Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 1 of 50
`
`AnthonyJ. Viola
`Andre K. Cizrnarik
`Jennifer L. Dereka
`Zachary W. Silverman
`EDV/ARDS V/ILDMAN PALMER LLP
`Attomeys for Plaintiffs
`Kowa Compan¡ Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chernical Industries, Ltd.
`T50Lexinglon Ave.
`New York, NY 10022
`(212) 308-44t1
`
`14 CW rf,
`
`T]NITED STATES DISTRICT CO
`SOUTHERN DISTRTCT OF NE1V
`
`D
`
`Ë1;r{ f irû14
`
`Kowa Company, Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chernical Industries, Ltd.,
`
`Civil Action No.
`
`Plaintiffs,
`
`COMPLAINT
`
`V
`
`Amneal Pharmaceuticals, LLC,
`
`Defendant
`
`Plaintiffs, Kowa Company, Ltd. ("KCL"), Kowa Pharmaceuticals America, Inc. ("KPA")
`
`(collectivel¡ "Kowa"), and Nissan Chemical Industries, Ltd. ("NCI") by their undersigned
`
`counsel, for their Complaint against defendant Amneal Pharmaceuticals, LLC ("Amneal"),
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`allege as follows:
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 2 of 50
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`Jurisdiction and Venue
`
`1.
`
`This is an action for patent infringement arising under the patent laws of the
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`United States, Title 35, United States Code and arising under 35 U.S.C. $$ 271(eX2),271(b),
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`271(c), and,287-283. Subject matter jurisdiction is proper under 28 U.S.C. $$ 1331 and 1338(a)
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`Venue is proper under 28 U.S.C. $$ 1391(b)-(c) and 1400(b). Personal jurisdiction over the
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`defendantsinNewYorkisproperunderN.Y. C.P.L.R.$$ 301 and 302(a) andbecause
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`defendants are doing business in this jurisdiction.
`
`Parties
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`2.
`
`KCL is a Japanese corporation having its corporate headquarters an<í principai
`
`place of business in Aichi, Japan. KPA is a wholly owned U.S. subsidiary of KCL. KPA has its
`
`corporate headquarters and principal place of business in Montgomery, Alabama and is
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`orgarized under the laws of Delaware.
`
`3.
`
`NCI is a Japanese corporation having its corporate headquarters and principal
`
`place of business in Tokyo, Japan.
`
`4.
`
`KCL and NCI are engaged in the business of research, developing,
`
`manufacturing, and marketing of a broad spectrum of innovative pharmaceutical products,
`
`including Livalo@.
`
`5.
`
`Upon information and belief, Amneal is incorporated in Delaware having a place
`
`of business in Bridgewater, New Jersey. Upon information and belief, Amneal filed Abbreviated
`
`New Drug Application ("ANDA") No. 20-5961.
`
`6.
`
`Upon information and belief, Amneal is currently transacting business in the
`
`Southern District of New York, at least by making and shipping into this Judicial District, or by
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`using, offering to sell or selling or by causing others to use, offer to sell or sell, pharmaceutical
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`products into this Judicial District.
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`2
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`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 3 of 50
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`7.
`
`Upon information and belief, Amneal derives substantial revenue from interstate
`
`and/or international commerce, including substantial revenue from goods used or consumed or
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`services rendered in the State of New York and the Southern District of New York. Amneal is
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`registered with the N.Y. State Department of State, Division of Corporations, to do business as a
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`foreign corporation in New York. By filing its ANDA, Amneal has committed, and unless
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`enjoined, will continue to commit a tortious act without the state of New York, that Amneal
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`expects or should reasonably expect to have consequences in the State of New York including in
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`this Judicial District.
`
`The New
`
`ApplicatÍon
`
`8.
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`KPA sells drug products containing pitavastatin calcium (the "pitavastatin drug
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`product") under the trade name Livalo@ in the United States pursuant to the United States Food
`
`and Drug Administration's approval of a New Drug Application ("NDA") held by KCL (NDA
`
`No.22-363).
`g.
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`Livalo@ is approved for use as an adjunctive therapy to diet to reduce elevated
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`total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to
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`increase HDL-C in adult patients with primary hyperlipidønia or mixed dyslipidernia.
`10. The approval letter for Livalo@, with approved labeling, was issued by the FDA
`
`on August 3,2009-
`11. Certain amendments to the approved labeling for Livalo@ have subsequently been
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`approved.
`
`The Patents in Suit
`12. United States Patent No. 5,856,336 ("the '336 patent"), entitled "Quinoline Type
`
`Mevalonolactones," a true and correct copy of which is appended hereto as ExhÍbit A, was duly
`
`J
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 4 of 50
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`issued on January 5,1999 to inventors Yoshihiro Fujikawa, Mikio Suzuki, Hiroshi Iwasaki,
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`Mitsuaki Sakashita, and Masaki Kitahara, and assigned to plaintiffNcl. The '336 patent claims,
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`inter alia, the pitavastatin drug product, and amethod for reducing hyperlipidemia,
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`hyperlipoproteinemia or atherosclerosis, which comprises administering an effective amount of
`
`the pitavastatin drug product.
`13. Plaintiff NCI has been and still is the owner through assignment of the '336
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`patent, which expires on December 25,2020 pursuant to a patent-term extension. KCL is NCI's
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`licensee for the '336 patent and KPA holds a license from KCL for the '336 patent.
