Sawai Ex 1013
`Page 1 of 98
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`Sawai Ex 1013
`Page 2 of 98
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`Sawai Ex 1013
`Page 3 of 98
`
`

`
`4
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`'
`
`.
`
`-,
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`_
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`1
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`_
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`'2-115 3/3 m/h
`(1573/1589)
`
`éééoxrxcawxou
`
`1.TITLE OF THE INVENTION:_
`
`QUINOLINE TYPE MEVALONOLACTONES
`
`2.SCOPE OF THE CLAIMS:
`
`1.
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`A compound of the formula:
`
`3"
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`\\R R
`
`
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`4
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`Y-Z
`
`( I)
`
`R’
`N
`'
`i
`R‘
`wherein R1, R2, R3, R4 and R6 are independently hydrogen,
`
`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
`
`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_
`
`each other, R
`15
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`(wherein R
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`‘and R
`
`16
`
`are independently hydrogen or ¢l_3
`
`alkyl); Y is -CH2-,,-CHZCH2-,
`-CH=CH-,
`- _
`.
`~
`12
`-CH—CH-CH2—; and z 15 -Q:§d2yCH2-COZR ,
`R11
`
`-CH2-CH=CH- or
`
`-Ho OI‘
`
`Sawai Ex 1013
`
`Page 4 of 98
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`Sawai Ex 1013
`Page 5 of 98
`
`

`
`secondary Cl_6 alkyl or C3_6 cycloalkylz and Y is —CH2—CHf-
`or —CH=CH~; and Z is
`
`H0
`
`-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
`
`2
`
`and R
`
`6
`
`are both hydrogen, R1 is hydrogeh, 5-fluoro, 6-fluoro,
`
`7+fluoro, 8-fluoro, 5-chloro, 6—ch1oro, 7-chloro,
`8-chloro, 5-bromo, 6-bromo, 7—bromo, 8-bromo, 5-fiethyl,
`
`6-methyl, 7-methyl, 8-methyl, 5-methoxy, 6—methoxy,
`
`7—methoxy, 8-metroxy, 5-trggluoromethyl,
`
`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
`
`6-n-butyl or 7-dimethylamino; when R
`
`is hydrogen, R
`
`1
`
`and
`
`R2 together represent 6-chloro-8-methyl,
`
`§~bromo—7-methoxy, 6-methyl—7—chloro, 6—chloro—8—hydroxy,'
`
`5-methyl—2~hydroxy, 6-methoxy—7-chloro,
`
`6-ch1oro—7~methoxy, 6-hydroxy-7-chloro,
`
`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,
`
`Sawai Ex 1013
`
`Page 6 of 98
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`Sawai Ex 1013
`Page 7 of 98
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`Sawai Ex 1013
`Page 8 of 98
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`

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`Sawai Ex 1013
`Page 9 of 98
`
`

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`Sawai Ex 1013
`Page 10 of 98
`
`

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`Sawai Ex 1013
`Page 11 of 98
`
`

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`Sawai Ex 1013
`Page 12 of 98
`
`

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`Sawai Ex 1013
`Page 13 of 98
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`

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`Sawai Ex 1013
`Page 14 of 98
`
`

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`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
`
`

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`Sawai Ex 1013
`Page 18 of 98
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`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
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`both R2
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`and R
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`5
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`are hydrogen, R
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`1
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`is hydrogen, 5-f;uoro,
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`6-fluoro, 7-fluoro, 8-flgoro, S~chloro, 6-chloro,
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`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,
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`Gjtrifluoromethoxy, 6-difluoromethoxy, 8-hydroxyethyl,
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`5—hydroxy, 6-hydroxy, 7-hydroxy, B—hydroxy, 6—ethyl,
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`6-n—butyl and 7-dimethylamino.
`
`Wnen R
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`6
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`is hydrogen, R
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`1
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`2
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`and R
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`together represent
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`6—chloro-8-methyl, 6-bromo~7-methoxy, 6-methyl-7~chloro,
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`‘6—chloro-8-hydroxy, 5-methyl-2—hydroxy,
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`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
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`Sawai Ex 1013
`Page 21 of 98
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`

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`Sawai Ex 1013
`Page 22 of 98
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`

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`Sawai Ex 1013
`Page 23 of 98
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`

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`Sawai Ex 1013
`Page 24 of 98
`
`

`
`methy1ethyl)—6',7‘-dimethoxy-quinolin-3'-yll-hept-6—enoic
`
`acid
`
`(u)
`
`(E)-3,5-dihydroxy—7-[4'-phenyl—2'-cyc1opropyl-
`
`quinolin-3‘—y1]-hept—6—enoic.acid
`
`(v)A(E)-3,5-dihydroxy—7-[4'—phenyl-2'-cyclopropyl-6‘~
`
`chloro-quinolinf3'—yl]-hept-6—enoic acid
`(w)
`(E)~3,S-dihydroxy-7-[4‘-phenyl-2'-cyc1opropy1-6'-
`
`methyl—quinolin-3‘-yll-hept-6—enoic acid
`
`(E)-3,5-dihydroxy-7-[4'-phenylez'-cyc1opropy1-
`(x)
`6’,7’—dimethoxy-quinolin-d‘-y1]~hept-64enoic acid
`(YT (E)-3,5-digydroxy-7-[4'—(4"-fluorophenyl)~2‘-
`(l"~meth¥lethyli-6'4methoxy—quino1in—3'-Y1]-hept-6-enoic
`
`acid
`
`(E)-3,5~dihydroxy=f§[4'—(4"—f1uoropheny1)—2'4
`(2)
`‘cyclopropyl-6'¥methoxy—quifi§}in~3'vy1]-hept~6—enoic acid
`- The mevalonolactones o£:%he formula I can be prepared
`
`by the following reaction scheme.
`
`yhe enal III can also
`
`_ be prepared by processes K, L and M;
`
`Sawai Ex 1013
`
`Page 25 of 98
`
`

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`Sawai Ex 1013
`
`Page 26 of 98
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`

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`Sawai Ex 1013
`
`Page 27 of 98
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`

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`Sawai Ex 1013
`
`Page 28 of 98
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`

`
`.._ 26 _
`
`3 S
`
`-.-
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`awai Ex 1013
`
`Page 29 of 98
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`

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`Sawai Ex 1013
`
`Page 30 of 98
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`Sawai Ex 1013
`Page 31 of 98
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`

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`Sawai Ex 1013
`Page 32 of 98
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`Sawai Ex 1013
`Page 33 of 98
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`Sawai Ex 1013
`Page 34 of 98
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