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`07/883,398
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`QUINOLINE TYPE MEVALONOLACTONES
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`342163US
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`Bibliographic Data
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`Application Number: O7/883,398
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`Correspondence
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`Address Customer
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`Number:
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`22850
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`05-15-1992
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`Status:
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`Status Date:
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`Location:
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`Location Date:
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`Earliest Publication
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`No:
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`Earliest Publication
`Date:
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`Patent Number:
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`Patented Case
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`01-04-1999
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`ELECTRONIC
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`5,856,336
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`Issue Date of Patent: O1-05-1999
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`International
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`International
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`Utility
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`STOCKTON, LAURA LYNNE
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`1613
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`3046
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`342163US
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`Filing or 371 (c)
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`514/311
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`YOSHIHIRO FUJIKAWA ,
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`FUNABASHI, (JP)
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`First named
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`QUINOLINE TYPE MEVALONOLACTONES
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`07/883,398
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`QUINOLINE TYPE MEVALONOLACTONES
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`342163US
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`Page 1 of 1
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`Parent Continuity Data
`Parent
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`O7/631,092
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`DeS°'"’“°"
`This application is a
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`Division of
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`O7/233,752
`is a continuation of
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`Child Continuity Data
`07/978,884 filed on 11-19-1992 which is Patented claims the benefit of 07/883,398
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`12-19-1990
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`08-19-1988
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`No
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`Patented
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`5,872,130
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`Abandoned
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`07/883,398
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`QUINOLINE TYPE MEVALONOLACTONES
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`342163US
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`08-02-2013
`PARALEGAL OR ELECTRONIC TERMINAL DISCLAIMER APPROVED
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`Terminal Disclaimer Filed
`07-31-2013
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`Patent Term Extension Certificate
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`Notice of Final Determination -Eligible
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`FDA Final Eligibility Letter
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`transaction for FDA Determination of Regulatory Review Period
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`Initial letter Re: PTE Application to regulating agency
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`Patent Term Extension Application under 35 USC 156 Filed
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`m:
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`JAl'A-v'; MASAKI KITAHARAi, SA'I TAMA-KEN, JAPAN,
`
`GROUP ART UNIT
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`01/26/88
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`
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`COUNTRY DRWQS.
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`
`TOTAT
`ATTORNEYS
`IflUMOFEE
`INDEP,
`CLAIMS
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`CLAIMS RECEIVED
`49-1.6B-^-DIV
`35
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`U p o
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`^ IflKi .nd AcMnowM^fftd •
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`IN RE APPLICATION OP;
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`YOBHIHIRO FUJIKAWA ET AL
`SERIAL NO.: NEW DIV APPLN
`EXAMINER: RICHTER
`OF 07/631,092
`:
`FILED: HEREWITH
`FOR: QDINOLINB TYPE MEVALONOLACTONES
`SIR:
`Attached hereto for filing are the following papers:
`DIVISIONAL APPLICATION, NOTICE OF PRIORITY, EXECUTED DECLARATION
`OF KELBER, PRELIMINARY AMENDMENT, AND UNEXECUTED DECLARATION OF
`MASAKI KITAHARA/WITH FEES
`Our check in the amount of $690.00 is enclosed covering any
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`In the event of any variance between the amount
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`the difference to our Deposit Account No. 15-0030. A duplicate
`copy of this letter is enclosed.
`Respectfully submitted,
`OBLON^SPIVAK, McCLELLAND,
`MAI
`STAl
`P.C.
`
`•Ntfrman F. 'oblon
`Registration No.: 24,618
`Steven B. Kelber
`Registration No.: 30,073
`Attorneys of Record
`
`Sawai Ex 1002
`Page 7 of 266
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`i7883398
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`IN
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`ICATION OP;
`IKAWA ET AL
`IA
`07/631/ 092
`v
`>332 A.*.
`:
`Fn^^gjKfflGMBER 19, 199 0
`FOR: QUINOLINE TYPE MEVALONOLACTONES
`
`GROUP ART UNIT: 129
`EXAMINER: J. RICHTER
`
`DECLARATION
`HONORABLE COMMISSIONER OF PATENTS S TRADEMARKS
`WASHINGTON, D.C. 20231
`SIR;
`I, STEVEN B. KELBER, declare the attached to be a true and
`accurate copy, as filed, of U.S. Patent Application Serial Number
`07/631,092 filed December 19, 1990 which ia a continuation of
`07/233,752, filed August 19,1988.
`The undersigned declares further that all statements made
`herein of his own knowledge are true and that all statements made
`on information and belief are believed to be true; and further that
`these statements were made with the knowledge that willful false
`statements and the like so made are punishable by fine or
`imprisonment, or both, under Section 1001 of Title 18 of the United
`States Code and that such willful false statements may jeopardize
`the validity of the application or any patent issuing thereon.
`Respectfully submitted,
`OBLON, SPIVAK, McCLELLAND,
`NEUS^y,^P^C. ^
`MAi:
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`an
`.Obion
`Attorney of Record
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`Steven B. Kelber
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`Sawai Ex 1002
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`. - ^
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`"I .'/^MSCK
`>S MA* V
`15 V '9S2 Ay
`N^flrtvy
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`V v-.
`
`Our Ref.: NC-115
`
`1
`QUINOLINE TYPE MSVALONOLACTONES
`The present invention relates to novel
`mevalon'olactones having a quinoline ring, processes for
`their production, pharmaceutical compositions containing
`them and their pharmaceutical uses particularly as
`anti-hyperlipidemic, hypolipoproteinemic and
`anti-atherosclerotic agents, and intermediates useful for
`their production and processes for the production of such
`intermediates.
`Some fermentation metabolic products such as
`compactine, CS-514, Mevinolin or semi-synthetic
`derivatives or fully synthetic derivatives thereof are
`known to be inhibitors against HMG-CoA reductase which is
`a rate limiting enzyme for cholesterol biosynthesis.
`Endo J. Med Chera., 28(4) 401 (1985))
`CS-514 and Mevinolin have been clinically proved to be
`potentially useful anti-hyperlipoproteinemic agents, and
`they are considered to be effective for curing or
`preventing diseases of coronary artery sclerosis or
`atherosclerosis.
`(IXth Int. Symp. Drugs Affect. Lipid
`
`( A .
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`5
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`10
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`15
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`20
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`Page 9 of 266
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`/> "
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`V
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`c
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`A i' tl
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`5
`t
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`15
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`20
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`25
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`Metab., 1986, p30f p31, p66)
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`However, with respect to fully synthetic derivatives,
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`particularly hetero aromatic derivatives of inhibitors
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`against HMG-CoA reductase, limited information is
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`disclosed in the following literatures:
`
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`WPI ACC NO. 84-158675, 86-028274, 86-098816,
`
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`86-332070, 87-124519, 87-220987, 88-07781, 88-008460,
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`88-091798 and 88-112505.
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`The present inventors have found that mevalonolactone
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`10 derivatives having a quinoline ring, the corresponding
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`dihydroxy carboxylic acids and salts and esters thereof
`
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`have high inhibitory activities against cholesterol
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`biosynthesis wherein HMG-CoA reductase acts as a rate
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`limiting enzyme,
`The present invention has been
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`accomplished on the basis of this discovery.
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`The novel mevalonolactone derivatives of the present
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`invention are represented by the following formula I:
`
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`R4
`
`R3
`
`
`
`R2
`
`
`Y-Z
`
`( I )
`
`
`O
`"N" R5
`R
`
`are independently hydrogen,
`R4 and
`wherein R1, R2, R3
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`C1_g alkyl, C3_g cycloalkyl, C1_3 alkoxy, n-butoxy,
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`
`
`
`7
`i-butoxy, sec-butoxy, R R N- (wherein R and R
`8
`*7 Q
`are
`
`
`
`
`
`
`
`
`independently hydrogen or C1_3 alkyl), trifluoromethyl,
`
`
`
`
`
`
`trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo,
`
`
`
`
`
`
`Sawai Ex 1002
`Page 10 of 266
`
`