`14- United States Patent No. 8,557,993 ("the'993 patent"), entitled "Crystalline
`
`Forms of Pitavastatin Calcium," a true and correct copy of which is appended hereto as Exhibit
`
`B, was duly issued on October 15,2013 to inventors Paul Adriaan Van Der Schaaf, FntzBlatter,
`
`Martin Szelagiewicz, and Kai-Uwe Schoening, and ultimately was assigned to plaintiff NCI.
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`The'993 patent claims, inter glig crystalline polymorphs or the amorphous form of pitavastatin
`
`or processes for preparing the same.
`15. Plaintiff NCI has been and still is the owner through assignment of the '993
`
`patent, which expires on February 2,2024- KCL is NCI's licensee for the '993 patentand KPA
`
`holds a license from KCL for the '993 patent.
`76. In accordance with its license, KPA sells the pitavastatin drug product under the
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`trade name Livalo@ in the United States. Sales of Livalo@ are made pursuant to approval by the
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`FDA of NDA No. 22-363.
`17. Plaintiff KCL manufactures the Livalo@ drugproducts as sold by KPA.
`
`4
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`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 5 of 50
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`18. Plaintiffs Kowa and NCI will be substantially and irreparably harmed by
`
`infringement of either of the '336 or'993 patents (the "Livalo@ patents"). There is no adequate
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`remedy at law.
`
`COUNT I
`
`INFRINGEMENT OF TIIE '336 PATENT UNDER 35 U.S.C. S 271(eX2XA)
`
`19. Plaintiffs repeat and incorporate herein by reference the allegations contained in
`
`each ofthe foregoing paragraphs.
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`20. Upon information and belief, defendant Amneal filed an Abbreviated New Drug
`
`Application ("ANDA") with the Food and Drug Administration ("FDA") under 21 U.S.C. $
`
`355(i) (ANDA No. 20-5961) seeking approval to market I mg,2 mg, and 4 mg tablets
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`comprising pitavastatin calcium.
`
`21. By this ANDA filing, Amneal has indicated that it intends to engage, andthat
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`there is substantial likelihood thatit will engage, in the commercial manufacture, importation,
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`use, offer for sale, andlor sale, or inducement thereof, of Plaintiffs' patented pitavastatin drug
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`product immediately or imminently upon receiving FDA approval to do so. Also by its ANDA
`
`filing, Amneal has indicated that its drug product is bioequivalent to Plaintiffs' pitavastatin drug
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`product.
`
`22. By its ANDA filing, Amneal seeks to obtain approval to commercially
`
`manufacture, use, import, offer for sale, andlor sell, alleged generic equivalents of Plaintiffs'
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`Livalo@ pitavastatin drug product prior to the expiration date of the '336 patent.
`
`23- By a letter dated March 5,2014 (the "Notice Letter"), Amneal informed KCL and
`
`NCI that Amneal had filed a certification to the FDA, pursuant to 21 U.S.C. $ 355ûX2)(B)(iv)(I).
`
`5
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`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 6 of 50
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`Upon information and belief on or about March 7,2014,KCL received the Notice letter. On or
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`about March 7,2014,NCI received the Notice Letter.
`24. The Notice Letter, purporting to be Amneal's Notification Pursuant to 21 U.S.C. $
`3550X2XBXiÐ(I), asserts that in Amneal's opinion, the '336 patent purportedly is
`
`"unenforceable, invalid, andlor not infringed, either literally or under the doctrine of equivalents,
`
`by the manufacture, use, sale, offer for sale, andlor importation of the drug product for which
`
`ANDA No. 205961 has been submitted byAmneal."
`25. Amneal's filing of ANDA No. 20-5961 for the purpose of obtaining FDA
`
`approval to engage in the commercial manufacture, use, importation, offer for sale andlor sale, or
`
`inducement thereof, of its proposed pitavastatin drug product before the expiration of the '336
`
`patent is an act of infringernent under 35 U.S.C. g 271(e)(2)(A).
`26. Amneal's manufacfure, use, importation, offer for sale, andlor sale, or inducement
`
`thereof, of its proposed pitavastatin drug product will directly infringe or induce infringement of
`
`at least one claim of the '336 patent under 35 U.S.C. g 271(e)(2)(A).
`27. Upon information and belief, Amneal's proposed label for its pitavastatin drug
`
`product will include the treatment of at least one of h¡iperlipidemia, hyperlipoproteinemia, and
`
`atherosclerosis.
`28. Unless Amneal is enjoined from infringing and inducing the infringement of the
`
`'336 paten|. Plaintifß will suffer substantial and irreparable injury. Plaintifß have no adequate
`
`remedy at law.
`
`6
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`

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`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 7 of 50
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`COUNT II
`
`INFRINGEMENT OF THE METIIOD CLAIM OF TTIE '336 PATENT
`UNDER 3s U.S.C. ñ 271ft)
`
`29. Plaintiffs repeat and incorporate herein by reference the allegations contained in
`
`each of the foregoing paragraphs.
