2'—cyclopropyl-
`
`
`
`
`
`6'-methyl-quinolin-3'-yl]-hept-6-enoic acid, a lactone
`formed by the condensation of the carboxylic acid with
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hydroxy at the 5-position, or a sodium salt or C1_3 alkyl
`
`ester of the carboxylic acid.
`
`
`
`
`
`21. The compound according to Claim 1, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)—3,5-dihydroxy-7-[4'—(4*P—ch1oropheny1)*2‘—cyc1opropyl-
`
`
`
`
`6'7'—dimethoxy-quinolin-3'-y1]-hept—6-enoic acid, a
`
`
`
`
`
`
`
`
`lactone formed by the condensation of the carboxylic acid
`with hydroxy at the 5-cositdon, on a sodium salt or Cl_3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘ alkyl ester of the carboxy
`fig acid.
`. mh_
`...
`
`
`
`:22, The compound accordingiio Claim 1, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)-3,S—dihydroxy—74[4'—phenyl-2'-(l"-methylethy1)-
`
`
`
`
`
`
`
`
`quinolin-3'-yl]-hept-Gjenoic acid, a lactone formed by the
`
`
`
`
`
`
`
`
`
`
`
`condensation of the carboxylic acid with hydroxy at the
`
`
`
`
`
`
`
`
`
`
`5-position, or a sodium salt or Cl_3 alkyl ester of the
`
`carboxylic acid.
`
`
`
`
`
`
`
`.23. The comfiound according to Claim 1, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)—3,5-dihydroxy-7-E4‘-phgnyl-2'—(l"-methylethyl)"
`6'-chloro-quinolin-3'—yl]-EE§t—6-enoic acid, a lactone
`
`
`
`
`
`'--
`
`formed by the condensationfiof the carboxylic acid with
`
`
`
`
`
`
`
`
`hydroxy at the 5-position, or a sodium salt or Cl_3 alkyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ester of the carboxylic acid.
`
`
`
`
`
`
`
`
`
`Sawai Ex 1013
`Page 11 of 98
`
`

`
`
`
`--9 _
`
`
`
`
`
`
`
`
`
`
`24. The compound according to Claim 1, which is
`
`
`
`(E)-3,5-dihydroxy;7-[4'-phenyl-2'-(l"-methylethyl)-6'-
`
`
`methyl-quinolin—3';yl]—hept-6—enoic acid, a lactone formed
`
`
`
`
`
`
`
`by the condensation of the carboxylic acid with hydroxy at
`
`
`
`
`
`
`
`
`
`the 5—§osition,-or a sodium salt or C1_3 alkyl ester of
`
`
`
`
`
`
`
`
`
`
`
`
`
`the carboxylic acid.
`25. The compound according to Claim 1, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)-3,54dihydroxy—7—[4'—phenyl-2'-(l"-methylethyl)“
`6',7'-dimethoxy-quinolin-3'-yl]—hept-6—enoic acid, a
`
`
`
`
`lactone formed by the condensation of the carboxylic acid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`with hydroxy at the 5-position, or a sodium salt or C1_3
`
`
`
`
`
`
`alkyl ester of the carboxylic acid.
`26. The compound according to Claim l, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)-3,5-dihydroxy-7-[4'—ph§nyl—2'-cyclopropyl—quinolin-
`
`
`
`
`
`
`' 3'-yl]—hept—6-enoic acid,_§§lactone formed by the
`
`—..___.
`
`
`
`
`
`
`
`
`
`
`
`
`
`;condensation of the carboxglic acid with hydroxy at the
`
`
`
`
`
`
`
`
`
`5-position, orfa sbdium salt or Cl_3 alkyl ester of the
`
`
`
`carboxylic acid.
`
`
`
`
`
`
`
`
`
`
`
`
`
`27, The compound according to Claim 1, which is
`
`
`
`_(E)-3,5-dihydroxy-7-[4'-phenyl-2'-cyclopropyl-6'-chloro—
`
`
`quinolin-3'-yl]-hept-6—enoic acid,
`
`
`
`
`
`
`
`a lactone formed by the
`
`
`
`
`
`
`
`
`
`
`
`condensation of the carboxylic acid with hydroxy at the
`
`
`
`
`
`
`
`
`
`5-position, or a sodium gait or C
`-.1.
