pATEfiT 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 fiollowing application as filed with this Office.
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`Date of Application:
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`January 26, 1988
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`Application Number:
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`Applicant:
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`-
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`'
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`Patent Application No. 15585/1988
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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 1014
`Page 1 of 72
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`(Internal priority claimed under Patent Law
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`Artic1e=42-241)
`_'
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`.(Fi1ing Date of the earlier application
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`_August 20, 1987)
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`(Application Number of the earlier application
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`207224/1987)
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`International Patent Classification
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`C07D
`215/00
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`PETIIION FOR PATENT APPLICATION
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`January 26, 1988
`To: Director—General, Patent Office: Kunio ogawa
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`Title of the Invention:
`QUiNOLINE TYPE MEVALONOLACTONES
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`Number of Inventions stated in Claims:
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`1
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`Inventorts):
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`Name:
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`Address:
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`1:.
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`YoshihircF%ujikaea
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`{and four others)
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`Nissan Gfiemfcal Industries Ltd.
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`Chuo Kenkigsho, 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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`(398) Nissan Chemical Industries Ltd.
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`Representative: Takeo Nakai
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`Address:
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`.
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`7-1, 3-chome, Kanda-Nishiki~cho,
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`
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`Chiyoda-ku, Tokyo
`101-
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`Please contact:
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`TEL. 0474—65—lll1
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`List of Attached Documents:
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`I
`'
`(1) Specification
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`(2) Duplicate of Petition
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`.
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`_
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`f
`auc-..
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`p-.'
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`1 copy
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`I 1 copy
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`Sawai Ex 1014
`Page 2 of 72
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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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`Name:
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`Address:
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`same as above
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`'
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`‘ Mitsuski Sakashita
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`Nissan Chemical Industries Ltd.
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`Seibutsukagaku Kenkyusho, 1470,
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`Qezawshiraoka, Shiraoka—machi,
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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 1014
`Page 3 of 72
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`Nc—115 2/3 m/h
`(1573/1589)
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`_ .1 H-
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`SPECIFICATION
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`I.TITLE OF THE INVENTION:
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`QUINOLINE TYPE MEVALONOLACTONES
`2.SCOPE OF THE-CLAIM:
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`A
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`l.
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`A compound of the formula:
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`RI1\
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`R4-
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`2
`3
`" wherein R1, R , R ,
`are independently hydrogen,
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`i-butoxy, sec-butoxy,
`Cl_4 alkyl, Cl_3 alkoxy; néfifitoxy,
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`7
`R7R8
`I
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`N“
`(wherein R _and R8"Efe—independeht1y hydrogen or'a
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`- a.---
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`trifluoromethyi, fludro, chloro, bromo,
`‘lower alkyl),
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`phenyl, phenoxy or beneyloxy; or when located at the-ortho
`2
`1
`3
`position to each other, R
`and R , or R
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`form —cH=CH—cH=cH¥; y is -CH2-,
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`‘-cH2-cH=cH- or —cH=cH—cH -; and z is
`2
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`and R4 together
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`2
`2
`-CH CH —,
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`-CH=CH—,
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`or
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`' R1:
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`I
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`-Q-CH2‘?-CH2? 02R”
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`0H
`"
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`.
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`Sawai Ex 1014
`Page 4 of 72
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`(wherein Q is
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`11
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`R
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`12
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`is hydrogen, R
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`15
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`is hydrogen-or Cl_3 alkyl; R
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`15
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`is physiologically hydrolyzable alkyl) or M
`(wherein R
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`(wherein M is NH4, a metal capable of forming a salt which
`is pharmaceutically acceptable, or an amine-H); R13 is
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`14
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`are the same primary or
`two R
`hydrogen or Cl_3 alkyl,
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`secondary Cl_6 alkyl; or two R14
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`together form -(CH2)2-,
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`5
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`is hydrogen, Cl_6
`alkyl, C 3-5’
`or -{CH2)3—) and R
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`-
`'
`'3.