`
`30. Upon information and belief, approval of ANDA 20-5961is substantially likely to
`
`result in the commercial manufacture, use, importation, offer for sale, and/or sale, or inducement
`
`thereof of a pitavastatin drug product which is marketed and sold for use in a method claimed in
`
`one or more claims of the '336 patent, immediately or imminently- upon approval of the ANDA,
`
`and prior to the expiration of the '336 patent-
`
`31. Upon information and belief, Amneal's proposed label for its pitavastatin drug
`
`product will include the treatment of at least one of hlperlipidønia, hyperlipoproteinemia or
`
`atherosclerosis.
`
`32. Upon information and belief Amneal is aware or reasonably should be aware, of
`
`the widespread use of pitavastatin as an adjunctive therapy to diet to reduce elevated total
`
`cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to increase
`
`HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidønia. The beneficial
`
`effects of pitavastatin as an adjunctive therapy to diet to reduce elevated total cholesterol, low-
`
`density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to increase HDL-C in adult
`
`patients with primary hyperlipidemia or mixed dyslipidemia would be readily apparent to
`
`customers of Amneal (9.g., including, without limitation, physicians, pharmacists, pharmacy
`
`benefits management companies, health care providers who establish drug formularies for their
`
`insurers andlor patients). Amneal will be marketing its pitavastatin drug product with specific
`
`7
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`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 8 of 50
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`intent to actively induce, aid and abet infüngement of the '336 patent Amneal knows or
`
`reasonably should know that its proposed conduct will induce infringement of the '336 patent.
`33. Unless Amneal is enjoined from infringing and inducing the infüngement of the
`
`'336 patent, Plaintiffs will suffer substantial and irreparable injury. Plaintiffs have no adequate
`
`remedy at law.
`
`COUNT III
`
`INFRINGEMENT OF TIIE
`CLAIM OF THE '336 PATENT
`UNDER 35 U.S.C. S 271(c)
`34. Plaintifß repeat and incorporate herein by reference the allegations contained in
`
`each ofthe foregoing paragraphs.
`35. Upon information and belief, Amneal's proposed pitavastatin drug product
`
`comprises pitavastatin calcium as referenced in the claims of the '336 patent.
`36. Upon information and belief Amneal's proposed pitavastatin drug product will be
`
`especially made for use in a manner that is an infringement of the '336 patent.
`37. Upon information and belief, Amneal knows that Amneal's proposed pitavastatin
`
`drug product will be especially made for use in a manner that is an infringement of the '336
`
`patent.
`
`38. Upon information and belief, sale of Amneal's proposed pitavastatin drug product
`
`will result in direct infringement of the '336 patent.
`39. Upon information and belief, Amneal's proposed pitavastatin drug product is not
`
`a staple article or commodity of commerce which is suitable for a substantial noninfringing use.
`40. Upon information and belief, Amneal knows that Amneal's proposed pitavastatin
`
`drug product is not a staple article or commodity of commerce which is suitable for substantial
`
`noninfringing use.
`
`8
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`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 9 of 50
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`41. Upon information and beliet approval of ANDA 20-5961is substantially likely to
`
`result in the commercial use, manufacture, offer for sale andlor sale (or the inducement thereof
`
`or contribution thereto) of a drug product which is especially made, adapted, marketed, sold, and
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`approved exclusively for use in a method claimed in the '336 patent, immediately or imminently
`
`upon approval of the ANDA.
`
`42. Plaintiffs will be substantially and irreparably harmed if defendants are not
`
`enjoined from contributing to the infringement of the '336 patent Plaintifß have no adequate
`
`remedy atlaw.
`
`COUNT IV
`
`INFRINGEMENT OF THE '993 PATENT UNDER 35 U.S.C. $ 271(eX2XA)
`
`43. Plaintiffs repeat and incorporate herein by reference the allegations contained in
`
`each ofthe foregoing paragraphs.
`44. Amneal's Notice Letter, purporting to be Amneal's Notice of Certification under
`
`21 U.S.C.$ 355cx2x8)(iv), indicates that Amneal intends to manufacture, use, sell, or offer for
`
`sale, its proposed pitavastatin drug product prior to the expiration of the '993 pai'rcrrt.
`45. The Notice Letter asserts that in Amneal's opinion, the'993 patent purportedly is
`
`"unenforceable, invalid, and/or not infringed, either literally or under the doctrine of equivalents,
`
`by the manufacture, use, sale, offer for sale, andlor importation of the drug product for which
`
`ANDA No. 205961 has been submitted by Amneal."
`
`46. Amneal's filing of ANDA No. 20-5961 for the pu{pose of obtaining FDA
`
`approval to engage in the commercial manufacture, use, importation, offer for sale andlor sale, or
`
`the inducement thereof, of its proposed pitavastatin drug product before the expiration of the
`
`'993 patent is an act of infringernent under 35 U.S.C. g 271(e)(2)(A).
`
`9
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`

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`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 10 of 50
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`47. Amneal's manufacture, use, importation, offer for sale, sale, and/or importation of
`
`its proposed pitavastatin drug product will directly infringe or induce infringement of at least one
`
`claim of the '993 patentunder 35 U.S.C. g 271(e)(2)(A).
`48. Unless Amneal is enjoined from infringing the '993 patent, plaintifß will suffer
`
`substantial and irreparable injury. Plaintiffs have no adequate rønedy atlaw.
