Kowa Company Et. Al. v. Aurobindo Pharma Et. Al.

I
Case 1:14-cv-02497-PAC Document 2

Anthony J. Viola Jennifer L. Dereka 'W. Zachary Silverman
Filed 04/09/14 Page 1 of 50
EDWARDS WILDMAN PALMER LLP Attorneys for Plaintiffs Kowa Company, Ltd., Kowa Pharmaceuticals America, Inc., and Nissan Chemical Industries, Ltd. 750 Lexinglon Ave. New York, NY 10022
(2r2) 308-44rt
,i
er"'
1n
r{.11.i.;*
a $
UNITED STATES DISTRICT CO SOUTHERN DISTRICT OF NEW
{Ft r} $; g$t4
Kowa Company, Ltd., Kowa Pharmaceuticals America, Inc., and Nissan Chemical Industries, Ltd.,
Civil Action No.
Plaintiffs,
v
Aurobindo Pharma Limited and Aurobindo Pharma USA Inc.,
Defendants.
COMPLAINT
14" CV f;1,ri;ffi?
Plaintiffs, Kowa Company, Ltd. ("KCL"), Kowa Pharmaceuticals America, Inc. ("KpA,' (collectively, "Kowa"), and Nissan Chemical Industries, Ltd. ("NCI") by their undersigned
counsel, for their Complaint against defendants Aurobindo Pharma Limited ("Aurobindo Ltd.',)
and Aurobindo Pharma USA Inc. ("Aurobindo Inc.") (collectively, "Aurobindo"), allege as
follows:
Jurisdiction and Venue
1.
This is an action for patent infringement arising under the patent laws of the
United States, Title 35, United States Code and arising under 35 U.S.C. gg 271(e)(2),271(b),
271(c), and281-283. Subject matter jurisdiction is proper under 28 U.S.C. $$ 1331 and 1338(a). Venue is proper under 28 U.S.C. $$ 1391(b)-(c) and 1400(b). Personal jurisdiction over the
defendants in New
York is proper under N.Y. C.P.L.R. $$ 301 and 302(a) and because
defendants are doing business in this jurisdiction.
Parties
2.
KCL is a Japanese corporation having its corporate headquarters and principal
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

organized. under the laws
of Delaware.
3. 4.
NCI is a Japanese corporation having its corporate headquarters and principal
place of business in Tokyo, Japan-
KCL
and
NCI are engaged in the business of research, developing,
manufacturing, and marketing of a broad spectrum of innovative pharmaceutical products, mcluomg Llvalo".
5.
Upon information and belief, Aurobindo Ltd. is a company organized and existing
under the laws of India, having its principal place of business in Hyderabad, Pradesh, India.
Upon information and belief, ANDA No. 20-6015 was filed under the name of Aurobindo Ltd.
6.
a
Upon information and belief, Aurobindo Inc. is incorporated in Delaware having
principal place of business in Dayton, New Jersey, and is a wholly owned subsidiary
of
Aurobindo Ltd. Upon information and belief, Aurobindo Inc. acts as the U.S. agent and distributor for Aurobindo Ltd.
7.
Upon information and belief, Aurobindo is currently transacting business in the
Southern District of New York, at least by making and shipping into this Judicial District, or by
using, offering to sell or selling or by causing others to use, offer to sell or sell, pharmaceutical products into this Judicial District.
8.
Upon information and belief, Aurobindo derives substantial revenue from
interstate and/or international commerce, including substantial revenue from goods used or
consumed or services rendered in the State of New
York
and the Southern
District of New York.
Upon information and belief, Aurobindo Inc. has been registered with the N.Y. State Department
of State, Division of Corporations, to do business as a foreign corporation in New York. By filing its ANDA, Aurobindo has committed, and unless enjoined, will continue to commit
a
tortious act without the state of New York, that Aurobindo expects or should reasonably expect
to have consequences in the State of New York including in this Judicial District.
The New Drus Application
9.
KPA sells drug products containing pitavastatin calcium (the 'itavastatin drug
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).
10.
Livalo@ is approved for use 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.

1
1.
The approval letter for Livalo@, with approved labeling, was issued by the FDA
on August
3,2009.
Certain amendments to the approved labeling for Livalo@ have subsequently been
12.
approved.
The
in Suit
13.
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 Exhibit A, was duly
issued on January 5,1999 to inventors Yoshihiro Fujikawa,
Mikio Suzuki, Hiroshi lwasaki,
Mitsuaki Sakashita, and Masaki Kitahara, and assigned to plaintiff NCI. The '336 patent claims,
inter alia, the pitavastatin drug product, and a method for reducing hyperlipidemia, hyperlipoproteinemia or atherosclerosis, which comprises administering an effective amount
the pitavastatin drug product.
of
14.
Plaintiff NCI
has been and
still is the owner through assignment of the '336
patent, which expires on December 25,2020 pursuant to a patent-term extension. KCL is NCI's licensee for the '336 patent and KPA holds a license from KCL for the '336 patent.
15.
United States Patent No. 8,557,993 ("Ihe'993 patent"), entitled "Crystalline
Forms of Pitavastatin Calcium," aIrue and correct copy of which is appended hereto as Exhibit B, was duly issued on October 15,2073 to inventors Paul Adriaan Van Der Schaaf, Fritz Blatter,
Martin Szelagiewicz,
and.
Kai-Uwe Schoening, and ultimately was assigned to plaintiff NCI.
The '993 patent claims, inter
4, crystalline polymorphs
or the amorphous form of pitavastatin
or processes for preparing the same.
16.
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.
17.
In accordance with its license, KPA sells the pitavastatin drug product under the
trade name Livalo@ in the United States. Sales of Livalo@ are made pursuant to approval by the
FDA of NDA No. 22-363.
18. 19.
Plaintiff KCL manufactures the Livalo@ drug products as sold by KPA.