`
`
`
`
`alkyl ester of the
`
`
`
`l-3
`
`
`
`
`carboxylic acid.
`
`
`
`F
`‘I
`
`..
`
`.‘
`
`
`
`
`
`
`
`
`28. The compound accordinégto Claim 1, which is
`(E)-3,5-dihydroxy-7—[4'-phenyl—2'—cyclopropyl-6'-methyl-
`
`
`
`
`quinolin—3'-yl]—hept—6-enoic acid,
`
`
`
`
`
`
`
`a lactone formed by the
`
`
`
`
`
`Sawai Ex 1013
`Page 12 of 98
`
`

`
`_ lb‘-
`
`- condensation of the carboxylic acid with hydroxy at-the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5-position, or a sodium salt or C1_3 alkyl ester of the
`
`carboxylic acid.
`
`
`
`
`
`
`
`
`
`
`
`
`
`29. The compound according to Claim 1, which is
`
`(E)-d,5-dihydroxy-7-I4'-phenyl-é‘-cyclopropyl-6',7‘-
`
`
`
`dimethoxy-quinolin-3'-yl]-hept-6—enoic acid, a lactone
`
`
`
`
`
`
`
`
`
`
`
`
`
`formed by the condensation of the carboxylic acid with
`
`
`
`
`
`
`
`
`
`
`
`
`hydroxy at the 5—position, or a sodium salt or Cl_3 alkyl
`
`ester of the carboxylic acid.
`
`
`
`
`
`
`
`
`
`
`
`
`
`30. The compound according to Claim 1, which is
`
`
`
`
`
`(E)-3,5~dihydroxy—7—[4'-(4"vfluorophenyl)~2'-(lf'-
`
`
`methy1ethy1)—6'-methoxy—quino1in43}—yl]—hept-6-enoicvacid,
`a lactone formed by the condensation of the carboxylic
`
`
`
`
`
`
`
`
`
`
`
`
`acid with hydroxy at the 5éEO5itiOnf or a sodium salt or
`
`
`
`
`
`
`
`
`
`
`'¢l_3 alkyl ester of the cai§o§ylic_acid.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`:31. The compound accordingfib Claim 1, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`' (E)~3,5-dihydroxy-74[4'-(4"—fluorophenyl)—2'—cyclopropyl—
`
`
`
`
`6'~methoxy-quinolin-3'-yl}—hept—6—enoic acid, a lactone
`
`
`
`
`
`
`
`
`
`
`
`formed by the condensation of the carboxylic acid with
`
`
`
`
`
`
`
`
`
`
`
`
`hydroxy at the 5—position, or a sodium salt or Cl_3 alkyl
`
`
`
`
`
`
`ester of the carboxylic acid.
`
`
`
`
`
`
`
`
`
`32. An anti-hyperlipidemia agent containing the compound
`
`
`
`
`
`
`
`
`
`of the formula I as defined in Claim 1.
`%
`
`33._An anti—hyperlipoproteihemia agent containing the
`
`
`
`
`
`-It
`‘compound of the formula-I Es dedined in Claim 1.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`34. An anti-atherosclerosis agent containing the compound
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the formula-I as defined in Claim 1.
`
`
`
`
`
`
`
`Sawai Ex 1013
`Page 13 of 98
`
`

`
`
`
`
`
`
`
`
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`
`
`
`3.DETAILED DESCRIPTION OF THE INVENTION:
`
`
`
`
`[Industrial Field of Utilization]
`
`
`
`
`
`
`
`
`The present invention relates to novel
`
`
`
`-'
`'
`I
`
`
`
`
`
`
`mevalonolactones having a quinoline ring processes for
`
`
`
`
`
`
`
`their PF°d”Cti°n: Pharmaceutical compositions containing
`
`
`
`
`
`
`
`them and their.pharmaceutical uses particularly as
`
`
`
`hypplipoproteinemic and anti—atherosclerotic agents,
`
`
`
`
`
`
`
`and intermediates useful for their production and processes
`
`
`
`
`
`
`for the production of such intermediates.