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`cycloalkyl, phenyl,f—<:::37/
`(wherein R7 is Cl_3 alkyl,.
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`Cl_3 alkoxy, fluoro, chlor§£_bromo_or trifluoromethyl),
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`phenyl-(CH2)m~ (wherein M Eiélf 2 0§.§)f Of
`pheny1—(CHé)nCH(CH3)
`(whe£;Efi_m is l or 2).
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`3.DETAILED DESCRIPTEOR OF THE INVENTION:
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`[Industrial Field of Utilization]
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`The present
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`invention relates to novel
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`mevalonolactones 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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`hypolipoproteinemic and antiéatherosclerotic agents, and
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`intermediates useful for their production and processes
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`for the production of such ifitermediates.
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`[Prior Art and its Problemltu
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`some fermentation metabolic products such as
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`compactine, CS-514, Mevinolin-or semi—synthetic
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`Sawai Ex 1014
`Page 5 of 72
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`_ 3 _
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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~5l4 and Mevinolin have been clinically proved to be
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`potentially useful anti—hyperlipoproteinemic agents, and
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`they are considered to be effective for curing or
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`'
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`preventing diseases of coronary artery sclerosis or
`atherosclerosis:
`(IXth Int. Symp. Drugs Affect. Lipid
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`Metab., 1986, p30, p31, p66T
`However, with respect to fully synthetic derivatives,
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`particularly heterocyclic derivatives of inhibitors
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`against HMG-CoA reductase,
`there has been disclosed
`e--a_.
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`limited information.
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`o
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`The present
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`inventorssfieve found that mevalonolactone
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`‘derivatives having a guinofihe ring,
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`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.
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`The present
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`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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`.:;R;_
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`Sawai Ex 1014
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`Page 6 of 72
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`_ 4 _
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`3
`2
`1
`wherein R_, R , R , R
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`4
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`6
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`and R
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`are independently hydrogen,
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`C1_4 alkyl, Cl_3 alkoxy, n—but9xy,
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`i-butoxy, sec-butoxy,
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`trifluoromethyl, fluoro, chldro, bromo, phenyl, phenoxy or
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`benzyloxy; or when located at the ortho position to each
`1
`2
`3
`4
`and R , or R
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`other, R
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`and R
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`together form
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`—CH=CH-CH=CH-; Y is -CH2—, -cfizcaz-,
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`-CH=CH—,
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`-CH2—CH=CH-
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`"or -CH=CH-CH2-; and Z is
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`0"-1."...
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`, _-...._fl--?.n-
`.-4.
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`-
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`- _
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`_(w‘ner'ein Q.1s
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`.
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`':-C.-I
`H
`0
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`_/-\
`0
`?
`:z|I RI‘
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`_
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`-.w«...
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`n
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`R11 is hydrogen or Cl_3 alkyl; R
`5
`(wherein R1
`is physiologically hydrolyzable alkyl) or M
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`'15
`12 is hydrogen, R
`
`. (wherein M is NH4, a metal capable of forming a salt which
`is pharmaceutically acceptable, or an amine-H); R13 is
`14
`
`are the same primary or
`twoJR
`hydrogen or Cl_3 alkyl,
`secondary C1_6 alkyl; or twe R14 together form -(§H2)2—,
`5
`.
`or -(CH2)3-) and R
`is hydapgen, Cl_6 alkyl, C3F6
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`cycloalkyl, phenyl,.<:::37/ “(wherein R7 is C1_3 alkyl, Cl_3
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`Sawai Ex 1014
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`Page 7 of 72
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`alkoxy, fluoro, chloro, bromo or trifluoromethyl),
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`5.5 -
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`2 °‘ 3)’ °”
`(wherein W is 1'
`Pheny1~(cHg>m-
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`2
`-
`-
`.