`
`r / V
`
`A"
`
`S ^ .
`
`3
`phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy,
`19
`diphenyl-t-butylsilyloxy, hydroxymethyl or -CHCF^jiPR
`19
`(wherein R
`is hydrogen or C1_3 alkyl, and £ is 1, 2 or
`3); or when located at the ortho position to each other,
`1
`2
`3
`4
`R and R , or R and R. together * formJ-CH=CH-CH=CH-
`I or
`when located at the ortho position to each other, R'1' and
`-OC(R15)(R16)0- (wherein R15 and R16 are
`independently hydrogen or
`alkyl); Y is -CH2-,
`-CH2CH2-, -CH=CH-, -CH2-CH=CH- or -CH=CH-CH2-; and Z is
`-Q-CH2WCH2-CO2R 12
`
`1 R2 together^forn\
`
`i
`
`I
`\t ^
`
`5
`
`i.'-v
`
`10
`
`15
`
`/ HO
`
`0
`
`0
`
`0
`
`C 02R, S
`
`R
`1 7
`/
`R '3
`0
`
`or
`13
`(wherein Q is -C(O)-, -C(0R"j)2- or -CH(OH)-; W is -C(O)-,
`-C{OR13)2- or ^(R11)(OH)-; R11 is hydrogen or C1_3 alkyl;
`R12 is hydrogen or R14 (wherein R14 is physiologically
`20 hydrolyzable alkyl or M (wherein M is NH4, sodium,
`potassium, 1/2 calcium or a hydrate of lower alkylamine,
`di-lower alkylamine or tri-lower alkylamine)); two R13 are
`13
`independently primary or secondary C^_g alkyl; or two R
`R17 and R18
`are
`together form -(CH2)2- or
`25 independently hydrogen or C-^
`R5 is
`hydrogen, C1_6 alkyl, C2_3 alkenyl, C3_6 cycloalkyl,
`9
`-/oO (wherein R is hydrogen,
`
`30
`
`1 'i >.
`
`/j
`
`alkyl r
`
`Sawai Ex 1002
`Page 11 of 266
`
`