`
`WHEREFORE, Plaintiffs request the following relief:
`(a)
`
`a declaratory judgment pursuant to 28 U.S.C. ç 2201et seg. that making, using,
`
`selling, offering to sell utdlor importing Amneal's pitavastatin drug product for
`
`which it seeks FDA approval or any drug product containing pitavastatin will
`
`infänge at least one claim of one or rnore of the Livalo@ patents;
`
`(b)
`
`a declaratory judgment pursuant to 28 U.S.C. ç 2201et Sgq. that the making,
`
`using, offering for sale, selling andlor importing of Amneal's pitavastatin drug
`
`product or any drug product containing pitavastatin, will induce the infüngernent
`
`(c)
`
`(d)
`
`at least one claim of one or more of the Livalo@ patents;
`
`a declaratory judgment pursuant to 28 U.S.C. ç 2201et !eq. that the making,
`
`using, offering for sale, selling andlor importing ofAmneal's pitavastatin drug
`
`product or arry drug product containing pitavastatin, will contribute to the
`
`infüngement of at least one claim of one or more of the Livalo@ patents;
`
`a declaratory judgment pursuant to 28 U.S.C. ç 2201et seq. and an order
`
`pursuant to 35 U.S.C. $ 271(e)@)(A) providing that the effective date of any
`
`FDA approval for Amneal to commercially make, use, sell, offer to sell or
`
`import its pitavastatin drug product or any drug product containing pitavastatin
`
`10
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`

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`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 11 of 50
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`be no earlier than the date following the expiration date of the last to expire of
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`the Livalo@ patents (as extended, if applicable);
`
`(e)
`
`a peTmanent injunction restraining and enjoining against any infüngernent by
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`defendants, their officers, agents, attorneys, employees, successors or assigns, or
`
`those actingin privity or concert with them, of the Livalo@ patents, through the
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`commercial manufacture, use, sale, offer for sale or importation into the United
`
`States of Amneal's pitavastatin drug product or any drug product containing
`
`pitavastatin, andlor any inducernent of or contribution to the same;
`
`Attorneys' fees in this action under 35 U.S.C. $ 285; and
`
`Such further and other relief in favor of Plaintifß and against defendants as this
`
`(Ð
`
`(e)
`
`Court rnay deern just and proper.
`
`Dated: New York, New York
`April 17,2074
`
`Kowa Compan¡ Ltd.,
`Kowa Pharmaceuticals America, Inc., and
`Nissan Chemical Industries, Ltd.
`
`By their attorneys,
`
`Anthony J. Viola
`Andre K. Cizmarik
`Jennifer L. Dereka
`Zachary W. Silverman
`EDV/ARDS WILDMAN PALMER LLP
`750 Lexington Avenue
`New York, NY 10022
`(212) 308-4411
`
`11
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 12 of 50
`
`David G. Conlin (to be admittedpro hac více)
`Kathleen B. Ca:r (to be admittedpro hacvice)
`Adam P. Samansky
`EDWARDS WILDMAN PALMER LLP
`111 Huntington Avenue
`Boston, MA 02199
`(617) 23e-0100
`
`72
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 13 of 50
`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 13 of 50
`
`EXITIBIT A
`
`EXHIBIT A
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 14 of 50
`l lillilllll]l ilillll ilil lillil]ll lilillilillil illl| llllil il ]llililt
`us005856-3-364
`Patent Number:
`Date of Patent:
`
`United States Patent rrel
`Fujikawa et al.
`
`[1 1]
`
`l4sl
`
`5,856,336
`Jan. 5,1999
`
`[-54] QUINOLTNE TYPE MEVAÍ.ONOT"A,CTONBS
`[7-5] Inventors: Yoshihiro Fujikawa; Mikio Srzuki;
`Hiroshi lwasaki, all of Funabashi;
`Mifsuaki Sakashita; Masaki Kitahara,
`both of Sbiraoka-machi, all of Japan
`[73] A,ssignee: Nissan Chcmical lndustries Ltd.,
`Tokyo, Japan
`
`Prinmry Exaninerl.arra L. Stockton
`,Anorney', Agent, or Firnr4lllo¡, Spivak, McClelland,
`Maier & Neustadt, P.C.
`
`ls1l
`
`ABSTRACT
`
`A compouncl of the formula
`
`F
`
`lAl
`
`l21l AppI. No.: 883,398
`l22l Filed: Mry 15, 1992
`Related U.S. Application Data
`
`162l Divisiou oI Ser No. 637,092, Dec. 19, 199O. which is a
`conLinuation oï Scr. No. 233,752, Aug, J.9, 1988.
`[30]
`tr-oreig¡n Application Priority Data
`Aug.2O, 1987
`[JP]
`pPl
`.Ian- 26- 1988
`63- r 558.1
`Japan
`Aug. -3- 1988 pPl Japan .............
`63-t93606
`[5r] Inr. Ct.6
`......... Ä61K 31147 C07D 2r5ft2
`ls2l u.s. cl.
`5L4l3lL; 546/173
`[58] Fiefd of Search
`... 5461773;' 514/3LL
`[5ó]
`References Cited
`
`U.S. PAIENT DOCUMENTS
`5,J53.6'75 -5/19s8 Watlarìasin ..... ........................ 574131.1
`
`z
`
`c-Pr
`
`N
`Z=-CH(OH)-CH'-CFI( O H)-C H2- CO o .%C a
`have IIMC-CoA inhibiting eftects, making them use-
`lul as inhihitors of cholesterol biosynthesis. The oom-
`pound may be prepared as a pharmaceutical tbr reduc-
`ing hyperlipidemia, hyperlipoproteineruia or
`atherosclerosis.