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`)
`(wherein n 15 l or
`Pheny1_(cH2)2cH(CH3)
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`The compound of the formula I will be described in
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`detail'with‘reference“°r the examples of the substituents.
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`1
`3
`4
`-6
`2
`alkyl for R , Re, R , R , R
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`and R7 includes, for
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`C
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`1-4
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`example, methyl, ethyl, n-propyl,
`i-propyl, n-butyl,
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`i~butyl, sec~butyl and t-butyl. Cl_3 alkoxy for R1, R2,
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`4
`3
`and R6 includes, for example, methoxy, ethoxy,
`R , R
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`'n—propoxy and i-propoxy.
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`alkyl for R11 includes, for example, methyl,
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`_
`°1—3
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`ethyl, n-propyl and i—propyl.
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`alkyl for R13 includes, for example, methyl,
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`C1-3
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`ethyl, n-propyl and i—propyl.
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`14
`Alkyl for R
`includes,TIor example, methyl, ethyl,
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`n—propyl,
`iapropyl, n-butYf%§Hd i—butylL
`a—-c-
`-
`.M is 3 metal capahle of formingia pharmaceutically
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`acceptable salt, and it includes, for example, sodium and
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`_potassium.
`CO2M includes, fer example, —C02NH4 and —CO2H
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`(primary to tertiary lower alkylamine such as
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`trimethylamine).
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`alkyl for R
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`5
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`includes, for example, methyl,
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`i—butyl, sec—butyl,
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`Cl-6
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`ethyl, n-propyl,
`i—propyl, E-butyl,
`t-butyl, n~pentyl and n-hegylv ~
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`C3_6 cycloalkyl for R5"includes, for example,
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`cyclcpropyl, cyclobutyl, cyclopentyl and cyclohexyl.'
`5
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`Phenyl—(CH2)m- for R
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`includes, for example, benzyl,
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`Sawai Ex 1014
`Page 8 of 72
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`-5...
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`Phenyl-(CH2)nCH(CH3)-
`B-phenylethyl and Y-phenylpropyl.
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`fer R5 ihcludes, for example, a-phenylethyl and
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`a-benzylethyl.
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`The mevalonolactones of the formula I can be prepared
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`by the follewing reactiqn scheme.
`The enal III can also
`be prepared hy processes K, L and M.
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`Sawai Ex 1014
`Page 9 of 72
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`Page 10 of 72Page 10 of 72
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`Sawai Ex 1014
`Page 11 of 72
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`Page 12 of 72Page 12 of 72
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`Page 13 of 72Page 13 of 72
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`_ 11 _
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`5
`4
`3
`2
`1
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`In the above reaction scheme, R , R , R , R , R , R
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`6
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`12 are as defined above with respect to the formula
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`and R
`21
`22
`independently represent_C1_4 lower
`‘and R
`I, and R
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`i—propyl or
`alkyl-such as methyl, ethyl, n-propyl,
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`nwbutyl.
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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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`diisobutylaluminium hydride,
`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
`to an aldehyde, which can be conducted by using
`_alcohol
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`various oxidizing agents. :Ereferably,.the reaction can be
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`conducted by using pyridis%§m“chlorochromate in methylene
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`‘chloride at a temperature-dftfrom 0.to 25°C, or by using
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`oxalyl ch1oride—triethyl amine—dimethyl sulfoxide (Swern
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`oxidation).
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`Step C represents a synthesis of a hydroxyvinyl ether,
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`which can be prepared by reacting a compound V to lithium
`compound which has been preliminarily formed by treating
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`cis—l~ethoxy—2-(tri-n-butylstannyl)ethylene with butyl
`lithium in tetrahydrofuranr
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`As_the reaction temper§§gre,_it is preferred to employ
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`a low temperature at a levei 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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`Sawai Ex 1014
`Page 14 of 72
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`— 12'-
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`employ p-toluene sulfonic acid, hydrochloric acid or
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`i sulfuric acid, and the reaction may be conducted in a
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`- solvent mixture of water and tetrahydrofuran or ethanol at
`temperature of from 10 to 25°C.