Plaintiffs Kowa and NCI will be substantially and irreparably harmed by
infngement of either of the '336 or'993 patents (the "Livalo@ patents"). There is no adequate remedy a.law.
COUNT
I
Q
INFRINGEMENT OF THE '336 PATENT UNDER 35 U.S.C.
271(el(2llAl
20.
each
Plaintiffs repeat and incorporate herein by reference the allegations contained in

paragraphs.
ofthe foregoing
21-
Upon information and belief, defendant Aurobindo filed an Abbreviated New
Drug Application ("ANDA") with the Food and Drug Administration ("FDA") under 21 U.S.C.
$
355(i) (ANDA No. 20-6015) seeking approval to market
-g, 2 ^g,
and 4 mg tablets
comprising pitavastatin calcium.
22.
By this ANDA filing, Aurobindo has indicated that it intends to engage, and that
there is substantial likelihood that it

use, offer
will
engage, in the commercial manufacture, importation,
for sale, andlot sale, or inducement thereof, of Plaintif' patented pitavastatin drug
product immediately or imminently upon receiving FDA approval to do so. Also by its ANDA
filing, Aurobindo has indicated that its drug product is bioequivalent to Plaintif' pitavastatin
drug product.
23.
By its ANDA filing, Aurobindo seeks to obtain approval to commercially
manufacture, use, import, offer for sale, andlor sell, alleged generic equivalents of Plaintiffs'
Livalo@ pitavastatin drug product
prior to the expiration date of the '336 patent.
24.
By a letter dated February 2I,2014 (the "Notice Letter"), Aurobindo informed

$
Kowa and NCI that Aurobindo had filed a certification to the FDA, pursuant to 21 U.S.C.
355CX2XA)(vii)(N).
On or about February
24,2014,KP4 received the Notice Letter. On or
about February 25,2014, KCL and NCI received the Notice Letter.
25.
The Notice Letter, purporting to be Aurobindo's Notification Pursuant to 21
U.S.C. $ 3550X2)(BXi, asserts that in Aurobindo's opinion, the'336 patent purportedly is
"invalid, unenforceable, andlor will not be infringed by the manufacture, importation, use or sale
of the drug product described in Aurobindo's ANDA."
26.
Aurobindo's filing of ANDA No. 20-6015 for the pu{pose 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 infringement under 35 U.S.C. g 271(e)(2)(A).
27.
Aurobindo's manufacture, uss, importation, offer for sale, and/or sale, or
inducement thereof of its proposed pitavastatin drug product will directly infnge or induce
infngement of at least one claim of the '336 patent under 35 u.s.c.
271(e)(2)(A).
28.
product
Upon information and belief, Aurobindo's proposed label for its pitavastatin drug
and
will include the treatment of at least one of hyperlipidemia, hyperlipoproteinemia,
atherosclerosis.
29.
the'336
Unless Aurobindo is enjoined from infringing and inducing the infringement
of
patenl, Plaintiffs
will suffer substantial and irreparable injury. Plaintiffs
have no
adequate remedy at law.
COUNT INF'RING
II
PATENT
OF THE CLAIM OF THE ' UNDER 35 U.S.C. 8 271(b)
30.
each
ofthe foregoing paragraphs.
31.
Upon information and belief, approval of ANDA 20-6015 is substantially likely to
result in the commercial manufacture, use, importation, offer for sale, andlot 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.
32.
Upon information and belief Aurobindo's proposed label for its pitavastatin drug
product will include the treatment of at least one of hyperlipidemia, hyperlipoproteinemia or

atherosclerosis.
33.
Upon information and belief, Aurobindo 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 dyslipidemia. The beneficial
effects of pitavastatin as an adjunctive therapy to diet to reduce elevated total cholesterol, lowdensity 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 Aurobindo (.g., including, without limitation, physicians, pharmacists, pharmacy benefts management companies, health care providers who establish drug formularies for their
insurers andlor patients). Aurobindo will be marketing its pitavastatin drug product with specific intent to actively induce, aid and abet infngement of the '336 patent. Aurobindo knows or
reasonably should know that its proposed conduct
will induce infringement of the '336 patent.
34.
Unless Aurobindo is enjoined from infringing and inducing the infringement
of
the '33 patent, Plaintif will suffer substantial and irreparable injury. Plaintiffs have no
adequate remedy at law.
COUNT
INF'RIN
III
oF'
METHOD OF THE '336 UNDER 35 tI .s.c. 2ttkr
35.
each
Plaintif repeat and incorporate herein by reference the allegations contained in
36. 37. 38.
Upon information and belief, Aurobindo's proposed pitavastatin drug product
comprises pitavastatin calcium as referenced in the claims of the '336 patent. Upon information and belief Aurobindo's proposed pitavastatin drug product
will
be especially made for use in a manner that is an infringement of the '336 patent.
Upon information and belief Aurobindo knows that Aurobindo's proposed
pitavastatin drug product will be especially made for use in a manner that is an infringement
of
the '336 patent.
39.
Upon information and belief sale of Aurobindo's proposed pitavastatin drug
product will result in direct infringement of the .336 patent.
40.
Upon information and belief, Aurobindo's proposed pitavastatin drug product is
not a staple article or commodity of commerce which is suitable for a substantial noninfringing
use.
41.
Upon information and belief Aurobindo knows that Aurobindo's proposed
pitavastatin drug product is not a staple article or commodity of commerce which is suitable for
substantial noninfringing use.
42.
Upon information and belief, approval of ANDA 20-6015 is substantially likely to
result in the commercial use, manufacture, offer for sale and/or sale (or the inducement thereof or contribution thereto) of a drug product which is especially made, adapted, marketed, sold, and approved exclusively for use in a method claimed in the '336 patent, immediately or imminently upon approval of the ANDA.
43.
Plaintiffs will be substantially and irreparably harmed if defendants are not
enjoined from contributing to the infngement of the '336 patent Plaintiffs have no adequate remedy at law.
CO INF'RIN OF THE '993 PA
IV
UNDER 35 U.S.C.
E
271klQl('tl
44.
each
45.
Aurobindo's Notice Letter, purporting to be Aurobindo's Notice of Certification
under 21 U.S.C. $ 355(D(2)(BXi, indicates that Aurobindo intends to manufacture, use, sell, or
offer for sale, its proposed pitavastatin drug product prior to the expiration of the '993 patent.
Filed 04/09/14 Page 10 of 50
46.
The Notice Letter asserts that in Aurobindo's opinion, the'993 patent
purportedly is "invalid, unenforceable, andlor
will not be infringed by the manufacture,
importation, use or sale of the drug product described in Aurobindo's ANDA."
47.
Aurobindo's filing of ANDA No. 20-6015 for the purpose 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 infngement under 35 U.S.C. g 271(e)(2)(A).
48.
Aurobindo's manufacture, use, importation, offer for sale, sale, andlor importation
of its proposed pitavastatin drug product

one claim of
will directly infringe or induce infringement of at least
the '993 patentunder 35 U.S.C. g 271(e)(2)(A).