`
`
`
`
`
`
`[Prior-_Ar‘t and its Problem]
`_
`
`
`
`
`
`Some fermentation metabolic products such as
`
`
`
`
`
`
`
`
`
`compactine, CS-514,iMevinolin or semi-synthetic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`derivatives or fully synthetic derivatives thereof are-
`
`
`
`
`
`
`
`
`
`
`
`known to be inhibitors against HMG-CoA reductase which is
`
`
`
`
`
`
`
`
`
`a rate limiting enzyme foriflkflesterol biosynthesis.
`
`
`Endo J. Med,Chem., 2ék4)'gé£E419a5r).
`
`
`
`
`- cs—5I4 and Mevinolin haée been Clinically proved to be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`potentially useful anti—hyperlipoproteinemic agents, and
`
`
`(A.
`
`
`
`
`
`
`
`
`
`
`
`
`
`they are considered to be effective for curing or
`
`
`
`
`
`
`
`
`
`preventing diseases of coronary artery sclerosis or
`
`
`
`
`
`
`(IXth Int, Symp. Drugs Affect. Lipid
`atherosclerosis.
`
`
`
`
`
`I935, p30, p31, p66)
`
`" Metab.,
`
`
`
`
`
`
`
`
`
`Sawai Ex 1013
`Page 14 of 98
`
`

`
`
`
`..
`
`However, with respect to fully synthetic derivatives,
`
`
`
`
`
`
`
`
`
`
`
`
`
`particularly 'hetéroc:,irq1ic' derivatives of inhibitors
`against HMG-CoA reductase,
`limited information is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`disclosed in the following literatures:
`
`
`
`
`
`
`
`
`
`WPI ACC NO. B4-158675, 86-028274, 86~09B8l6,
`as"-332070, 37-i245'1i9, 87-520337,
`ss‘ioo*2.~z's'1‘f,;'3e—ooal16o,
`
`
`
`
`
`88*09l798 and 88-ll2505.
`
`
`
`
`
`
`
`
`
`
`
`
`The present inventors have found that mevalonolactone
`
`
`
`
`
`
`
`derivatives having a quinoline ring,
`the corresponding
`'dihydroxy carboxylic acids and salts and esters tpereof
`
`
`
`
`
`
`
`
`
`
`
`
`have high inhibitory activities against cholesterol
`
`
`
`
`
`
`biosynthesis wherein HMG-CoA reductase acts as a rate
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The preséfit invention has been
`limiting enzyme.
`
`accomplished on the basisgggfthis discovery.
`
`
`
`
`
`
`
`
`- The novel mevalonqlactghe derivatives of the present
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`invention are represented by the following formula I:
`
`
`
`R“
`
`R.‘
`
`
`
`
`
`
`
`
`
`
`
`’1234
`wherein R , R , R , R
`
`
`
`
`
`
`6
`
`
`
`
`are independently hydrogen,
`and:
`
`
`
`
`
`
`Cl_6 alkyl, Cl_6 cycloalkyli glfi3 alkoxy, n-butoxy,”
`
`
`
`i-butcxy, sec-butoxy, R7R8fi;
`(wherein R7 and R8 are
`
`
`
`
`
`
`
`
`
`
`
`
`
`trifluoromethyl,
`independently hydrogen or Cl_3 alkyl),
`
`
`
`
`
`trifluoromethoxyr Wifluoromethoxy, fluoro, chloro, bromo,
`
`
`
`
`
`
`
`Sawai Ex 1013
`Page 15 of 98
`
`

`
`-13 -
`
`phenyl, phenoxy, benzyloxy, hydroxy,
`trimethylsilyloxy,
`diphenyl-t-butylsilylohy, hydroxymethyl or -O(CH2)lORl9
`19 is hydrogen or-C143 alkyl,-and 2
`is 1, 2 or
`3); or when located at the ortho position to each other,
`
`.(wherein R
`
`1
`‘R and R
`
`2, or R3 and R9 together form -cH=cH+cH=cH-; or
`
`when located at the ortho position to each other, R1 and
`2
`15
`R 'together form -0C(R;5)(Rl6)0- (wherein R
`
`and R
`
`16
`
`are
`
`independently hydrogen or Cl_3 alkyl): Y is -CH2—,
`~ca2cH2—,"-cH=cH-;
`-CH2-CH=CH- or 4cH=cH-CH2-; and z is
`-co Riz,
`2
`
`‘-Q-cazwca
`
`2
`
`R11_
`
`,or.