`The hydroxyvinyl ether
`-a
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`in Step C can be used in Step D without purification i.e.
`I by simply removing tetra~n-butyl tin formed
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`.simultaneously.
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`The step E represents a double anion condensation
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`(IV) and an acetoacetate.
`reaction between the enal
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`condensation reaction is preferably conducted by using
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`Such
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`sodium hydride and n—butyl lithium as the base in‘
`tetrahydrofuran at —73°Cr-
`I
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`Step F represents a_reduction reaction of the carbonyl
`_group, which can be conudcied by using a metal hydride,
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`preferably sodium borohyd;¥§é~in ethanol at a temperature
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`:of'from 410 to 25°C, preferably from -10 to 5°C.
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`Further,
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`using zinc borohydride in dry ethyl ether or dry
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`tetrahydrofuran at a temperature of —l00 to 25°C,
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`preferably from -so to 930°C.
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`Step G is a step for hydrolyzing the ester.‘ The
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`‘hydrolysis can be conducted by using an equimolar amount
`of a base, preferably potassium hydroxide or sodium
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`hydroxide,
`in a solvent migEure_pf water and methanol or
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`ethanol at a temperature oégfrom 10 to 25°C.
`The free
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`acid hereby obtained may be converted to a salt with a
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`suitable base.
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`Sawai Ex 1014
`Page 15 of 72
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`Step Q is a step for forming a mevalonolactone by the
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`dehydration reaction of the free hydroxy acid I-2.
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`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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`sieve.
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`Further,
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`the dehydration reaction may be conducted in
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`’ dry methylene chloride by using a lactone~forming agent
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`such as carbodiimide, preferably a water soluble
`carbodiimide such as
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`N~cyclohexyl+N'—f2‘-(methylmorpholinium)ethyl]carbodiimide
`p-toluene sulfonate at a temperature of from 10 to 35°C,
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`preferably from 20 to 25°C.
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`Step J represents a regction for hydrogenating the
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`double bond connecting theggevalonolactone moiety and the
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`‘quinoliné'ring. This hydrdfienation reaction can be
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`conducted by using a catalytic amount of palladium—carbon
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`or rhodium-carbon in a solvent such as methanol, ethanol,
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`tetrahydrofuran or acetonitrile at a temperature of from 0
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`to 50°C, preferably from 10 to 25°C.
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`Step K represents a reaction for the synthesis of an
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`__ d,B—unsaturated carboxylic acid ester, whereby a
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`trans—form a;B—unsaturatedncarboxylic acid ester can be
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`obtained by a so—called Ho£her—Nittig reaction by using an
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`alkoxycarbonylmethyl phosehonate.
`The reaction'is
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`conducted by using sodium hydride or botassium t—butoxide
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`as the base in dry tetrahydrofuran at a temperature of
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`Sawai Ex 1014
`Page 16 of 72
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`. - 14 -
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`from -30 to 0°C, preferably from -20 to -15°C.
`Step L represents a reduction reaction of the
`a,B-unsaturated carboxylic acid ester to an allyl alcohol.
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`This reduction reaction can be conducted by using various
`metal hydrides, preferably diisobutylaluminiumhydride,
`in
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`a solvent such as dry tetrahydrofuran or toluene at a
`temperature of from -10 to 10°C, preferably from -10 to
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`0°C.
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`Step M represents an oxidation reaction of the allyl
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`alcohol to an enal. This oxidation reaction can be
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`conducted by using various oxidizing agents, particularly
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`active manganese dioxide,
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`in a solvent such as
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`tetrahydrofuran, ethyl.ether or ethyl acetate at a
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`temperatrue of from 0 to 135°C, preferably from 15 to
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`50°C.