Unless Aurobindo is enjoined from infringing the '993 patett plaintiffs will
49.
suffer substantial and irreparable injury. Plaintiffs have no adequate remedy atlaw.
WHEREFORE, Plaintiffs request the following relief,
(a)
a declaratory judgment pursuant to 28
u.s.c. 2201d
*:that
making, using,
selling, offering to sell and/or importing Aurobindo's pitavastatin drug product
for which it seeks FDA approval or any drug product containing pitavastatin will infringe at least one claim of one or more of the Livalo@ patents;
(b)
a declaratory judgment pursuant to 28
u.s.c . 2201et
seq. that the making,
using, offering for sale, selling and/or importing of Aurobindo's pitavastatin

drug product or any drug product containing pitavastatin,
will induce the
infringement at least one claim of one or more of the Livalo@ patents;
10
Filed 04/09/14 Page 11 of 50
(c)
a declaratory judgment pursuant to 28 U.S.C . 2201et !eq. that the making,
using, offering for sale, selling andlor importing of Aurobindo's pitavastatin

drug product or any drug product containing pitavastatin,
will contribute to the
infringement of at least one claim of one or more of the Livalo@ patents;
(d)
a declaratory judgment pursuant to 28 u.S.c . 220r et sq. and an order
pursuant to 35 U.S.C. $ 271(e)@)(A) providing that the effective date of any
FDA approval for Aurobindo to commercially make, use, sell, offer to sell or
import its pitavastatin drug product or any drug product containing pitavastatin
be no earlier than the date following the expiration date of the last to expire the Livalo@ patents (as extended,
of
if
applicable);
(e)
penanent injunction restraining and enjoining against any infringement by
defendants, their officers, agents, attorneys, employees, successors or assigns, or
those actingin privity or concert with them, of the Livalo@ patents, through the commercial manufacture, use, sale, offer for sale or importation into the United
States of Aurobindo's pitavastatin drug product or any drug product containing
pitavastatin , andlor any inducement of or contribution to the same;
( (g)
Attorneys' fees in this action under 35 U.S.C.
2g5; and
Such further and other relief in favor of Plaintiffs and against defendants as this
Court may deem just and proper.
11
Filed 04/09/14 Page 12 of 50
Dated:
New York, New York
April 9,2014
Kowa Company Ltd., Kowa Pharmaceuticals America, Inc., and Nissan Chemical Industries, Ltd.
attorneys
,/e
Anthony J. Jennifer L. Zachary W. Silverman EDV/ARDS WILDMAN PALMER LLP 750 Lexington Avenue New York, NY 10022 (212) 308-441r
David G. Conlin (to be admitted pro hac vice) Kathleen B. Carr (to be admitted pro hac vice) Adam P. Samansky EDWARDS WILDMAN PALMER LLP lll HuntingtonAvenue Boston, MA02199 (617) 23e-0100
t2
Filed 04/09/14 Page 13 of 50
EXITIBIT A
Case 1:14-cv-02497-PAC Document 2 Filed 04/09/14 Page 14 of 50 I lllll ilil]t ilr ililt ililt llllt l]] ]ilt ]llt illlt ililt ]llil llt ]]l llll
IJnited States Patent

Fujikawa et al.
us0058-563-36A
ilel
[1 1]
[4s]
Patcnt Numbcr: Date of Patent:
5,856,336 Jun. 5,1999
[-54] QUINOT.TNE TypE MI,VAT.ONOI_ACTONES
[75]
Inventors: Yoshihiro Fu.iikawa; Mikio Suzuki; Hiroshi lwasaki, all of Funabashi; Vlitsuaki Sakashita; Masaki Kitahara, both olShiraoka-machi, all of Japan Assigncc: Nissan Chemical tndrrstrics Ltd.,
Tokyo, Japan
Prinary Exannerl,a:ura I-. Stockton AttorrLey, Agent, or Frnr4lllon, Spivak, McClelland, lVlaicr & Nousrdt, P.C.
ls7)
ABSTRAC'f
[]31
A compouncl of the formula

F
tAl
[21] Appl No.: 883,398 I/21 lilcd: Nlay 15,1992

Related U.S. Application l)ata
162l
coutinuation ol Scr: No. 233.752. Aug. 19, 1988.
Division oI Ser No. 63l,Oc)2, Dec. t9,
1c)Ou..
wbictr
ir
[30]
l'oreign Application lrriority Data

IJPI
c-P
Aug. 2Q, 1987 .lan. 26. 1988 Aug.3. 1988
pPl
UP]
Japan Japan Japan
Cl. ls2l U.S. cl.

[s1]
Int.
....... .. ...... ......... A6lK
......... 62-207224
...... 63-15585 63-193606
3'1.147;
z:-cH(oH)-cH"-cFI(
have
OH)-CHr-CO
O.%Ca
C07D 275/72
IIIVIG-CoA inhibiting eftcts, making them useful as inhibitors of choleslerol biosynthesis. The compound may be prepared atherosclerosis.
as a
[58]
Field of Search
.....
sl4/3lt; s46tlj3
5L4i3tI
phalmaceutical tbr recluc-
........... 5461173;
ing hyperlipidemia, hyperlipoproteinemia or
[56]
References Cited
U.S. PAIENT DOCUMENTS
5,753,675 -5l1998 Wauanasin
..... .... .....
-........... 5t4l31t
2 Clairns, No Drawings

5,856.336
1
Filed 04/09/14 Page 15 of 50
2
R
QUINOLINE TYPE IEVALONOT-ACTONES 'Ihis is a division, of application Scr. No. 01i63I,092, 752,IedAug l9, l988
f,lcd on Dcc, 19, 1990, which is a continuation of 07t233,
The present invention relafes to novel mevalonolactones having a quinoline ring, processes fbr their procluction, pharmaceutical cornpositions containing tlem ancl their pharmaceutical uses particularly as anti-hyperlipiclemic, hypolipoproteinemic and anti-aherosclerolic agcnts, ancl,.. intcrmcditcs uscful t'or their procluction ancl proccsscs for '" thc production ol such intcrmccliatcs. compactine, CS-514, Mevinolin or semi-syntbetic dc.rivatives ol frrllv synthetic derivrtives thereof are known to Le inhibitors against HMG-Co rechrctase which is a rare limiting anzyme tbr cholesterol biosynthcsis. (4. Endo J. Med Chem., 28(4) 401 (1985)) CS-514 and Mev.ioolin have been clinicall.v provecl to be o
l tt
R18
Y
o
Ru
CO]RL2
Some fermentation metabolic proclucts such
as
w
1-s
(rvhcrcin Q is
is
-Cl(O)-, -C(Oi13)2-CH(OH)-; or R'1 is -C(O)-, -C(RuXoH)-r hyclrogen or Cr_. -C(oR13)2alkyl; Rt2 is hydroge n or R14 (wherein Rl'r
or
potentiall;r useful anti-hyperlipoproteinemic agents, ancl they are consiclerecl to le elfective for curng crr preventing diseases of coronary artery sclerosis or atheroscleosis.
is physiologically hvdrolvzable alkyl or M (wherein M is NH.*, soclium, potassiurn, % calcium or a h;rclrate of lorver aikvlamine, two R13 are
20
or two I{r3
and l18 arc
p3l, p66)
(IXlh Int Syup. Drugs Affect Lipid Metab.,
1986, p30,
hyclrogen, Cr-u alkyl, Cr_. alkenyl, Cr_u cycloalkyl,
Horvever, with respect to trlly synthetic clerivatives, particularly hetero aromtic clcrivtivcs of inhiLritors againsr HMG-CoAreductase, limitecl int'ormation is clisclosed in the
25
following literaLures:
36
wPI ACC NO. 84-l-58675, E6-O28274,86-098816,