`
`
`
`r
`
`
`
`
`
`
`
`4
`
`
`alkoxy, fluoro, chloro, bromo or trifluoromethyl)f
`
`
`
`
`
`
`
`
`phenyl-(wherein m is 1, 2 or 3),
`
`
`
`
`
`
`
`-(CH2)nCH( ) - p h e n y i o r p h e n y l - ( C H2)nC H ( C H3) -
`
`
`is 0, 1 or 2).
`
`
`
`
`
`
`( w h e r e i n n
`
`
`
`5
`
`
`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.
`
`
`10
`
`
`
`
`
`
`
`
`
`
`
`
`
`f o r r 1' r 2' r 3' r 4' r 6 a n d r 9 includes, for
`
`Cl-6
`
`example, methyl, ethyl, n-propyl, i-propyl, n-butyl,
`
`
`
`
`
`
`1 2
`
`
`i-butyl, sec-butyl and t-butyl. ^1-3 alkoxy for R , R ,
`
`
`
`
`
`
`
`
`
`
`
`R3, R4 and R6 includes, for example, methoxy, ethoxy,
`
`
`
`
`
`
`
`
`
`
`n-propoxy and i-proppxy.
`
`
`
`
`
`15
`
`C1_3 alkyl for R1 1 includes, for example, methyl,
`
`
`
`
`
`
`
`
`ethyl, n-propyl and i-propyl-
`
`
`
`
`
`
`alkyl for R^ includes, for example, methyl,
`
`
`
`
`
`
`
`
`
`ethyl, n-propyl and i-propyl.
`
`
`
`
`
`Alkyl for
`
`
`
`
`
`includes, for example, methyl, ethyl,
`
`
`
`
`
`
`20 n-propyl, i-propyl, n-butyl and i-butyl.
`
`
`
`
`
`
`
`M is a metal capable of forming a pharmaceutically
`
`
`
`
`
`
`
`
`acceptable salt, and it includes, for example, sodium and
`
`
`
`
`
`
`
`
`
`
`potassium.
`
`CC^M includes, for example, -CC^NH^ and -C02H*
`
`
`
`
`
`
`
`25 (primary to tertiary lower alkylamine such as
`
`
`
`
`
`
`
`
`
`trimethylamine).
`
`
`5
`
`alkyl for R includes, for example, methyl,
`
`
`
`
`
`
`
`
`
`Sawai Ex 1002
`Page 12 of 266
`
`

`
`
`
`
`r* V.
`
`
`
`
`
`
`
`ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,
`
`
`
`
`
`
`
`5
`
`
`t-butyl, n-pentyl and n-hexyl.
`
`
`
`
`
`cycloalkyl for R includes, for example,
`
`
`
`
`
`
`cyclopropyl; cyclobutyl, cyclopentyl and cyclohexyl.
`
`
`
`
`
`
`5
`Cj.g alkenyl for R includes, for example, vinyl and
`
`
`
`
`
`
`
`
`i-propenyl.
`
`
`Phenyl-(CH2)m- for
`
`
`
`
`
`
`includes, for example, benzyl,
`
`
`
`
`
`
`5
`
`10
`
`
`/3-phenylethyl and y-phenylpropyl.
`
`
`
`
`
`Phenyl-(CH2)nCH(CH2)- for
`
`
`includes, for example,
`
`
`
`
`a-phenylethyl and a-benzylethyl.
`
`
`
`8 includes, for example,
`7
`
`
`
`
`
`
`
`
`alkyl for R and R
`
`methyl, ethyl, n-propyl and i-propyl.
`
`
`
`
`
`
`Further, these compounds may have at least one or two
`
`
`
`
`
`
`
`
`
`
`
`asymmetric carbon atoms and may have at least two to four
`
`
`
`
`
`
`
`
`
`
`
`
`
`15
`
`optical isomers. The compounds of the formula I include
`
`
`
`
`
`
`
`
`
`
`all of these optical isomers and all of the mixtures
`
`
`
`
`
`
`
`
`
`
`
`thereof.
`
`
`Among compounds having carboxylic acid moieties
`
`
`
`
`
`
`12 of the
`
`falling outside the definition of -CC^R
`
`
`
`
`
`
`
`carboxylic acid moiety of substituent Z of the compounds
`
`
`
`
`
`
`
`
`
`
`20
`
`
`of the present invention, those which undergo
`
`
`
`
`
`
`
`
`physiological hydrolysis, after intake, to produce the
`
`
`
`
`
`
`
`
`corresponding carboxylic acids (compounds wherein the
`
`
`
`
`
`
`12
`-CO2R
`
`moiety is -CC^H) are equivalent to the compounds
`
`
`
`
`
`
`
`
`of the present invention.
`
`
`
`
`
`25
`
`
`Now, preferred substituents of the compounds of the
`
`
`
`
`
`
`
`
`
`present invention will be described.
`
`
`
`
`
`
`Sawai Ex 1002
`Page 13 of 266
`
`