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`' In addition to the coh38flnas disclosed in Examples
`
`given hereinafter, compounds of the formula I~2 given in
`
`Table 1 can be prepared by the process of the present
`
`invention.
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`In Table 1,
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`i- means iso,
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`sec— means secondary
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`and c- means cyclo. Likewise, Me means methyl, Et means
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`ethyl, Pr means propyl, Bu means butyl, Pent means pentyl,
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`Hex means hexyl and Ph~means phenyl.
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`Sawai Ex 1014
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`Page 17 of 72
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`Sawai Ex 1014Sawai Ex 1014
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`Page 18 of 72Page 18 of 72
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`R=-
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`R‘
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`H
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`H
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`6-"ca
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`6-ca
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`H
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`~H
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`_B-Ofle
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`7-0Me
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`H
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`5-cz
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`6—0(;H.;Ph.
`H
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`H
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`4—Ph
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`4-PhCH; H
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`4-F
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`‘.12
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`H
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`4-F
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`4'—F
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`4-F‘
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`4-. F
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`:m’r.mmm‘..::::u::::.m.::::-u::n
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`8-CE
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`H
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`6-02.
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`5-Me
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`7-Me.
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`'§-one
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`5—Br
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`H-5-i-Pr
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`5-CE
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`CEIECEZEIEZEIZEZECEZEZECEIEIJEDIE
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`Sawai Ex 1014
`Page 19 of 72
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`R‘
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`R‘
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`R’
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`5-F‘.
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`6—0He
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`6-Me_
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`6-c2
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`6-131‘
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`7-one
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`4 -1?
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`4 —F
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`7-Mel‘ 4-F
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`7-“c2
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`‘4—F
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`H
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`4-F
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`it-F
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`Further, pharmaceutically acceptable salts such as
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`manner .
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`sodium salts or esters such as ethyl esters or methyl
`cl-
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`esters of these compounds Ean be prepared in the same
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`‘ The compounds of the present invention exhibit high
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`inhibitory activities against the cholesterol biosynthesis
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`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 in blood as.lipoprotein. Thus,
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`the compounds
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`of the present invention are useful as curing agents
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`against hyperlipidemia, hyperlipoproteinemia and
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`atherosclerosis.
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`3'
`5
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`They may be formulatedéinto various.suitable
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`_
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`formulations depending upon the manner of the
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`administration.
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`The compounds of the present invention
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`Sawai Ex 1014
`Page 20 of 72
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`.__13._
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`may be administered in the form of free acids or in the
`form of physiologically hydrolyzable 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
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`form of powders, granules,
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`tablets or capsules formulated
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`by mixing the compound of the present invention with a
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`suitable pharmaceutically acceptable binder such as syrup,
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`gum arabic, gelatin, sorbitol,
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`tragacanth gum, polyvinyl
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`pyrrolidone, an excipient such as lactose, sugar; corn
`starch, calcium phosphate, sorbitol, glycine or a
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`talk, polyethylene
`lubricant such as magnesium stearate,
`glycol or silica, and a diiintegrator such as potato
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`':1pl—.
`starch.
`V
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`the pharmaceutical composition of the present
`'_However,
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`invention is not limited to such oral administration and
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`it is applicable for'perenteral administration.
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`For
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`example, it may be administered in the form of e.g.
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`a
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`-suppository formulated by using oily base material such as
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`cacao butter, polyethylene glycol,
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`lanolin or fatty acid
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`triglyceride.
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`Further,
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`the compounds'of the present invention may be
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`‘combined with basic anion-exchange resins which are
`I-
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`capable of binding bile acids and yet not being absorbed
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`in gastraintestinal tract.
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`The daily dose of the compound of the formula Iiis
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`Sawai Ex 1014
`Page 21 of 72
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`-19..
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`from 0.05 to 500 mg, preferably from 0.5 to 30 mg for an
`adult.