30
88-091798 and 8B-11-2505. Ttre present inventors have t'ouncl that mevrlonolactone clerivatives baving a quinoline ring, the corresponding dihydroxv carboxyLic acids and salts and esters theeof have high inhibitory activitics againsr cholcstcro [riosynlhcsis rn'hcrein FIMG-CoA recluctase acts as a rate limitin-e enzvme. The present invention has been tccomplishecl on tbe bsis o[ tbis
discovery'.
-33207 0, 87 -1245 19, 87 -220981, 8.q-0778 1, 88 -008460,
chloro, bromo or lrifluoromethyl), phenyl-(CH.),,, (wherer'n m is l, 2 or 3), --{CHr),,CH(CHr)lhenyl or phenyl-(CFI"),,CH(CH3)- (rvherein n is 0, t or 2). Various subsliluents in tfie t'ormula I will be describecl in detil rvith reference to speoific examples. Flowever, it
shoulcl be unclerstctocl that the prescnt invcntion is by no mcans rstricted by such specifie exlmples. Or_u alkyl tbr l{r, I2, R3, l{4, I6 and l{e incluclos, tbr cxamplc, mcthyl, cthyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-bu1yl and rbutyl. C,_, alkoxy tbr Rr, R:, R3, R4 and R6
(rvbcrcin I{e s hydrogcn, C,-,,
alI,
C,-., altrioxy, fluoro,
35
The uovel mevalonolactoe derivatives of tbe present invention are represented by rhe tbllowing formula I:
RJ
R{
o,, '
includes,
l-propoxy.
for examle,
methoxy, ethoxy, n-propoxy
ancl
(r)
4-\ Alkyl ibr ll1a includes, tbr cxamplc, mcthyl,

R
Cr-. alkyl tbr Rll inclucles, for example, methyl, etl-ryl, n-propyl ancl ipropvl. Cr-, alkvl lcrr Rr3 inclucles, lbr example, methyt, ethyl, n-propyl anct i-propyl.
cth.rrl,
n-propyl, i-propyl, n-butyl and i-butyl.
v-7.
N
Rr
Mis a melal
capable
of forming a
lbr
acceptable salt, and it inclur-les, potassium. -i0 COTIVI inclucles, tor exaurple,
pharmaceutically example, scldium antl and
-CO"FI. (primary to tortiary lowcr-CO2NI4 alkylaminc such as
trimethylanine) wherein R1, R2, R3, Ru and R are indepenclently hyclrogen, Cr-o altriyl fbr ll' inchrclcs, for examplc, mcrhvl, cthyl, Cr_u a1kyl, C._,, cvcloalkyl, Cr_. alkoxy, n-butoxy, i-butox nlropyl, i-propyl, n-butyl, i-[rutyl, sec-trutyl, t-butyl, 5s-utoxy, RR"N- (wherein R7 ancl RS are inclepencleutlv .;5 n-pentyl rnc{ n-hexyl. hyclrogen or Cr_- alkyl), trifluoromethyl, trifluoromethoxy, C:-c cvcloalkyl t'or R5 include.s, tbr example, cyclopropyl, difluoromethoxy, fluoro. chloro, bromo, phenyl, phem-rxy, cyclobut)l, cyclopentyl ad cyclhcx)rl bcnzyloxy, hydroxy, trimethylsilyloxy, cliphcny'1-tC-_, alkenyl tr R' inclucles, tor example, vinvl ancl bu tylsilyloxy, hyclroxymetbyl or (rvhereiu i-propenyl. -O(CFI=)rORre Rlo is hvdrogen or C-r-, alkvl, ancl I is 7,2 or 3); or when tto Phcnyt-(CFI.).,,- for [5 incluclcs, tbr examplc. bcnzyl, locatecl at the crtho posirion to each other, Rr ancl R2. o R' 13-phenylethyl ancl y-phenylpropyl. and Ra together tbrm -{IFI:CFI CH:CH ; or when Phenyl-(CH.),,UH(CFI)- itrr R' inclutles, tbr example, Itrcated at the ortho tosition to each other, I1 ancl Rr trlhenylethyl and c-trenrylethyl. I i)(R t")O5 togetlrer tbrm -(where in R' rncl R1' arc C, . alkyl tbr R7 ancl RB includes, lor example, mcthvl, independently-OC(R hydrogen or C,_. alkyl); Y is 6-5 ethyl, n-propyI and i-lxol>yl. -CIIr-.or Further, these courpounclsmrv have at least onc ol two -C]H?CH^-, -Cl:CFl-. -CIJ2-CFI:CH- 1?, and Z is -Q-CH.W'CFIr-COI asymmetric carbon atoms ancl may have at least trvo to t'our
-CH:CH-(]FI--;

5,856.336
Filed 04/09/14 Page 16 of 50
34
crptical isomcrs- The compounds oI the [<rmula I incucle all of these optical iscrmers nd all of the mixtures rbereol.
dimethyl, 6.8-cJimethvl, 6,7-<imethoxy, 6,7-dietbctxy, 6,7clilrrom o ,g-cjibrom<_. Whcn l{1, l2 ancl l(6 arc not bydrogcn, thcy togcthcr reprcseot 5,7-dimothoxy-8-hyclroxy, -5,8-dichloro-6hyclroxy, 6,7,8-trimethoxy, 6,7,S-rrimethyl, 6,7,8-trichloro,
5
-5-tluoro-6,B -dibromo or
-ch loro-6,8-dibromo_
Now, prelrrecl substiluents