`
`r r*.
`
`
`C'
`
`
`
`
`
`6
`
`
`In the following preferred, more preferred still
`
`
`
`
`
`
`
`
`further perferred and most preferred examples, the
`
`
`
`
`
`
`
`
`numerals for the positions of the substituents indicate
`
`
`
`
`
`
`
`
`
`the positions on the quinoline ring. For example, N1
`
`
`
`
`
`
`
`
`
`
`5
`
`
`shown by e.g. 1' 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 1'). The meanings of the respective
`
`
`
`
`
`
`
`
`
`
`
`substituents are the same as the above-mentioned meanings.
`
`
`
`
`
`
`
`
`1
`2
` 6
`
`Preferred substituents for R , R and R are hydrogen,
`
`
`
`
`
`
`
`
`
`alkoxy, C3_g
`alkyl,
`fluoro, chloro, bromo,
`
`
`
`
`
`
`
`
`cycloalkyl, dimethylamino, hydroxy, hydroxymethyl,
`
`
`
`
`hydroxyethyl, trifluoromethyl, trifluoromethoxy,
`
`
`
`
`difluoromethoxy, phenoxy and benzyloxy.
`
`
`
`
`
`
`
`is hydrogen, it is preferred that R"1"
`
`
`
`
`
`
`
`
`Further, when
`
`
`2
`
`and R together form methylenedioxy.
`
`
`
`
`4
`4
`• 3
`As preferred examples for R and R r when R is
`
`
`
`
`
`
`
`
`
`
`3
`hydrogen, R is hydrogen, 3'-fluoro, 3'-chloro, 3'-methyl,
`
`
`
`
`
`
`
`
`10
`
`
`15
`
`
`4'-methyl, 4'-chloro and 4'-fluoro.
`
`
`
`
`
`20
`
`
`4
`3
`Other preferred combinations of R and R include
`
`
`
`
`
`
`
`
`
`3 '-methyl-.4'-chloro, 3' jB'-dichloro, 3',5'-difluoror
`
`
`
`
`
`
`
`
`
`
`
`
`3',51-dimethyl and 3'-methyl-4'-fluoro.
`
`
`
`
`
`
`5
`Preferred examples for R include primary and
`
`
`
`
`
`
`
`secondary C^g alkyl and
`
`
`
`
`
`Preferred examples for Y include
`
`
`
`
`
`
`cycloalkyl.
`
`
`25
`
`
`and
`
`
`-CH=CH-.
`
`
`Preferred examples for Z include
`
`
`
`
`
`
`
`
`
`
`Sawai Ex 1002
`Page 14 of 266
`
`