`
`2 Clairns, No Drawings
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 15 of 50
`
`5,856.336
`
`2
`
`\-l.yv' o
`
`co.Rrl
`
`R
`
`o
`
`o
`
`o
`
`Rtt
`
`Rl;
`
`R.,l/
`o
`
`(rvherein Q is -C(O)-, -C(Ol{rr)r- or -CH(OH)-;
`'or
`'iv ir -c1o¡-, -Ò1'oR"¡,
`ní, ;i
`-Õ1R"¡1oHÈ;
`hrvclrogen or Cr_u alkyl; Rr2 is hydrogen or R1'r (wherein Rl'r
`is physiologically hydroiyzabie alkyl or M (wherein M is
`NHo, soclium, potassium, % calciunr or a hvdrate of lower
`alkylamine,
`tr,vo Rr3 a¡e
`or two Iì.13
`and R18 are
`hydrogen, Cr_u a1kyl, C.-. alkenyl, Cr_u cycloalk¡,I,
`
`5
`
`1-s
`
`10
`
`1
`QUINOLINE TYPE MEVALONOI.ACTONES
`'Ihis is a division, of application Ser. No. 071631,092,
`flled on Dec. 19, 1990, which is a continuation of (171233,
`752,fr1edAug. 19,198B.
`The prÞsent invention relates tr¡ novel mevalonol&ctones
`having a quinoline ring, processes fo¡ thei¡ procluction,
`pharmaceutical conrpositions containing them ancl their
`pharmaceutical uses particularly as anti-hyperlipiclemic,
`hypolipoproteinemic and anti-alberosclerotic agents, an<I .^
`inùrmè¿iates useful for their procluction ancl prõcessós for 10
`the production of such intermcdiates.
`Some fermentation metabolic proclucts such as
`compactine, CS-514, Mevinolin or semi-synthetic deriva-
`tives or fu1ly synthetic clerivatives thereof are known to be
`inhibitors against HMG-CoA recluctase wlrich is a rate
`limiting cnzyme for cholesterol biosynthcsis. (4. Endo J.
`Med Chem., 2B(4) 401 (1985))
`CS-514 and Mevinolin have been clinically proved to be
`potentiall,v useful anti-byperlipoproteinemic agents, ancl
`they are consirlered to be eflective for curing or preventing
`diselses of coronary artery sclerosis o¡ atherosclerosis.
`(lXih lnt. Syrnp. Drugs A.trect. Lipiri ivletab., 198ó, p30,
`p3L, p66)
`However, with respect to fully synthelic cle¡ivatives,
`particularly hetero a¡omatic derivatives ofinhibitors against 25
`HMG-CoA reductase, limitecl information is clisclosed in the
`following literatures:
`v/Pr ACC NO. B4-158675, S6-028274, 86-098816,
`B 6 - _73207 0, B7 -1245 19, 87 -2209B7, BB-0778 1, 88-008460,
`88-091798 and 88-112505.
`The present inventors bave tbund that mev¿rlonolactone
`derivatives having a quinoline ring, the corresponding dihy-
`droxy carboxrvlic acids aod salts and esters thereof have high
`inhibitory activities againsr
`cholestcrol [riosynthcsis whcrci n
`HMG-CoA recluctase acts as a rate liruiting enzyme. The
`present inventiou has been accomplishecl on the basis of this
`discovery.
`The novel mevalonolactone derivatives of the present
`invention are represented by the following formula I:
`
`30
`
`(wherein I{n is hydrogcn, C,-* alþI, Cr_. altrioxy, fluoro,
`chloro, bromo or trifluoromethyi), phenyl-(CH-),"-
`(w.herein m is 1, 2 or 3), -{CFIr)"CH(CHr)-phenyl or
`phenyt-(CHr),,CH(CH.)- (rvherein n is 0, 1 or 2).
`Various substìh¡ents in the i'ormula I will be clescribecl in
`detail with reference to specific examples. Howeveç it
`be uncle¡stoocl that the present invention is lry no
`,t should
`restriclecl by such spccilic examples.
`mcans
`alkyl t'or l{r, lì2, Iì3, l{4. l{6 a¡d Rs' incluclcs, tbr
`Cr-u
`e xample, mcthyl, cthyl, n-propyl,
`i-propyl, n-butyl, i-butyl.
`sec-butyl and t-butyl. Cr_, alkoxy
`for R], R:, R3, Ra ancl Rd
`.,, include,s, for example, melhoxy, ethoxy, n-propoxv ancl
`r-propoxy.
`(r)
`Cr_, alkyl f'or Rrl inclucles, t'or example, methyl, ethyl,
`n-propyl ancl i-plopy.l.
`Cr_, alkyl lbr R13 incluclcs, lbr example, merhyl, ethyl,
`n-propyl and i-propyl.
`4-s Alkyl tbr R1a includes, t'or examplc, methyl, ethyl,
`n-propyl, i-propyl, n-butyl and i-butyl.