prcseDt invcntion
In thc following prcferrccl, morc prcfcrccl srill furlhcr
will bc described
oI the compouncls o[
the
-CHr-CH.mentionecl. As more preferrecl -CFI:CFI-mav ._ examples Eor Z, ha above pretrred examples for Z may be
lre
mentionecl.
As prefred examples t'or Y,
and
(E)-
20
25
As pref'errecl examples for R-t aocl Ra, when Ra is ishyclrogeo,Raishyclrogen,4'-ch1oroor4,-fluoro,orR3and hytlrogen, R3 is bydrogen, 3'-fluoro, 3'-cblorr, 3'-methyl, t{'t iogcthcr ."pr"r"t 3'-mcthyl-4'-fluoro. 4'-metbyl,4'-chloro and 4'-fluoro. Still further pret'erred exrmples t'or R5 inclucle erhyl, other preferred combinations of R3 ancl R+ inchrcle 30 n-propyl, ipropyl ancl cyclopropyl. 3'-mcthyl-4'-chloro, 3',-5'-dichloro, 3',5'-difluoro, 3,,5'Still furrher pre trrecl exim1ils for y inclucle (El_ dimethyl ancl 3'-methyl-4'-fluoro CFI:CH-. Prelerred examples for R5 inclucle primary ancl seconclary ,4s still further preferred examples tbr Z, the a[roveCr_u alkvl and Co_u cycloalkyl. mcntioned prelerrecJ example or Z mtty be mnticuecl. Prclrred examples for Y incude Norv, thc most prcftrrcd substitucnts tbr thc compounds ancl 35 -CH2-CH.of the present inveotioo lvill le clescribed. -CII:CII-. Preferre(l examples f'or Z inchLde As thc most prctbrrccl cxamplcs tbr l.r, l{2 and l6, whcn Lroth R: and Rd are hvclrogen, Rtis hyclrogen,6-methyl or HO o 6-chlorc. 4tr When only R6 s hydrogen, Rt and Rtr together represent, lbr example, 6,7-climelhoxy. o ,4s the mosr pretned examples t'or. R3 ancl R't, R3 is hydrogeo and R' is bycrogen, 4'-chloro or 4,-fluoro.
-cr(or-r)cr2crr:(orr)crr:co,R1, -cr-r(o*r)cn,c(o) cH2corRr::Lnrl

present invention
-cH(oH)cHrc(oR'r)-cHrco-R.. "rlli.;itt:','j"","i.t:::":i:T;tJi:j ;_' [,r:,.r,_. Now, more prefrrecl sul-r,stituens

will
Lre
.,
iii.':
above-
mentionecl preferrcl examples foi Z ma,y be mentoned. Now, paiticularly prefeirect specr'fic compounds ol the -,AtT::"preferredexamplestbrRt,R2andll,rvhenboth R' ancl Ro are hvdrogen, Rt is hyclrogen, 5-flrroro, 6-luoro, -50 prcsent invcnLion wil be presentecl. 'Ihe lbllowing .9m. 7-fluoro, S-luoro' 5-chloro, 6-chloro, 7-chloro, S-chloro, pouncls (a) ro (z) are shown in the torm of carboxyli acicls. .5-bromo, 6-bromo, 7-bromt, 8-bromo, .5-methvl, 6-methyl, ilow-ever, rhe piesent ioventioo inclucle uot onl.v the com_ pounds in the tbrm of carboxylic acicls lrut also ihe corresponcling lactones lormecl by the cclnclensation ol the car5 boxyfic acic]s with byclroxy r tbc s-posirion, and soclium salts ancl lower alkyl esters (such as methy, ethyl, i-rropyl an<J n-propyl esters) oI Lhe carboxylic acicls, which can be
clescribed.
of the compouncls of
the
As the most
preterred examples
for Z, the
6-chloro-B-hyclroxy, 5-rnethyl-2-hydroxy, 6-methoxy-7- (trj (e-j,j-ilyar""y-i-[.i,-(4"-fluorphenyl)-2,-(1 'chkrro,6-chkro-7-methoxy, -hyclroxy-7-chloro,6-chloro- *"n,vtctty-0,_chlro_quinolin_-3;_yl]_hcpt__euoic
when R6 is hycrr.gen, R, ancr R2 rogetrrer represenr 6-chloro-.3-methy[,6-bromo-7-merhox.v, 6-methyl-7-chloro, 60 ms,thylethyl)-quinoiin-:,_1,t]_trepr_O_enoic
tti'ti:]l1.llii:ilJit.ll?-:l',?l;.Lliriij,
acid
r,
acicl
icj 1e-a,:-alhydroxy-7-[4'-("-iuor..pbe'yl)-z -(1 '6-Lrromo-.s-chloro' 6-bromo-8-bydnrxy, 5-me thyl-S-chloro, mcnvt"yl)-o'-r"itryt-qioolin-'-yl]-hcpt-'6-cnoic acic 7-hyclroxy-8-chloro, -bromcr-.9-byclroxn 6-metboxy-7- o-s ti tei-:,-s-crihidr;x),-7-[+ -1i"-nuo.ophenyl)-2'_ methvl,6-cbloro-8-b61,6-r-.erhyl-S-L-rr.mo,6,7-crifhroro, (L';methylethil)-6',7,-dim;th.--ry-qu.inolin-3,lvr]-"t-o6,8-ctifluoro, ,7-mcthylcncdioxv, 6,8-dichloro, -5,8- enoicaccl
7-hydroxy, 6-chloro-8-bromo, -5-chloro-6-hyclroxy,

5,856,336
5
hydrox y-7-[4'-( 4 " - fl ucr rop he oy t) -2, cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid (f) ( E) -3,-s -di tr ydroxy -7 -[4'-(4 " -fl rLo roptren yl) -2' cyclopropyl-6'-chloro-quinolin-3,-yl]-hept-6-enoic acid
-3,-s -cli
Filed 04/09/14 Page 17 of 50
(e,) (E)
6
-continuccl
RJ
Rr
(g) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophelyl)-2'hep t-
cyclopropvl-'-me thyl-quinolin-3'-yl]-hcpt--enoic acicl
(b) (E)--1,5-clih5,droxy-7-[4'-(4"-fluorophenyl)-2,-enoic
ro
N'
cyciopropyl-6',7'-d imetb oxy-quino lin-3'-rl]acid

methyte thyl)-quinoli n-3'-y1l- hep r-6-enoc acicl
me
RL
CHOFI
(i) (E)-3,5-dihyclroxy-7-[4'-(4',-chlorophenyl)-2'-(1"(E)-3,-s-dihrclroxy-7-[4'-(4"-chlorophenyt)-!, -( t,, thylethyl)-6'-chloro-quinolin-3'-yll-hepr-6-enoic acid (k) (E)-3,-5 -dih yclroxy -7-[4'-(4" -chtorop l.ren yl)-z, -(1,, -
-E->
0)
Ri
vl
RJ
1_s
mcthyiethyl)-'-mcth/-quinolm-3'-yl]-hcpr--cnoicacicl
(E)-3,-5-dihyctroxy-7-[4'-(4"-chlorophenyl)-2'-( 1,,methylethyl)-6',7'-climeth<,rxy-quinoln-3'-yl]-hepr-6-enoic
acid
(t)
(m) (E) -3,-5-dh ydroxy-7-[4'-(4" -chlo roph eny cyclopropyl-quinolin-3'-yl]-hepr--enoic acicl