`
`rr»
`
`f 'v '
`
`t
`
`HO
`
`7
`
`0
`
`0
`
`0
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`12
`-CH(0H)CH2CH2(0H)CH2C02R12, -CH(0H)CH2C<0)CH2C02RJ-*' and
`-CH{0H)CH2C{0R13)2CH2C02R12.
`Now, more preferred substituents of the compounds of
`the present invention will be described.
`
` 6
`1
`2
`As more preferred examples for R , R and R , when
`both R2 and R6 are hydrogen, R1 is hydrogen, 5-fluoro,
`6-fluoro, 7-fluoro, 8-fluoro, 5-chloro, 6-chloro,
`7-chloro, 8-chloro, 5-bromo, 6-bromo, 7-bromo, 8-bromo,
`5-methyl, 6-methyl, 7-niethyl, 8-methyl, 5-methoxy,
`6-methoxy, 7-iiiethoxy, 8-methoxy, 5-trifluoromethyl,
`6-trifluoromethyl, 7-trifluoromethyl, 8-trifluoromethyl,
`6-trifluoromethoxy, 6~difluoromethoxy, 8-hydroxyethyl,
`5-hydroxy, 6-hydroxy, 7-hydroxy, 8-hydroxy, 6-ethyl,
`6-n-butyl and 7-dimethylaniino.
`
`6
` 1
`2
`When R is hydrogen, R and R together represent
`6-chloro-8-inethyl, 6-bronio-7-methoxy, 6-methyl-7-chloro,
`6-chloro-8-hydroxy, 5-methyl-2-hydroxy,
`6~methoxy-7-chloro, 6-chloro-7-methoxy,
`6-hydroxy-7-chloro, 6-chloro-7-hydroxy, 6-chloro-8-bromo,
`5-chloro-6-hydroxy, 6-bromo-8-chloro, 6-bromo-8-hydroxy,
`5-tnethyl-8-chloro, 7-hydroxy-8-chloro, 6-bromo-8-hydroxy,
`6-methoxy-7-methyl, 5-chloro-8-bromo, 6-methyl-8-bromo,
`
`V
`
`Sawai Ex 1002
`Page 15 of 266
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`8
`
`
`6.7-difluoro, 6,8-difluoro, 6,7-methylenedioxy,
`
`
`
`
`6.8-dichloro, 5,8-diinethyl, 6, S-dimethyl, 6,7~dimethoxy,
`
`
`
`
`
`6,7-diethoxy, 6,7-dibromo or 6,8-dibromo.
`
`
`
`
`
` 6
`2
`1
`
`
`
`
`
`
`
`
`
`
`When R , R and R are not hydrogen, they together
`represent 5,7-dimethoxy-8-hydroxy, B/S-dichloro-e-hydroxy,
`
`
`
`6,7,8-trimethoxy, 6,7,8-trimethyl, 6,7,8-trichloro,
`
`
`
`
`
`5
`
`5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo.
`
`
`
`
`As more preferred examples for R3 and
`
`
`
`
`
`
`
`
`, when R3 is
`
`
`
`
`
`When both R3 and R4 are not hydrogen, they
`
`
`
`
`
`
`
`
`
`
`hydrogen, R4 is hydrogen, 4'-methyl, 4,-chloro or
`
`
`
`
`
`
`
`10 4'-fluoro.
`
`
`together represent 3',51-dimethyl or 3l-methyl-4'-fluoro.
`
`
`
`
`
`
`c
`As more preferred examples for R , the above-mentioned
`
`
`
`
`
`
`
`
`5
`
`. preferred examples of R may be mentioned.
`
`
`
`
`
`
`
`As preferred examples for Y, -CH2-CH2- and (E)—CH=CH-
`
`
`
`
`
`
`
`15
`
`
`may be mentioned.
`
`
`
`
`
`As more preferred examples for Z, the
`
`
`
`
`
`
`
`above preferred examples for z may be mentioned.
`
`
`
`
`
`
`
`Now, still further preferred substituents of the
`
`
`
`
`
`
`
`
`
`
`
`compounds of the present invention will be described.
`
`
`
`
`
`1 2
`2
`6
`6
`
`
`
`
`
`
`
`
`examples for R , R and R , when both R and R
`
`
`
`
`hydrogen, R1 is hydrogen, 6-methyl, 6-ethyl,
`
`
`
`
`
`are
`
`
`
`20
`
`As
`
`
`6-trifluoromethyl, 6-hydroxy, 6-methoxy, 6-chloro,
`
`
`
`
`
`6-bromo, 6-n-butyl and 7-dimethylamino.
`
`
`
`
`
`
`2
`6
`1
`When only R is hydrogen, R and R represent
`
`
`
`
`
`
`
`
`
`
`6,8-dichloro, 5,8-dimethyl, 6,8-dimethyl, 6,7-dimethoxy,
`
`
`
`
`
`25
`
`
`6.7-diethoxy, 6,7-dibrorno, 6,8-dibromo, 6,7-difluoro and
`
`
`
`
`
`
`6.8-difluoro.
`
`
`3
`As still further preferred examples for R
`
`
`
`
`
`
`
`
`4
`and R ,
`
`
`
`Q
`
`
`Sawai Ex 1002
`Page 16 of 266
`
`

`
`t'*'
`
`r
`
`
`
`
`
`9
`
`
`
`
`
`
`
`
`
`
`when R3 is hydrogen, R4 is hydrogen, 4,-chloro or
`
`
`
`
`
`
`
`
`
`
`
`4
`3
`4I-fluoro/ or R and R together represent
`
`
`
`
`
`
`
`3 ' -niethyl-4' -f luoro.
`
`Still further preferred examples for R
`
`
`
`
`
`n-propyl, i-propyl and cyclopropyl.
`
`
`
`
`
`c
`
`
`include ethyl,
`
`
`
`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.
`
`
`
`
`
`
`
`
` 6
`2
`1
`As the most preferred examples for R , R and R , when
`
`
`
`
`
`
`
`
`
`
`
`1
`6
`2
`both R and R are hydrogen., R is hydrogen, 6-methyl or
`
`
`
`
`
`
`
`
`
`
`
`
`5
`
`
`10
`
`
`6-chloro.
`
`
`
`15 '
`
`1 5
`6
`
`
`
`
`
`
`
`
`
`When only R is hydrogen, R and R together
`
`represent, for example, 6,7-dimethoxy.
`
`
`
`
`
`4 3
`3
`As the most preferred examples for R and R , R is
`
`
`
`
`
`
`
`
`
`
`
`4
`hydrogen and R is hydrogen, 4'-chloro or 4'-fluoro.
`
`
`
`
`
`
`
`
`5
`
`The most preferred examples for R include i-propyl
`
`
`
`
`
`
`
`
`20 and cyclopropyl. The most preferred example for Y may be
`
`
`
`
`
`
`
`
`
`
`
`
`
`(E)—CH=CH-.
`
`
`As the most preferred examples for Z, the
`
`
`
`
`
`
`
`
`
`
`above-mentioned preferred examples for Z may be mentioned.
`
`
`
`
`
`
`
`
`
`Now, particularly preferred specific compounds of the
`
`
`
`
`
`
`
`
`25 present invention will be presented. The following
`
`
`
`
`
`
`
`
`
`compounds (a) to (z) are shown in the form of carboxylic
`
`
`
`
`
`
`
`
`
`
`
`
`acids. However, the present invention include not only
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sawai Ex 1002
`Page 17 of 266
`
`