`It is administered from once to three times per
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`The dose may of Course be varied depending upon the
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`day.
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`age,
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`the weight or the condition of illness of the
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`patient.
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`The compounds of the formulas II to VI are novel, and
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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 V1 and the processes for their production.
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`[Examples]
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`Now,
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`the present invention will be described in
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`-further detail with reference to Test Examples for the
`e
`_ pharmacological activities:of the compounds of the present
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`their Preparat§§§7Examples and Formulation
`invention,
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`:ExamplesC' However, it shbbifi be understood that the
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`present invention is by no means restricted by such
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`specific Examples.
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`PHARMACOLOGICAL TEST EXAMPLES
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`
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`Test_A:'
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`Inhibition of cholesterol biosynthesis from
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`acetate in vitro
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`Enzyme solution was prepared from liver of male wistar
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`rat (weighing from 200 to 250 g) cannulated to the
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`- bile-duct and discharged b$le_fqr over 24 hours.’ Liver
`I-
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`was cut out at mid—dark and microsome and 10500 xg
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`supernatant fraction which was precipitable with 40-80% of
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`saturation of ammonium sulfate (sup fraction) were
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`Sawai Ex 1014
`Page 22 of 72
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`-20-
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`prepared from liver homogenate according to the modified
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`method'of Knauss et al.; Kuroda, M., et. a1., Biochim.
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`.By the cannulation td the
`Biophys._Acta, 489, 119_(197#).
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`bile-duct of rats, it has been confirmed that the ability
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`for cholesterol biosynthesis is increased from a few to 10
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`timtes.
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`The measurement of the ability for cholesterol
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`biosynthesis was conducted in accordance with a method of
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`Endo, The netabo1ism,_l6{ 1757 (1979). Namely, microsome
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`(Oul mg protein) and sup fraction (1.0 mg protein) were
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`incubated for 2 hours at 37°C in 200 pl of reaction
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`mixture containing ATP;
`1 mM, Glutathione;
`6 mM and 0.2 mM
`14
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`[2— C] sodium acetate (0,l uCi) with 4 pl of test
`compound solution in water or dimethyl sulfoxide (DMSO).
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`To stop reaction and saponify,
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`1 ml of 15% EtOH—KOH was
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`added to the reactions andggéated at-75°C for 1 hour.
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`’Nonsaponifiable lipids were”extracted with petroleum ether
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`and incorporated 14 C radioactivity was counted.
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`Inhibitory activity of compounds was indicated with IC50,
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`which is the concentration for inhibiting radioactivity
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`incorporated in the nonsaponifiable lipids at the level of
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`50%.
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`‘Test B:
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`Inhibition of cholesterol biosynthesis.in
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`a
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`culture cells
`(Hep G2 cells) at from
`Human liver cancer celéi,
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`several to several tenspassage were seed to 6 well plates
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`and incubated with Dulbecco's modified Eagle (DME) medium
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`containing 10% of fetal bovine serum (FBS) at 37°C,
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`5% CO2
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`Sawai Ex 1014
`Page 23 of 72
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`_ 21 _
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`until cells were confluent for about 7 days. Cells were
`exposed to the DME medium containing 5% of lipoprotein
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`deficient serum (LpDS) prepared by ultracentrifugation
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`method and the incubation was continued.
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`By changing the
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`FBS containing medium to the LpDS containing medium, it
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`has been confirmed that the ability for cholesterol
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`, biosynthesis in vivo increases about 1.4 times. After 24
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`hrs_incubation the medium was removed, 1.5 ml of DME
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`medium containing 5% LpDS was added fresh and 15 ul of
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`test compound solution dissolved in water or DMSO was
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`added.
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`0.5 uCi er
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`[2—l4C]sodium acetate was added at o
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`hr(B—1) or 4 hrs(B-2) after addition of compounds. After
`14
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`cr.