c1
t) -2' zo
CTIO
(n) (E)-3,5-clihydroxy-7-[4'-(4', -cfilorophenyl)-2'-
cycloprop-vl-'-chloro-quinolin-3'-yl]-hcpt--enoic acid ( o ) (E) --r,5 - cl ihy r oxy - 7 -14' - (4 " -chlo r.op he n yl) - 2'cyclop ropyl-6'-mcthyl-quinolin-3'-yl]- hcp t-6-cnoic acicl ( p ) (E)--r,5 -cl ihyclroxy-7-[4'-(4', -chloroph e oyl) -2' c yclop rop yl-6'7'-clime t ho xy-qu ino lin-3'-yl]-b ep t-6-enoic
acid
-->
t\
Rr
zs
Rt
Ri
Rr
(q) (E)-3,5-dihyclroxy-7-[4'-ptrenyl-2'-(1"-methylethyl)quinolin-3'-yll-hept-6-enoic acid (r) (E)--1,5-dihydroxy-7-[4'-pbeoyt-2,-(t''-merhytethyl)- :o 6'-chloro-quinolin-3'-yt]-hcpt-6-cnoic acid (s) (E)-3,5-dihyclroxv-7-[4'-phenyl-2'-(t"-methylerhyl)6'-me thyl-quinolin-3'-yll-hep t-6-eaoic acid (t) (E)-3,-5 -clih ydloxy-7-[4'-ph enyl-2' -( 1,' - me r b ylerh.rrl)',7'-dimethoxy-quinolin-3'-yl]-hept-6-enoic acid 35
oEr
Rl OII
N
Rt
R R5
-D->
(u) ( E)-3,-5-dihyclroxy-7-[4'-phenyl-2'-cycloirropyl-
quinolin-3'-yl]-hept-6-cnoic acid
(v) (E)-3,5-clihydroxy-7-[4'-phenyl-2'-cvclopropyl-6'+o
IV
Rr
chloro-quinolin-3'-y1]-hept-6-enoic acicl (w) (E)-3,-5-clihydroxy-7-[4'-phenyt-2'-cyclopropyl-6'methyl-quinoln-3'-yl]-[-rep t-6-enoic acicl
(x)
clim
(y) (E)-3,5-dihyctroxy-7-[4'-(4"-tluorophenyl)-2,
ethoxy-quinotn-3'-yl]-hep
(E)-3,5-dih'clroxy-7-[4'-phcnyl-2'-cyclopropyl-6',1' t-6-enoic cicl

-(1,,, 4_5
cHo
methylethyl)-6'-methoxy-quinolin-3'-yll-hept-6-enoc acicl (z ) ( E)-3,5 -di h yclrc-rx y -7-[4' -(4" - Iluo ro p h c ny l)-2, cyclopropyl-6'-mc thoxy-quinolj-lr-y1]- bcp r- 6-cnoic acicl The mevalonolactones of the formula I can L-e prepared lry thc t'ollor,ving rrractio schcmc. Thc cnal III can also be
preparecl
-r-->
N
Rt
I
R3
by processes K,
RJ
L, ancl
N,f
-i(J
o
Corz
R4
OFI
-\
Rr COR]L
R:
-F->
-->
6.1
N
R
l II
Rs
VII

5,856,336
7
-continucd
Ri
R{
Filed 04/09/14 Page 18 of 50
I
-continued
OH
COR12
5
R3
Rl
COR2
OH
Rl
N
Rr R
R5
-E>
10
-->
N
R1
Rs
I-1
VTII
R3 R4
OH
CosRtz
OH
1-5
CHOI
R2
1
R2
=->
N
RL Rs
T>
N
Rr
LX R3
R-5
I-2 r2= H) I-5 (Rt3 = Na)
25
R4
R:
R{
OH CHO
30
R2
Rl
N
t-.3
-->
R5
N
35 Rt
R3
R5
IIT R
OH CO,Rrz
RJ
R4
OH
40
OII
o
45
>
N
R5
R2
N Rl I-4
RJ
Rs
Rr
R 50
I-1
R1
otr
CO"Rl
R{
-t)
Rl
CFIO
KN Rt
R5
\
6rl
N Rt
I-6
Rs
In the above reaction scheme, Rl, R2, R3, Ra, R-, R6 ancl Rttr are as defned ahove with respect to tbe formula I, and
65