`
`— or -CH(OH)~; W is -C(O)-,
`
`—C(OR
`
`(wherein Q is -C(0f#,V-C(OR
`13)2— or —c(R11)(oH)-: all
`14
`Rl2_is hydrogen or R
`
`(wherein R
`
`is hydrogen or Cl_3 alkyli
`14 is physiologically
`
`hydrolyzable alkyl or.M (wherein M is NH4, sodium,
`
`potassium,
`
`l/2 calcium or a hydrate of lower alkylamine,
`13
`
`-di-lower alkylamine or tri-lower alkylamine));
`
`two R
`
`are
`
`independently primary or_se§ondary Cl_6 alkyl; or two R13
`R17 and R18 are‘.
`together form —(CH2)2— or {IEH2)3-;
`independently hydrogen or é;:3 alkyl; and R5 is
`
`hydrogen, Cl
`alkyl, C2 3 alkenyl, C3_6 cycloalkyl,
`9
`.
`_
`.
`.<:3{R (wherein R
`15 hydrogen, c1_4 alkyl, Cl_3
`
`6
`
`-
`
`9
`
`.
`
`Sawai Ex 1013
`
`Page 16 of 98
`
`

`
`">14 -
`
`alkoxy, fluoro, chloro, bromo or trifluoromethyl),
`phenfl-(CH2)m~ (wherein m is l,
`2 or 3),
`-(CH2)nCH(CH3)-phenyl or phenyl-(CH2)nCH(CH3)-
`is o, 1 or 2).
`
`lwherein n
`
`:
`
`"Various substituents in the formula I will be
`
`described in detail with reference to specific examples.
`However, it should be understood that the present
`
`invention is by no means restricted by such specific
`
`examples.
`
`C1--4
`
`4
`3
`2
`1
`alkyl for R , R , R , R , R
`
`6
`
`9
`
`and R
`
`includes,
`
`for
`
`example, methyl,.ethyl, n-propyl,
`i-propyl, n—butyl,
`i-butyl, sec—butyl and tebutyl. Cl_3 alkoxy for R1, R2,
`3
`4
`6
`R , R
`and R
`includes, for example, methoxy, ethoxy,
`
`n—propoxy and-i—propoxy.'-ff‘
`
`Cl_3 alkyl for Rll incigdgs, for_example, methyl,
`;ethyl, nwpropyl and i-prcpfle
`13
`
`C _3 alkyl for R
`1
`
`includes, for example, methyl,
`
`ethyl, n—propyl and i-propyl.
`14
`
`Alkyl for R
`
`includes, for example, methyl, ethyl,
`
`n—propyl,
`
`i—propy1, n~butyl and i—butyl.
`
`M is a metal capable of forming a pharmaceutically
`
`acceptable salt, and it includes, for example, sodium and
`
`potassium.
`; i
`sCO2NH and —CO2H'
`ICOZM includes, for example,
`(primary to tertiary lowergglkylamine such as
`trimethylamine).
`.
`
`4
`
`*~.
`
`Cl_6 alkyl for R
`
`5
`
`includes, for example, methyl,
`
`SawmiEx1013
`
`Page 17 of 98
`
`

`
`
`
`
`
`.
`
`
`
`'—
`
`
`
`
`i-propyl, n—butyl,
`ethyl, n—propyl,
`'t—butyl, n—pentyl and nshexyl.
`
`
`
`
`5
`
`
`
`
`
`
`i-butyl, sec—butyl,
`
`
`
`
`
`
`
`
`
`includes, for example,
`C3_6 cycloalkyl for R
`
`cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
`
`
`
`
`
`
`
`C2_3 alkenyl for R5 includes, for example, vinyl and
`
`
`
`
`
`
`
`i-propenyl.