`M is a metal capable of fbrming a pharmaceuticallv
`acceptable salt, and i1 includes, tbr example, sodium ancl
`potassium.
`50 CO,M inclucles, I'or example,
`-COrNHu and -co2FL
`(prim ary to t.crtiary lowcr alkylamine such as
`Rr
`trimethylamine).
`Cr_u alkyl tbr R' includes, fbr examplc, methyl, ethyl,
`wherein Rr, R2, R3, Ru and Ró are independcntly hydrogen,
`Cr-u alkyl, C._u cvcloalkyl, C, .
`n-propyl, i-propy1, n-butyl, i-buty1, sec-butyl, t-butyl,
`alkoxy, n-butoxy, i-t'rutoxy,
`7 and R8 are inclepenclently -ss o-pertyl and n-he-xyl.
`sec-butoxy, RtRtN- (whereiu R
`hyclrogen or Cr_. alkyl), trifluoromethyl, trifluoromethox;,.
`C._o cycloalkyl ttrr R5 includes, tbr example, cyclopropyl,
`difluoromethoxy, flroro, chloro, lrromo, phenyl, phenoxy,
`cyclobutyl, cyclopentyl and cyclohexyl
`benzyloxy, bydroxy, trimethylsilyloxy, diphcnyl-t-
`C-_, alkenvl ttrr R' inclucles, t-or example, vùyl and
`butylsilyloxy, hydroxymethyl or
`(wherein
`ipropenyl.
`-O(CFI-),ORle
`60 Phenyl-(CH.)-- for R' includcs, for example, trenzyl,
`Rre is bydrogen or Cr-j aikyl, ancl I ts 1,,2 or 3); or when
`locatecl al the o¡tho position to each other, Rr and R2, or R3
`B-phenyletby-l ancl y-phenylpropl'1.
`tnd Ra togethe¡ lb¡m -{H:CH-CH:CH-;
`or when
`Phenyl(CFIr),,CH(CHs)- t'or Rs inclucles, tbr example,
`located at the ortho position to each other, Rl and R:
`cr-phenylethyl and cr-benrylethyl.
`t5)(R L'r)O-{w-herein R'5 ancl Rr6 are
`Cr,, alk;rl tb¡ R7 ¿Lncl RB includes, for example, methyl,
`together t'orm
`-OC(R
`independently hydrogen or C,-. alkyl); Y is
`ó.5 ethyl, n-propyl and ilropyl.
`-CII"-.
`Further, lhese courpoundsmay have a1 least one or hvo
`-CH,CH2-,
`-CH'-CH:CH-
`-CFI:CH-.
`-CH:Cf I-C'FI.-; and Z is - Q-C]H2WCH2-COZI( 12,
`asymmetric cafbou atoms ald may have ¿rt loast trvo to t'our
`
`RJ
`
`R¿
`
`.{-z
`
`N
`
`R5
`
`or
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 16 of 50
`
`34
`oplical isomers- The compounds of the formula I include ull
`o[ these optical isomers and all of the mixtures there.t'.
`
`5,856.336
`
`dimethyl, 6.8-dimethyl, 6,7-rlirucLhoxy, 6,7-<Jiethoxy, 6,7-
`dibrom-o or 6,g-clibromo.
`When R1, R2 ancl 116 a¡e no¿ hydrogcn, they together
`rcpresent 5,7-dimethoxy-8-hydroxy, 5,8-dichloro-6-
`5 hy-clroxy, 6,7,8-t¡imethoxir, 6,7,8-rrimethyl, 6,7,8-trichloro,
`-5-lluoro-6,8-dibromo or 5-chloro-6,8-dibromo.
`
`and (E)_
`pretÈriecl
`Zmavl>e
`
`Now, prelèrred substituents of the compouncls of lhe
`p¡esent invention will be dcscribed.
`In the following prcferred, more prefctcd srill furtbcr
`pert'erred
`, the numerals tbr the
`As pretèrred exa
`positions
`the positioos on the
`-CH:CH-may
`quinoline
`wn by e.g. 1., or 2,
`exampies LotZ,tlte
`inclicates
`nent on the phenyl l-s nendãnecl.
`
`qu
`ls
`tue
`
`o
`
`o
`
`cl substi
`1 be des
`Rr and
`l, 6-trifl
`:o 6-methoxy, 6-chloro, 6_bromo, 6_n_butyl ancl
`Rz
`fluoro, chloro, bromo, Cr_. alkyi, Cr_, alkoxy, C, u
`7-dimethylamino.
`cycloalkyl, dimcthyÌi'mino, hydroxy, h]'clroxymctbyi, When only Rd is hydroger, R1 and R2 represent 6,E-
`hydroxyethyl, trifluoromethyl, trifluoromerhoxy, diclforo, 5,S-dimeth¡4, 6,8-dimethyl, 6,7-dimãrhox.v, 6,7-
`difluoromethoxy, phenoxv and [renz¡rloxy-
`cliethoxy, 6,7-clibromo, 6,8-dibromo, 6,7-difluoro un¿ 6,g-
`when Ró is hydrogen, it is preferred that Rr and z5 difluoro.
`^Further,
`R" together form methylenedioxy.