5,856.336
cubon
Filed 04/09/14 Page 19 of 50
lower altriyl sucb methyl, etbyl, n-propyl, i-propyl or n-butyl. step A represents a recluction reactioa of the ester to a primary alcohol, Such ecluction reaction can be conducted by using various metal hydrides, preferably cliisolutvlalu- 5 minium hydride, in a solvcnt such as tctrahydrofuran. or loluene al a temperture of liom -20' to 20. C., preferably tiom -10'to 10" C. Srep B represenrs an oxicrarion reacrion or the primary alcohol to an aldehycle, which can be conclucted bv usrng 10 various oxicliz.ing asenrs. pretraLrly, rhe rercrion ian oi
R22 indepenclentlv represent C-r,u as
Rrr and
910
in
a so-tvent such as methrnol, eLhan6l, l.elrahyclro-
o,l3_ri.rtu.i!Jca.toxyli. acicl ester,whereby a traos_f.orm ct,j-unsaturatcc carboxylic acid estcr can lrc obrainecl by a ,nl"ott"J Uo."".-W;u;g reaction by using an alkoxrcar.l.:o-
furan or acetonitrile at a remperarure of om " to Sd" C., prefer.ably from 10o to 25. i. Step K represenls a eaction for lhe synthesis of an
:J.iitili:::'::i:i"Ihi:,"'::ti:';*t#i1
tetrahJclrofuran
;;;ffi;'f."*
at a temperature of fiom _;' ; : --zo" ,o -15" c. of the a,p'l'hs a1cohol. various metal ricle, in a sola temperature
l-s
Step C represents
2-pro1>ene
between the enal
t synthesis of a 3-ethoxy-1-hy<Jroxv- of tiom _10" to 10" C., preferatrly frorn _10. to 0o C. derivative, lvhich can be prepared by reactrng a , art oxidation reaction of the allyl compund V to lithium compound ihi"t hn, u"n p..t-ii^,^l-t*, .Y I"l_teseots nariliy formed by treating cis--edroxy-2-(rri-n-Uur'l"tunilril , |]::.T] j"..1n enal' This oxiclarion eaction can Lre conclnctecl by using valiclus oxiclizing agcnts, particularly activc manetbyiene witb trutyl litl"iurn in tetrah-yclofura.. oîilo^:l t" a solvent such as tetrabydrofuran, ,As thc rcction rcmpcrarure, it is prcfcrrcd ro cmploy acctLno' ctbyl cthcr or eth)4 acctatc al 0 lemperatrue of from ^ l:::_i. low temperalure at a lvel of from -60. tr -7Bo C. Stcp D rcprcscotsasynthcsisof ancnalbyacidichyclroly- 0"fo l0o' c', preferably tom 1-5" to -50" c. N reprsenls a reaction fcrr the synthesis o[ an sis..As the icid catalysi, it i-s pretrrecl to employ p-olr". zs ^SLep ketone by the selective oxidarion of the sulfonic acicJ, hycrothtoric acicl or sultricâcitl, an<1 rhe cr,l3-unsaturated reaction may be tonducted in a solvent mixture ofwaier ancl dihyclroxy carboxylic acid ester'. This reaction can be conduc,ted [rv. using activatecl mangoese clioxide in a solvent telrahyclrofuran or ethanol at a temperture of lrom 10o to 25" C. The 3-ethoxy-l-hydroxy-2-propene derivarive such as eth;rl ether, tetrahydrofuran, lrenzene or toluene at a obtainecl inStepCcantreuseiostepDwiihourpurification i0 tcmpcraturc of tiom 20o to 80" C., pretrably tiom 40'to i.c. by simply rcmoving tctra-n-buiyl rin t'ormd simuftr- 80" C. neorLsly. In aclciition to the compounds disclosecl in Examples given Step E represents a clouble anion concleusation reacton lrereinafter, comporLnds of the formulas I-2 ancl I--5 given in
III
and an ecetoacetate Such
reaction is prelrablv conductecl by using sodium hyclricl" 35 invention. In Table 1, i- means iso, sec- means seconclary ancl n-butyl lithium as the base in tetrahydrofurn at a and c- means cyclo Likewisc, Mc mcans methyl, Et mcans tcmperalure tf fr<m -80" to 0" C., prcferably liom -30" lq ethvl, Pr means propyl, Ru means butyl, Pent means pentyl, Hex meaos hexyl and Pb means phenyl. -10' C. Step F represenls a recluction reaction of lhe carbonyl group, which can bc conudctcd by using a mcral hydridc, +o TARI_E I preferablv sodium borohyclride in ethancl at a temperature I-2 (Rt? = H) oI lrom -10" to 25" L., pretrably lom -10" to -5o C. Ri R OH t-5 (tt2: \a)
Further, the reducticn reaction may be conducted by using zinc borohyclride in tlry elhyl ether or clry telrahvclrolurrn at a temperture of -100" to 25" C., pretrably tiom -80" to
conclenstion 'lhblc 1 can bc
prcparr:d
by thc
proccss
of thc
prcsent
_s
-50" c.
solvent nixtue of rvater ancl methanol or ethanol at a lcmperaturc of tom 10" to 25' C. lhc ticc acicl hcrcby
Stcp G is a stcp for hydrolyzing the cstcr.'I'he hydrolysis crn tre cooducted by using an equimolar amount of a Lrase, prctcrably potassium hydroxidc or sodium hydroxidc, in a
Rd
ot{
5l)
olrtained mav be convertecl to a salt with a suitable base. Step H is a step l'or lbrmiug a mevalonolactone by the dehydration reaoion of the iiee hvclroxy acicl I-2. The clehydration reaction can be conclucted in Lrenzene or toluene s under reflux rvhile removing thc resulting watcr or by adding a suitable dehydrating agent such s molecular sieve. Further, thc clehydration reaclion may be conductecl in dry methylene chloide by using a lactone-forming agent such as .... carbodiimide, preferably' a lvater soluble carbodiimicle such OU
N
R1 R1
R5
R2 H
R4
H
4-F
R5
R6
6-OlVle
II
LI H H
i-Pr
H
H H tJ
FI
-OMe 6-Br 6-Me 7-OMc 6-B

6.'1
H
H
i-Pr
i-Pr
4-t
4-F 4-F 2-F 4-F
S-Me 3-OMc
TI
H
FI
i-Pr i-P i-P i-Pr
H H
as N-cyclohexyl-N'-[2'-(merhylmorpholinium)erhyl]
carbodmicle p-toluene sulfonatc a( a tempcralurc o[ lrom t0" to 35 ' (., pretrably tiom 20" ro 25' C. Step J represents a reaction I'or hydrogenating the double lactone moicty rncl the quinorection can be conclucted by alladium-cartron or rhocl ium-
o-s

5,856.336
11
Filed 04/09/14 Page 20 of 50
l2
I-2 (Rr2- FI) I-5 (Rtz = Na'
TABLE l-continued
R3
R4
otI
They may be lormulalecl into vLrious suitable formulalions clepending upon rhc manner of tbe administration. The prcscnt invcntioo may bc administcrcd in acicls or in rhe form of physiologicallv acceptable esters or lactones, or pharmable salts.
OH
N
Rr R1 RT
R]
4-F
H
R5
The plrarmaceutical comrosition of tl]e present inventon il rhe lorm of the compoun<J of tbe presenl invention per se or in the form of 1o powders, granules, tablets or capsues t'ormulated by mixing the compouncl of the present invenlion with a suitabie pharmaceutically acceptable canier including a binder such as hydroxypropyl celhrlose, syrup, gum arabic, gelatin, sorbitoi, tragacenth gum, polyvinyl pynoiiclone or CMC-Ca, ,- an excipienl such as lactose, sigar, corn starch, calcium phcrspbate, sorbirol. gly.cine or crystal cellulose powcler, a lubricant such s magnesium stearate, talk, polycthylene glycol or silica, an<l a rlisintegrator such as potato starch.
is pretrably adminstered orally
20
I I HH HH 6-Cl H 6-Mc,N H 6-Me II 6-iPr H 7-Mc H 6-OMe I 6-Bt E 6-i-PL H 6-Ct 8-C 5-F 6-8r 6-Ole 7-olvle 6-Me 7-Me 6-C 7-Cl HII TI TI 6-OMe 7-Ovfe 6-OMe 7-Olvle 6-OMe 7-Olvte 6-OMe 7-OMe &OMe 7'ONfe 6-Mc tl 6-Me II 6-Me H 6-Me H 6-Me H rt-cl H 6-CI H 6-C] II 6-CI TI ri-ct H HH
6-OCH2P
HT HI 6-CI 6.CL
4-Ph
4-PhCH,
II
FI
4-F
.1-F
4-F
4-I-
4-F
4--
4-F 4-F 4-F
4-t
4-F
4-F
4-F 4-F 4-F
4-t
+-F 4-F
4F
4TT
tr
4-Ct H 4-Ct 4-F
H 4-Cl H
4-Crt
4-1.
H 4-Ct
tI
4-Ct 4-F
H
HFI TI TI
ut{
4-Cl
H
T
II
4-L1
4-F
H H II H H H H H H FI H H H H H II I H H H FI H H H H H FI H tI H FI H t{ I fI II H H H H tI II
i-Pr i-Pr c-Pr