`4 hrs further incubation with {2— Clsodium acetate,
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`_ medium was removed and celgs were washed with phosphate
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`buffered saline(PBS) chil§§§7at 4°C'three times. Cells
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`:were scraped with rubber pdliceman and collected to tubes.
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`To the resulting cell pellet, 200 pl of 0.5 NKOH was added
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`and the cells were digested by heating them overnight..
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`Aliquot of the digestion was saponified with 15% Et0H-KOH.
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`3B—Hydroxysterol was separated from the resulting
`nonsaponifiable lipids by precipitatiton method with
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`digitonin in accordance with the method of Sperry et a1.,
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`J.Biol Chem., 187, 97 (l95q).
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`thegamount of the protein was
`_0n the other hand,
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`measured by using the remafhing of the cell digestion.
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`Ihe ability of cholesterol biosynthesis was indicated with
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`DPM/mg cell protein.
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`Inhibitory activity of compounds was
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`Sawai Ex 1014
`Page 24 of 72
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`-22..
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`indicated with IC50, which is the concentration for
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`inhibiting radioactivity-incorporated in the digitonide at
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`the level of 50%;
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`With respect to the compounds of the present
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`invention,
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`the inhibitory activities against the
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`cholesterol biosynthesis in which HMG-COA reductase acts
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`as a rate limiting enzyme, were measured by above Test A
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`and B.
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`The results are as shown in Table 2.
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`Sawai Ex 1014
`Page 25 of 72
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`-23..
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`Table 2: Inhibitory activities by Test A
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`icso (molar concentration)
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`Compound
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`(Compounds
`
`
`of the present
`
`invention)
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`I~5l
`
`I-52
`
`
`
`I453
`
`I-13
`
`cs—514
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`
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`(Reference
`
`compounds)
`
`Mevinolin '
`
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`‘
`
`"
`
`'
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`1.4 x l0"8
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`9.0 x 1o'9
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`u...
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`the relative
`With respect to the foiécwing compounds,
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`‘activities are shown baseflfign the activities of CS—514
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`being evaluated to be-i.
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`Relative activities
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`Compound
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`I
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`fcomounds of
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`the present
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`invention)
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`I-16
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`Sawai Ex 1014
`Page 26 of 72
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`.
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`— 24 ~'
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`Structures pf reference compounds:
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`(1)'Mevinolin
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`'(2) cs-514
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`Sawai Ex 1014
`Page 27 of 72
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`

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`_
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`Table 3: Inhibitory activities by_Test B-1
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`Compound
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`-
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`icsd (molar concentration)
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`(Comoound
`of the present
`invention)
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`I-51
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`(Reference
`compound)
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`cs—514
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`3.5 x 1o'7
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`The compounds of the present
`
`invention exhibited-
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`activities superior to the reference compound such as
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`CS-514 or Mevinolin in Test A, and exhibited activities
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`‘_*superior to CS~514 in Test;:§ and C.
`
`EXAMPLE 1
`lib _
`' Eth I’ E)—3 5—dih'droki:$—[4'- 4"-fluoro hen 1
`§l"—methglethyl)—guinolin-3'—yl]-hegt—6-enoate (comgound
`I-ll) (gregared by stage or Examgle 1-a through Examgle
`
`1:91
`
`.
`
`EXAMPLE l—a: Ethyl 4-(4'—f1uoroQhenyl)—2-(1'-
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`methylethyl)—guinolin-3-21-carboxylate (comgound VII-1)
`
`"
`
`The synthesis was conducted in accordance with the
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`method disclosed in J. Orgr'Chem., 2399 (19665.