`As still further preferred examples ibr Rì ancl Ra, lvhen R3
`,ds preferrecl examples fbr R3 anci R't, when R't is
`is hyclrogen, Ra is hyclrogeo,4'-chloro or 4'-fluoro, or R3 and
`hydrogen, R] is hyclrogen, 3'-fluoro, 3'-chlorr.¡, 3'methy1, Iìa together reproscnt 3'-meth)r1-4ifluoro.
`4'-methyl, 4'-chloro and 4'-fluo¡o.
`Still fi:rther pretèrred examples for R5 include ethy1,
`Otber preferred combinations of R3 and Ra inclur.le 30 n-propyl, i-propyl and cyclopropyl.
`3'-mcthyl-4'-chloro, 3',5'-dichloro, 3',5'-difluoro, 3',5'-
`Still furrher pret'erred examples for Y include (E)-
`CH:CFI-,
`dimethyl and -1'-methyl-4'-fluoro.
`Ècferrecl examples for Ri include primary anc{ seconclary
`,4s still further pretèrecl examples t'or Z, the above-
`C.-u alkyl and C.-u cyc'loaLkyl.
`mentioned preferred example lor Z mtty be menticuecl.
`ancl 35 Notv, the most prcf'errcd substitucnts tbr thc compouuds
`llferred examples ft¡r Y include -CFI2-{ìH'-
`of the present inveutior: will be clescribecl.
`-CIì:CII-.
`Preferred examples for Z include
`As tllc most prct'crrccl examples t'or Rl, lì2 and R6. when
`both R2 and Rd are hyclrogen, Rr is hydrogen, 6-metbyl or
`6-chloro.
`40 Wheo only R6 is hydrogen, Rl and Rz together represent,
`t-or example, 6,7-dimelhoxy.
`,As the most pretèrred exampies tbr R3 ancl R4, R3 is
`hydrogen and Ra is b¡rdrogen, 4'-chloro o¡ 4,-fluoro.
`
`v o
`
`., *l$.i;;l t;"riï*-;iÏå".'f:ÏJîïyiïî"åiiï:
`
`-cr(orDcrrcFr2(orÐcrr2co2R,¿,-cr(oH)*r,c(o)
`cH2co'Rr2and-cH(oH)cFIf(oRt:)zcH,co-R12.
`¡É¡___i'¡1:an_.
`Now,morel:referredsulxtituentsofthec-ompounclsofthe As the most pretèred example.s for Z, the above-
`presenl invention w-ill Lre clescribed.
`men¡ioned preferrèd examples foi z ma-J be mentioned.
`-AsmorepretèrredexamplesforRt,RtandR6,rvhenboth Noiv, paiticulariy prefeired specific Lompounds of the
`Rz_andR6arehydrogen,Rtishyclrogen,5-fluoro,6-fluoro, :0 presenl inventi<.¡n will be presented. The tbilowing com-
`7-fluoro, B-lluoro, 5-chloro, 6-chloro, 7-chloro, 8-chloro, pounds (a) to (z) are showrrin the ttrrm of carboxyliJ acicts.
`5-bromo, ó-bromo. 7-bromo, B-bromo, .5-methvl, 6-methy1, i{o*",r".,.'th" present invention inc-lucle not only the com_
`7-methyl, 8-methyl, S-melhox¡ ó-methox¡ 7-methoxy, pounds in the t'orm of carboxylic acicls but also the cor¡e-
`B-methoxy, -5-trifluoromethyl, 6-rrifluoromethyl, sponcling lactones tbrmecl byihe condensation of the c¡rr-
`7-tlifluoro¡¡ethyl, B-trifluoromethyl, ó-trifluoromethoxy, -ss boxyücãcicls with hyctroxv at the 5_position, and soclium
`6-difluoromethoxy. B-hydrox-verhyl, 5-hydroxy, 6-bydrox¡'. salti ancl lower alkyl esters (such as methyl, ethyl, i-¡rropyl
`7-hydrox¡1, B-hydroxy, 6-ethy1, 6-n-butyl ancl an{ n-propyl esters) of Lhe òarb¡xylic acicls, which can be
`7-climetbylamino.
`physioiogiialiy hydrolyzed to the carboxylic acids.