`
`
`
`
`
`
`
`
`
`
`10
`
`
`the compounds in the form of carboxylic acids but also the
`
`
`
`
`
`
`
`
`
`
`
`
`corresponding lactones formed by the condensation of the
`
`
`
`
`
`
`
`
`
`carboxylic acids with hydroxy at the 5-position, and
`
`
`
`
`
`
`
`
`
`sodium salts and lower alkyl esters (such as methyl,
`
`
`
`
`
`
`
`
`
`
`
`5
`
`ethyl, i-propyl and n-propyl esters) of the carboxylic
`
`
`
`
`
`
`
`
`
`acids, which can be physiologically hydrolyzed to the
`
`
`
`
`
`
`
`
`
`carboxylic acids.
`
`
`
`
`
`
`(E)-3,5-dihydroxy-7-[4'-(4''-fluorophenyl)-2 (a)
`
`
`(1
`
`10
`
`
`-methylethyl)-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(b)
`(E)-3,5-dihydroxy-7-[41 -(4
`
`
`
`-fluorophenyl)-2
`
`-methylethyl)-61-chloro-quinolin-3'-yl]-hept-6-enoic
`
`
`(1
`acid
`
`
`
`
`(E)-3,5-dihydroxy-7-t4,-(41'-fluorophenyl)-2'-(c)
`
`
`(1' ' -methylethyl) -61 -niethyl-quinolin-3' -yl ] -hept-6-enoic
`
`
`15
`
`
`acid
`
`
`(d) (E)-3,5-dihydroxy-7-141-(4'1-fluorophenyl)-2
`
`
`
`(111-methylethyl)-6',7•-dimethoxy-quinolin-31-yl]-hept-6-
`
`
`
`enoic acid
`
`
`
`(e) (E)-3/5-dihydroxy-7-[4'-{41'-fluorophenyl)-2'-
`
`
`
`20
`
`
`cyclopropyl-quinolin-31-yl]-hept-6-enoic acid
`
`
`
`(f) (E)-3,5-dihydroxy-7-[41-{411-fluorophenyl)-2'-
`
`
`
`cyclopropyl-61-chloro-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`( g ) (Ej- S f B-dihydroxy^-^'-^' '-fluorophenyl)-2
`
`
`
`cyclopropyl-61-methyl-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`25
`
`
`(h) (E)-3,5-dihydroxy-7-[4'-(4''-fluorophenyl)-2
`
`
`cyclopropyl-6',7'-dimethoxy-quinolin-3'-yl]-hept-6-enoic
`
`
`
`acid
`
`
`Sawai Ex 1002
`Page 18 of 266
`
`

`
`
`
`11 * •
`
`r
`
`
`
`
`t
`
`
`
`11
`
`
`..(i) (E)-3 ,5-dihydroxy-7- [4' -{41 *-chlorophenyl)-2
`
`
`
`[I1•-methylethyl>-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(j) (E)-3,5-dihydroxy-7-[41-(4'1-chlorophenyl)-21 -
`
`
`(111-methylethyl)-6'-chloro-quinolin-3'-yl]-hept-6-enoic
`
`
`
`5
`
`
`acid
`
`
`(E)-3,5-dihydroxy-7-[4,-(4''-chlorophenyl)-2'-
`<k)
`
`
`{111-methylethyl)-6'-methyi-quinolin-3'-yl]-hept-6-enoic
`
`
`acid
`
`
`(1) (E)-3,5-dihydroxy-7-[4'-(4l1-chlorophenyl)-2'-
`
`
`10 {1' '-methylethyl)-67'-diinethoxy-quinolin-3 '-yl]-hept-6-
`
`
`
`enoic acid
`
`
`
`(E)-3,5-dihydroxy-7-{4,-(4'•-chlorophenyl)-2
`(m)
`
`
`cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(E)-3,5-dihydroxy-7-[4'-(4''-chlorophenyl)-2'-
`(n)
`
`
`
`
`15
`
`cyclopropyl-61-chloro-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(E)-3,5-dihydroxy-7-[41-(4'1-chlorophenyl)-21 -
`(o)
`
`
`
`
`
`
`
`cyclopropyl-6'-methyl-quinolin-3'-yl1-hept-6-enoic acid
`
`
`-chlorophenyl)-2
`
`
`
`
`
`(E)-3,5-dihydroxy-7-[4'-(4 (p)
`
`
`cyclopropyl-6' 7 ' -diiiiethoxy-quinolin-3 ' -yl] -hept-6-enoic
`
`
`20 acid
`
`
`
`(q) (Ej-S^-dihydroxy^-N'-phenyl^'-d1 '-
`
`
`
`methylethyl)-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`{r) (E)-3,5-dihydroxy-7-[41-phenyl-2'-{1
`
`
`methylethyl)-61-chloro-quinolin-31 -yl]-hept-6-enoic acid
`
`
`
`
`25
`
`{s) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-(1
`
`
`
`
`methylethyl)-6'-methyl-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(t) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-(1'
`
`
`
`Sawai Ex 1002
`Page 19 of 266
`
`