`
`'
`
`6.45 g
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`(0.03 mol) of 2faminq:4‘-fluorobenzophenone,
`B
`
`5w53 g (0.035 mol) hf ethy§ isobutyrylacetate and 0.1 ml
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`of cone. sulfuric acid were disso1ved_in 30 ml of glacial
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`acetic acid, and the mixture was heated at 100°C for about
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`Sawai Ex 1014
`
`Page 28 of 72
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`

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`_ 26 _
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`10 hours. After confirming the substantial disappearance
`of 2?amino—4'—fluorobenzophenone by thin layer
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`chromatography,
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`the reaction solution was cooled to room
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`temperature, and gradually added into a mixture solution
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`of 45 ml of conc. aqueous ammonia and 120 ml of water
`cooled with ice.
`A separated oily substance was
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`solidified-when left to stand overnight
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`in a refrigerator.
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`‘This solid was recrystallized from a small amount of
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`-ethanol’to obtain 6.47 g (55%) of white powder. Melting
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`point: 68-70.5°C_
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`EXAMPLE l—b: 4—(4'—fluorophenyl)-3-hydroxymethyl—2—(1'-
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`
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`methylethyl)-guinoline (compound VI~l)
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`‘5.4 g (0.015 mol) of cgmpound vi:-1 was dissolved in
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`‘dry toluene under a nitrogég atmosphere and cooled in ice
`_-'.._':u:.-_ -
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`' _bath to Q?C.' To this_soly§ign, 40 ml of a 16 wt%
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`diisobutylaluminium hydride-toluene solution was dropwise
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`added, and the mixture was stirred at 0°C for two hours.
`After confirming the complete disappearance of compound
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`VII—l by thin layer chromatography,
`a saturated ammonium
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`chloride solution was added thereto at 0°C to terminate
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`the reaction. Ethyl ether was added to the reaction
`mixture, and the organic layer was separated.
`A gelled
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`product was dissolved by an addition of an aqueous sodium
`hydroxide solution and extéattedmanew with ethyl ether.
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`The ethyl ether extracts were put together, dried over
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`anhydrous magnesium sulfate and filtered.
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`The solvent was
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`distilled off.
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`The residual oil underwent crystallization
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`Sawai Ex 1014
`Page 29 of 72
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`-27-
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`when left to stand.
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`It was recrystallized from ethyl
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`acetate—n-hexane to obtain 3.3 g of white crystals.
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`Yield: 70%. Melting point: 136-137°C.
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`
`EXAMPLE 1-c: 4-(4'-fluorophenyl)-2-(l'-methylethyl)-
`
`
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`guinolin-3:yl~carboxyaldehyde (compound V-1)
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`2.0 g (9«3_mmol) of pyridinium chlorochromate and 0.4
`g of anhydrous sodium acetate was suspended in 10 ml of
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`dry dichloromethane.
`To this suspension, a solution
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`obtained by dissolving l g (3.4 mmol) of compound VI—l
`10 ml of dry dichloromethane, was immediately added at
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`room temerature}' The mixture was stirred for one hour.
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`in
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`Then, 100 ml of ethyl ether was added thereto, and the
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`mixture was thoroughly mixed.
`a..—
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`The reaction mixture was
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`filtered under suction th&&Egn a silica gel layer.
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`The residue
`filtrate was dried underlgéghced pressure.
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`‘was dissolved in the isoprdpyl ether, and insoluble
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`substances were filtered off.
`The filtrate was again
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`The
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`dried under reduced pressure, and the residue was
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`recrystallized from diisopropyl ether to obtain 0.7 g
`(Xield: 70%) of slightly yellow prism crystals. Melting
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`
`point: 124—12a°c.
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`::.,l.‘,.’.;l a. gag)
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`1.1 (t.
`J=THz. 3H)éi1..37-(d-
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`3.7 <q‘-;- J=7Hz.
`3.7 (rn.
`111')
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`6H)
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`J=7Hz.
`2H)
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`
`
`4.75Ct.
`J=7Hz.
`1H)
`'7.o5~s.2 (m. an)“
`
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`
`
`5.T(m.
`
`1H)
`
`
`
`5.95(m.
`
`1H)
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`Sawai Ex 1014
`Page 30 of 72
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