`
`'Phenyl-(CHé)m~ for R5 includes, for example, befizyl,
`
`
`
`
`B—phenylethyl and Y-phenylpropyl.
`
`
`
`
`5
`Phenyle{CH2)nCH(CH3)- for R
`includes, for example,
`
`
`
`a-phenylethyl and d-benzylethyl.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Cl_3 alkyl for R
`
`
`
`
`
`methyl, ethyl, n-propyl and i-propyl.
`
`
`
`includes, for example,
`
`
`7 and R8
`
`
`
`
`
`
`Further,
`
`
`
`
`
`
`
`
`
`
`these compounds have at least one or two
`
`
`
`
`
`
`
`
`
`
`
`asymmetric carbon atoms andfhave at_least two to four
`
`The compggfigs of the formula I include
`-optical'isomers.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`;all of these optical isomergaand all of the mixtures.
`
`
`
`
`
`
`
`
`thereof.
`
`
`
`
`
`
`
`
`Among compounds having carboxylic acid moieties
`12
`
`
`
`
`
`
`
`
`
`of the
`falling outside the definition of —CO2R
`carboxylic acid moiety of substituent Z of the compounds
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the present invention,
`
`
`
`
`
`those which undergo
`
`
`
`
`
`
`physiological hydrolysis, after intake,
`
`corresponding carboxylicljacids (compounds wherein the
`
`
`
`
`
`
`12
`
`~CO2R moiety is -CO2H) ane equivalent to the compounds
`
`
`
`
`
`
`_t—-.
`
`
`
`
`
`of the present invention.
`
`
`
`
`
`to produce the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Now, preferred and mostprefiwred substituents of the
`
`
`
`
`
`
`
`
`
`
`compounds of the present invention will be described.
`
`
`
`Sawai Ex 1013
`Page 18 of 98
`
`

`
`“-16 _
`
`
`
`
`
`
`
`
`In the following preferred, more preferred still
`
`
`
`
`
`
`
`
`
`
`further perferred and most preferred examples,
`the
`ndmerals for the positions of the substituents indicate
`
`
`
`
`
`
`
`the positions on the quinoline ring.
`For example, N’
`
`
`
`
`
`
`
`
`
`shown by e.g. l' or 2'
`indicates the position of the
`
`
`
`
`
`
`
`
`
`
`
`substituent on the phenyl substituted at the 4-position of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the quinoline ring (the carbon connected to the quinoline
`ring is designated as l’).
`The meanings of the respective
`
`
`
`
`
`
`
`
`
`substituents are the same as the above~mentioned meanings.
`
`
`
`
`
`
`
`l
`2
`6
`
`
`
`
`
`
`
`Preferred substituents for R , R
`and R
`fluoro, Chloro, bromo, Cl_3 alkyl, C1_3 alkoxy, ¢3_6_
`
`
`
`
`
`
`
`
`cycloalkyl, dimethylamino, hydroxy, hydroxymethyl,
`
`
`
`
`~hydroxyethy1, trifluoromethoxy, difluoromethoxy,
`
`
`
`
`
`
`
`
`
`are hydrogen,‘
`
`
`
`
`
`
`
`phenoxy and.benzyloxy.
`6
`
`
`Further, when R
`
`
`2
`
`
`
`
`--éL=
`
`
`
`1
`
`
`
`
`
`
`is hgggogen, it is preferred that R
`
`
`
`
`
`
`
`
`I
`together form methyfehedioxyu
`
`As preferred examples for R3 and R4, when R4 is
`
`
`
`
`
`
`
`
`
`3
`
`hydrogen, R
`is hydrogen, 3'-fluoro, 3'-chloro, 3'—methyl,
`
`
`
`
`
`4'—methyl, 4'-chloro and 4'-fluoro.
`
`
`
`
`
`
`;and R
`
`
`
`Other preferred combinations of R
`
`
`
`
`
`3
`
`
`and R4 include
`
`
`
`
`
`3'—methyl-4'¥chlorc, 3',5'-dichloro, 3',5'—difluoro,
`
`
`
`
`
`
`
`
`3',S'—dimethyl and 3J—methyl-4'-fluoro.'