`
`
`
`
`
`
`
`
`
`
`
`t ' * '
`
`
`
`*
`
`
`
`
`12
`
`
`,7'-dimethoxy-quinolin-3'-yl]-hept-6-enoic
`methylethyl)-6
`
`
`
`acid
`
`
`(u) (E)-3,5-dihydroxy-7-[41-phenyl-2*-cyclopropyl-
`
`
`quinolin^3'-yl]-hept-6-enoic acid
`
`
`
`5
`
`
`(v) (E}-3,5-dihydroxy-7-[4'-phenyl-21-cyclopropyl-6
`
`
`chloro-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(w) (E)-3,5-dihydroxy-7-[4'-phenyl-21-cyclopropyl-61 -
`
`
`methyl-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`(x) (E)-3,5-dihydroxy-7-[41-phenyl-2'-cyclopropyl-
`
`6',7'-dimethoxy-quinolin-31-ylJ-hept-6-enoic acid
`
`
`
`10
`
`
`(y) (EJ- S f S-dihydroxy-?-^'-^' '-fluorophenyl)-2'-
`
`
`
`(1'•-methylethyl)-6'-methoxy-quinolin-3'-yl]-hept-6-enoic
`
`
`acid
`
`(2)
`(E)-3,5-dihydroxy-7-[4'-(411-fluorophenyl)-2'-
`
`
`
`15
`
`
`cyclopropyl-61-methoxy-quinolin-3'-yl]-hept-6-enoic acid
`
`
`
`The mevalonolactones of the formula I can be prepared
`
`
`
`
`
`
`
`
`
`
`by the following reaction scheme,
`
`
`
`
`
`
`The enal III can also
`
`
`
`
`
`
`be prepared by processes K, L and M.
`
`
`
`
`
`
`
`
`
`
`
`
`Sawai Ex 1002
`Page 20 of 266
`
`

`
`\
`
`t
`
`«13 ^
`
`• -Y
`
`R1
`
`8>
`
`R
`R2
`
`w
`
`a
`
`R*
`
`2 J
`
`CO^R
`s
`
`B3
`
`6
`
`>
`
`R'
`RS
`
`$
`
`CII*0«
`R3
`
`VI
`
`R'
`
`R4
`
`« »
`
`RJ
`R'
`
`CHO
`R5
`
`^9
`V
`
`R3
`fi. .
`
`R*
`
`RS
`
`o "fT
`
`IV
`
`C
`
`->
`
`R'
`
`OCt
`OH
`
`•>
`
`D
`
`/I
`
`Sawai Ex 1002
`Page 21 of 266
`
`

`
`\
`
`
`>'< *
`
`1
`
`
`
`- 14
`
`
`COiR
`
`1 z
`
`0
`
`OH
`
`R 6
`
`E > Rl
`
`R'
`
`V
`
`R4
`
`Lo N *'
`
`I
`
`R1
`
`COjR
`I 2
`
`Oil
`
`OH
`
`COiR11
`
`R3
`
`R4
`
`o ""N"
`
`R1
`R5
`R
`I - 2 (R'*-H)
`I - 5 {R1 I = Ha)
`
`R1
`
`h
`
`D
`
`R 2'
`
`R'
`
`R4
`
`CHO
`
`o vr
`
`R1
`
`I
`
`Oil
`
`Oil
`
`R1
`
`R4
`
`o "N"
`
`R1
`
`1 - 1
`
`St
`
`B*
`H1
`
`
`
`Sawai Ex 1002
`Page 22 of 266
`
`

`
`s
`
`4 •*
`
`»'' •
`
`-15
`
`Oli
`
`0 0
`
`R3
`
`R4
`
`or W
`
`B5
`
`I - 3
`
`PJ
`
`»'
`B
`
`0«
`
`0 0
`
`R*
`
`R4
`
`B *
`B'
`
`9^ »>
`
`I - 4
`
`lb
`
`Sawai Ex 1002
`Page 23 of 266
`
`