`When Ró is hyclrogen, Rl and Rz together reprcseot ^ (a) (E')-3,-s'-cti-hyclróxy-7-[4'-(4',-fluoíophen.vl)-2,-(1,'-
`6-chloro-8-methyl, 6-bromo-7-methoxy 6-methyl-7-chloro, 60 merhylethyl)-quinoiin-:'-,vf]-fr"pt-i-"noi" oËid
`6-chloro-B-hyclroxy,5-rnethyi-2-hyctroxy,6-merhoxy-7- (b) (E)-3,j-ditr¡,aroxv-1_[4'-(4,'_fluorophenyl)_2,_(1,,_
`chlo¡o, 6-chlonr-7-methox¡ 6-hydroxy-7-chloro, 6-chloro- m"ìh¡,lcthyl¡-6,-chlóro_quinolin-3ì-yl]_heprå_enoic acid
`7-hydroxy,6-chloro-8-bromo, -5-chloro-6-hydroxy, 1cj 1uj-a,s-aihycJroxy-7-[4,-(í',-fluoroptre¡yl)-?,-(1,,-
`6-Lrromo-B-chlo¡o, 6-bromo-8-bydroxy, 5-methyl-8-ch1oro, meìtryietÉyl)-o'--"ihyl-qniooli¡-j.yll-hepr6-cnóic
`acict
`7-hyclroxy-B-chloro, ó-bromo-B-hyclroxy, 6-merhoxy-7- o-s (dj (E)_3,_5_clihidråx],_7_[4 _i+,,_nìoroptrenyl)_2,_
`methyl, 6-chloro-8-hronro, 6-methyl-8-bromo, 6,7-ditluoro. (l';merhylerhyl)-6,,7'-dim;rhoxy_quinolin_3 lut]_ú"ít_O_
`6,8-ctifluoro, 6,7-methylcncclioxy, 6,8-dichloro, 5,8- enoicacicl
`
`

`

`Case 1:14-cv-02758-PAC Document 2 Filed 04/17/14 Page 17 of 50
`
`5,856.336
`
`5
`(e) (E)-3,5-dihydro x y-7-[4'-(4" -lluorop |.eny l) -2' -
`cyclopropyl-quinolin-3'-yll-bept-6-enoic acicl
`(f) ( E)-3,-5 -dihydroxy-7-[4'-(4 "-fl uorophenyl)-2'-
`cyclopropyl-6'-chloro-quinolin-3r-y1]-hept-6-enoic acid
`(g) (E)-3,5 -d ihycl rox,v-7-[4'-(4" -Èuorop henyl)-2'- s
`cyclopropyl-6'-mcthyl-quinoli¡-3'-yl]-hcpt-ó-cnoic
`acid
`(h) (E)--1,5-clihydroxy-7-[4'-(4'' -fl uorop henyl)-2'-
`cyclopropyl-6',7' -dime thoxy-quinolin-3'-_vl]- hept-6-enoic
`acid
`(i) (E)-3,5-clih y dr o xy -7 -14' - (4" -chlorophenyl) -2' -(t " - to
`methylethyl)-qui noli n-3'-yl]- hep t-6-enoic acid
`ú) (E)-3,-5-dihydrox,v-7-[4'-(4"-chlorophenyl)-2'
`-( I" -
`me thylethyl)-6'-chloro-qtLinolin-3'-yl]-hept-6-enoic acid
`(k) (E)-3,-5-clihyclroxy-7-[4'-(4" -chlorophe ny1)-2' -(L" -
`molhylethyl)-6'-methyl-quinolin-3'-y1]-hept-6-cnoic acid
`(l) (E) -3,-5-dih y droxy -7 -f4' - (4 "-chlorop henyl)-2'-( l " -
`methyle thyl)-6',7'-dimethoxy-quinolin-3'-y1]-hcpt-6-enoic
`acicl
`(n) (E) -3,-5 -dih ytlro x y-7 -[4'-( 4" -chlo rop h eny l) -2' -
`cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid
`(n) (E)-3,5-ctihydroxy-7-[4'-(4"-chlorophen.vt)-2'-
`cllclopropyl-6'-chloro-quinolin-3'--vÌ]-hept-ó-enoic acid
`(o) (E)--1,5-dihyd roxy-7-[4'-(4 " -chlorop h enyl) -2' -
`cyclopropyl-6'-methyl-quinolín-3'-yl]-hept-6-onoic ¿rcicl
`(p ) (E)--i,5 -d rhy ck oxy -7 -14'-(4 " -chioroph e ny1) -2' - zs
`c;rcloprcrpvl-6'7'-climelhoxy-quinolin-3'-yl]-hepl-6-enoic
`acicl
`(q) (li)-3,5-dibyclroxy-7-[4'-phenyi-2'-(
`quinolin-3'-yI]-hept-6-enoic acid
`G) G)-3,5-dihydrox¡r-7-[4'-phenyl-2'-(1"-methylethyl)- :o
`6'-chloro-quinolin--l'-yll-hept-6-enoic acid
`(s) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-(1
`6'-methyl-quinolin-3'-yl]-hept-6-enoic acid
`(Ð (E)- 3,-5-clihydroxir-7-[4'-ph e oy7-2' -( 1 "-me thylethyt)-
`6',7'-dimethoxy-quinolin-3'-.vl]-bept-6-enoic acid
`(u) (E)-3,-5-dihyclroxy-7-[4'-phen.vl-2'-cyclol:ropyl-
`quinoliu-3'-yI]-hept-6-enoic acid
`(v) (E)-3,5-clihydroxy-7-[4'-phenyl-2'-cyclopropyl-6'-
`chloro-quinolin-3'-y1]-hept-6-enoic acicl
`(w) (E)-3,-í-clihyclroxy-7-[4'-phcnyl-2'-cycloi-rrop¡rl- ó'- +o
`meth¡rl-quinolìn-3'--v1]-hep t- 6-enoic acicl
`(x) (E)-3,5<tihyrJroxy-7-[4'-phenvl-2'-c¡iclop ropyl-6',1' -
`dimethox1l-quinolin-3'-yl]- hep t-6-e noic acid
`(y) (E)-3,5-dihytlrox¡r-7-[4'-(4"-lluorophenyl)-2'-(1 "-
`methylethyl)-ó'-methoxy-quinolin-3'-yl]-hept-6-enoic acicl 4-s
`(z) (E)-3,5-dihy clrox y-7-[4'-(4" -.[uo rop he ny l)-2