`
`Preferred examples f9kE§5 include primary and
`
`
`
`
`
`
`secondary ci_5 alkyl and.c;:; cycloalkyl.
`
`
`
`
`
`
`Preferred examples forzg include -CH2—CH2— and
`
`
`
`
`
`
`-CH=CH- .
`
`
`
`
`
`
`
`Preferred examples for Z include
`
`
`
`
`
`
`
`
`
`
`
`Sawai Ex 1013
`Page 19 of 98
`
`

`
`.12
`,
`~CH(OH)CH2CH(OH)CH2C02R
`l3)2CH2C02R12.
`~CH(OH)CH2C(OR
`Now, more preferred substituents of the compounds of
`
`R12 and
`
`.
`-CH(0H)CH2C(O)CH2C0
`
`2
`
`the present invention will be described.
`
`As more preferred examples for R1, R2 and R6, when
`
`both R2
`
`and R
`
`5
`
`are hydrogen, R
`
`1
`
`is hydrogen, 5-f;uoro,
`
`6-fluoro, 7-fluoro, 8-flgoro, S~chloro, 6-chloro,
`
`7—chloro, B-chloro, 5-bromo, 6-bromo, 7~bromo, 8-bromo,
`
`5-methyl, 6—methyl, 7-methf}; 8-methyl, 5—methoxy,
`
`.5—methoxy, 7—methoxy, 8-me§§o§y, Sfitrifiluoromethyl,
`__.;—.
`’;6-trifluoromethyl, 7—trif1§3romethyl, 8-trifluoromethyl,
`
`Gjtrifluoromethoxy, 6-difluoromethoxy, 8-hydroxyethyl,
`
`5—hydroxy, 6-hydroxy, 7-hydroxy, B—hydroxy, 6—ethyl,
`
`6-n—butyl and 7-dimethylamino.
`
`Wnen R
`
`6
`
`is hydrogen, R
`
`1
`
`2
`
`and R
`
`together represent
`
`6—chloro-8-methyl, 6-bromo~7-methoxy, 6-methyl-7~chloro,
`
`‘6—chloro-8-hydroxy, 5-methyl-2—hydroxy,
`
`6-methoxy-7-chloro, 6—oh}o§é~7-methoxy,
`6-hydroxy-7-chloro, 6-chlo£S:7—hydroxy, 6-ch1oro—8-Bromo,
`5fchloro—6~hydroxy, 6-bromggbecnioro, 6-bromo—8-hydroxy,
`5—methyl~8—chloro, 7—hydron§-8-chloro, 6-bromo-8-hydroxy,
`
`6-methoxy-7-methyl, 6-chloro~8-bromo, 6—methy1-8-bromo,
`
`Sawai Ex 1013
`
`Page 20 of 98
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`_'
`
`
`
`6,7-difluoro, 6,8-difluoro, 6,7-methylenedioxy,
`
`
`
`6,8-dichloro, 5,a—aimethy1, 6,81dimethyl, 6,7—dimethoxy,
`
`
`
`
`
`
`
`
`
`6,7-diethoxy, 6,7-dibromo or 6,8~dibromo.
`
`1
`2
`6
`
`
`
`
`
`they together
`when R , R
`
`
`represent 5,7~dimethoxy%8—hydroxy, 5,8—dichloro—6-hydroxy,
`
`
`and R
`
`
`
`are not hydrogen,
`
`
`
`
`
`§,7,8¥trimethoxy, 6,7,8—trimethyl, 6,7,8—trich1oro,
`
`
`
`
`
`
`
`3
`
`
`is
`
`
`
`5-fluoro-6,8—dibromo or 5-chloro-6,8—dibromo.
`
`
`
`3
`4
`
`
`
`
`
`
`
`
`
`As more preferred examples for R
`and R , when R
`4
`
`
`
`iss4'7methyl,.4'-chloro or
`
`
`
`3
`4
`
`together represent 3',5'—dimethyl or 3'-methyl—4!;fluoro.