`
`\
`
`J*' •'
`
`*
`
`- 16 -
`
`fi4
`
`R1
`
`>
`
`RJ
`
`6
`
`R4
`
`z z
`COjR
`
`R *
`
`R1
`
`9
`
`C R O
`
`Rs
`
`V
`
`K
`
`^ R '
`
`R1
`
`k
`
`L
`
`•>
`R8
`
`R '
`
`Ra
`
`R4
`
`C H r O i l
`
`o " N ' R3
`
`K
`
`6
`
`M
`
`•>
`
`Rz
`
`R
`
`Q
`
`R5
`
`vu
`R3
`
`->
`
`L
`
`R-
`
`CHO
`
`9-
`
`ffi
`
`R '
`
`Sawai Ex 1002
`Page 24 of 266
`
`

`
`- 17 -
`
`OH
`
`OH
`
`R'
`
`R*
`
`Rl
`R1
`
`9-
`
`J - I
`
`R5
`
`•CO.R"
`
`R'
`
`R4
`
`OH
`
`0
`
`COiR
`11
`
`N
`
`R'
`R
`
`R!
`
`I - 6
`
`Sawai Ex 1002
`Page 25 of 266
`
`

`
`18
`
`In the above reaction scheme, R"*", R^, R"^, R^r ^
`
`
`
`
`
`
`
`
`
`
`
`are as defined above with respect to the formula
`and
`
`
`
`
`
`
`
`
`
`
`
`I, and R21 and R22 independently represent C1_4 lower
`
`
`
`
`
`
`
`
`
`alkyl such as methyl, ethyl, n-propylr i-propyl or
`
`
`
`
`
`
`
`
`n-butyl.
`
`Step A represents a reduction reaction of the ester to
`
`
`
`
`
`
`
`
`
`
`Such reduction reaction can be
`a primary alcohol,
`
`
`
`
`
`
`
`
`conducted by using various metal hydrides, preferably
`
`
`
`
`
`
`
`diisobutylaluminium hydride, in a solvent such as
`
`
`
`
`
`
`
`tetrahydrofuran or toluene at a temperature of from -20 to
`
`
`
`
`
`
`
`
`
`
`20oC, preferably from -10 to 10oC.
`
`
`
`
`
`
`Step B represents an oxidation reaction of the primary
`
`
`
`
`
`
`
`
`
`alcohol to an aldehyde, which can be conducted by using
`
`
`
`
`
`
`
`
`
`
`Preferably, the reaction can be
`various oxidizing agents.
`
`
`
`
`
`
`
`
`conducted by using pyridinium chlorochromate in methylene
`
`
`
`
`
`
`
`chloride at a temperature of from 0 to 250Cr or by using
`
`
`
`
`
`
`
`
`
`
`
`
`oxalyl chloride, dimethyl sulfoxide and a tertiary amine
`
`
`
`
`
`
`
`
`such as triethylamine (Swern oxidation), or by using a
`
`
`
`
`
`
`
`
`
`sulfur trioxide pyridine complex.
`
`
`
`
`Step C represents a synthesis of a
`
`
`
`
`
`
`
`3-ethoxy-l-hydroxy-2-propene derivative, which can be
`
`
`
`
`
`prepared by reacting a compound V to lithium compound
`
`
`
`
`
`
`
`
`
`which has been preliminarily formed by treating
`
`
`
`
`
`
`
`cis-l-ethoxy-2-(tri-n-butylstannyl)ethylene with butyl
`
`
`
`lithium in tetrahydrofuran.
`
`
`
`As the reaction temperature, it is preferred to employ
`
`
`
`
`
`
`
`
`
`
`
`a low temperature at a level of from -60 to ~780C.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5
`
`
`10
`
`
`15
`
`
`20
`
`
`25
`
`
`I • /
`
`
`Sawai Ex 1002
`Page 26 of 266
`
`

`
`
`
`. * •
`
`
`
`
`
`5
`
`
`10
`
`
`15
`
`
`20
`
`
`25
`
`
`19
`
`Step D represents a synthesis of an enal by acidic
`
`
`
`
`
`
`
`
`
`
`hydrolysis. As the acid catalyst, it is preferred to
`
`
`
`
`
`
`
`
`
`employ p-toluene sulfonic acid, hydrochloric acid or
`
`
`
`
`
`
`
`sulfuric acid, and the reaction may be conducted in a
`
`
`
`
`
`
`
`
`
`
`solvent mixture of water and tetrahydrofuran or ethanol at
`
`
`
`
`
`
`
`
`
`a temperature of from 10 to 250C. The
`
`
`
`
`
`
`
`
`3-ethoxy-l-hydroxy-2-propene derivative obtained in Step C
`
`
`
`
`
`
`can be used in Step D without purification i.e. by simply
`
`
`
`
`
`
`
`
`
`
`
`removing tetra-n