`
`
`
`
`
`
`
`
`
`hydrogen, R
`
`
`
`
`4'—fluoro. when both R
`
`
`and R
`
`
`are not hydrogen,
`
`
`
`they
`
`
`
`
`
`
`
`the above—mentioned
`
`
`As more preferred examples for R5,
`
`
`
`
`
`5
`
`
`preferred examples of‘R may be mentioned.
`
`
`
`
`
`
`
`
`
`
`-CH2-CH2- and (E)~-CH=CH-
`As preferred examples gpr Y,
`may be mentioned. As moreéE§§ferred_examples for Z,
`the
`
`
`
`
`
`
`
`
`
`-
`—
`
`
`
`
`
`
`
`;above preferred examples fo;;Z may be mentioned.
`
`
`
`
`Now, still further preferred substituents of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`compounds of the present invention will be described.
`2
`1
`2
`6
`6
`
`
`
`
`
`
`
`
`
`
`examples for R , R
`and R , when both R
`
`hydrogen, Rl is hydrogen, 6-methyl, 6-ethyl,
`
`
`
`
`
`
`and R
`
`are
`
`
`
`
`
`
`
`
`"As
`
`
`
`
`6—trifluoromethyl, 6—hydroxy, 6-methoxy, 6—chloro,
`
`
`
`
`
`
`
`6-bromo, 6~n—bgtyl and 7-dimethylamino.
`
`When.only R6 is hydrogéi, Rl and R2 represent
`
`
`
`
`
`
`
`
`
`
`6,8—dichloro, 5,8-dimethylrl6,3—dimethyl, 6,7-dimethoxy,
`
`
`
`L-
`
`
`6,7—diethoxy, 6,7—dibromo,35,8-dibromo, 6,7-difluoro and
`
`
`
`
`
`
`
`
`
`
`
`
`5,8—difluoro.
`
`
`
`As still further preferred examples for R
`
`
`
`
`
`
`
`3
`
`
`4
`and R ,
`
`
`
`
`
`
`
`
`Sawai Ex 1013
`Page 21 of 98
`
`

`
`
`
`.w_19 _
`
`
`
`‘when R
`
`3 is hydrogen, R4 is hydrogen, 4'-chloro or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4‘Ffluoro, or R3 and R4 together represent
`
`
`
`3'-methyl—4'—fluoro.
`
`
`
`Still further preferred examples for R
`
`
`
`
`
`
`5
`
`
`
`include ethyl,
`
`
`
`
`n—propyl,
`
`
`
`
`
`i-propyl and cyclopropyl.
`
`
`
`
`
`
`
`
`
`Still further preferred examples for Y include
`
`
`
`(E)--CH=cH-.
`
`
`
`
`
`
`
`
`
`As still further preferred examples for Z,
`
`
`
`the
`
`
`
`
`
`
`
`
`
`above-mentioned preferred example for Z may be mentioned.
`
`
`
`
`
`
`
`
`
`
`Now,
`the most preferred substituents for the compounds
`of the present-invention will be described.
`
`
`
`
`
`
`As the most preferred examples for R1, R2 and R6, when
`
`
`
`
`
`
`
`
`
`
`
`6
`1
`
`
`
`
`
`both R2 and R
`
`
`
`
`.are hydrogen, R
`
`
`
`
`
`
`is hydrogen, 6-methyl or
`
`
`
`
`
`
`
`6-chloro.
`.
`'
`--55'
`1
`
`when only R6 is hydrqggE,_R and_R2 together
`
`
`
`
`
`
`
`
`,represent, for example, 3,iHdimethoxy.
`
`
`
`
`
`
`
`
`
`
`
`
`
`As the most preferred examples for R
`
`
`
`
`
`
`
`3
`
`
`4
`and R , R
`
`
`
`3
`
`
`is
`
`
`
`
`
`hydrogen and R
`
`4 is hydrogen, 4'~chloro or 4'-fluoro.
`
`
`
`
`
`
`5
`
`
`
`
`
`
`
`
`
`
`The most preferred examples for R
`include i-propyl
`_and cyclopropyl.
`The most preferred examp