sec-Bu i-PL i-tst c-Pent c-Pctrt
H H
II
H H
H H
,-
by using oily basc material such as cacao buttcr, polycthylene glycol, lanolin or latty acid triglyceride, a trans<lermal lherapeut liquic{ paralhn, whire vaseline, ointment, hyclrophilic
ointrnent
H
I
i-Pr c-P i-Pr c-Pr
tion tbrmulated by using one or more materials
an injection formulaselected
II
t
[I
cPr
c-Pr c-Pr c-Pr i-Pr i-P i-Pr i-Pr c-B
c-I-Iex
H H
TI
II
B-B 8-OMc
.3-Me
s-cl
FI
I
i-Pr i-P c-Pr c-Pr
H H
FI
cP
i-Pr i.Pr c-Pr c-P c-Pr i-Pr i-Pr c-Pr c-P c-Pr -P i-Pr c-P c-Pr c-Pr
II
TI
H
H IJ
H
FI
II
FI
Ir is administered from <noe lo lhree times per clay. The close may of course he varied clepending upon the age, the weight or the condilion oI illness o[ the patientThe compouncls of the ttrrmuias II ro VII tre novel, ancl 4-. they are important iutelnediates t'or the preparation of tbe compounds of the tbrmrLla I Accorclingly, the present invention relates also to the compounds of the fomrulas II to VII and thc processcs tbr thcir procluction. Now,, the present invention will be clescribecl in further -n cletail with reference to Test Examples tbr the pharmacological activiries of tbe compouncls of the presenr invention,
from the group consistiug of polyethylene glycol, hyclro-gel basc matcrial, disrillcd watcr, tlistillcd rvatcr lor injcclion ,o ancl excipient sucb as lactose or corn starch, or a t'onnulation tbr a(lministration tbrough mucous memtrranes such as an ocularmucous mentbrane, a nasal mucous membrane and a oral mucous membanc. 35 Fuher, the cornpouncls of the present invention may be crrmlinecl with Lrasic ion-exchange resins wt.icb are capalrle of binding bile acids aud yet not lreing absorbed in gastrointestinal tract. 'l-he daily dosc of the compound of thc formula I is tiom 0 05 to -500 mg, preferably fron 0.5 to 50 mg f'or an adult. 4.
H
I
FT
tbeir Preparation Examples and Formulation
Examples,
fi
II
Ilowever, it should be understclod thal the preseot invention is by oo meaos resticlecl by such specilc Eramples.
55
Test
vi
Lrc.
PFIAIIMACOT,OC;ICAL 'I'L,S'I' I,XAMPL,S
: Inhibitio of cholesterol biosynthesis tor
ace ta te
in
Enzvme solution was prepared fiom ljver of male Wistar rat billal.v cannulalecl zncl clischargecl bile for over 24 bours 6(l Liver was cut out at micl-clark and microsome trncl supernatant fraction rvhich was precipitable r/ith 40-8020 of saturation of ammonium sulttc (.sup traction) wcrc prcpared from liver honogenate according to the moclifled metlrocl of capable oI suppressiug or retlucing the mo unt oI choleste rol Knauss ct. aI.; I(urocla, M., ct. al., Biochim. Biophys. Acta, the compound.s of the present 0-: 489, l]-q (1977). For assay of cholesterol biosynthesis, agen ls agarrst hyperlipidemia, microsome (0,f mg protein) aocl sup liaction (1.0 rng eroscleosis. protein) were incubated lor 2 hours at -17" C. in 200,rl o[. the
Filed 04/09/14 Page 21 of 50
5,856,336
13
rcaction mixture containiog AT?; I mM, GluLaLhione; mM. Glucose-l-phosphate; l0 mM, NAD;0.2- mM, NADP; 0.25 mM, CoA; 0.04 mM and 0.2 mlVI [2-]'1C]sodium acetate (0.2 4Ci) with 41 of test compound solurion dis.solvecl in warer or tlimethyl sulfoxicle. To stop react-ion ancl saponify, 1 ml o[ 15% EIOH-KOFI lvas adcled to the eactions and heated al 7-5' C. t'or 1 bour. Nonsaponiflable lirids were extrauerl with pctroleum cther ancl incorporatccl laC radioactivity lvas counted. Inhibitory activity of compouncls was indrcatecl
l4
-T.BLE
2
[rhibiLorv activities bv'lst A
5 Compound (C'oor:ounds of tbe presonL rnventtonj t-13 r-51
t.,
(nrolar conccntlrtion)
125 x
.1
with
IC-50.
10
Test B: Inhibition of cholesterol biosynrhesis in culturc cclls
7I x
I--sj
(Relerence conrpounrJs.)
Vlev inoLin
1,s
0x l0
'
s
l.-8
1
).9
x ID
In'Iable 2-2, he relative activities tre sholvn based on the ultraccntrifugation mcthod tbr over 24 hours. Medium was activitics of CS-514 bcing cvaluatcd ro bc 1. changed to 0.5 ml of fesh 5% LpDS containing DME before ?0 assay ancl 10 d of tcst compound solution dissolvccl in warer TABLE 2-2 or DMSO were aclded. 0.2 pCi of l2-1'rC]sodium acetare (20 4l) was addecl at O hr(B-f) or 4 hrs(B-2) Iter ddirion of Reiatil'e activities bv Test A compouocls. Afler 4 hrs further incubarion wirb [2-1'rC] Corrrpouod Relative acivilies sodium acetate, mediuut was removecl and qel1s were 25 washcd with phospbate buftbred satinc(PBS) chillcd at 4" C. (Compourds of the Celis were scraped with rubler policeman ancl collectecl to presenl i[\u!ion) tutres with PBS and cligestccl wirb 0.2 ml of 0.-5N KOFI ar t-_l 6 1.7-S -37" C. Aliquot of digeslion was usecl for protein analysis and I- 116 2.25 remaining was saponifred r,ith 1 ml of 157 EIOH-KOFI at 30 l-111 o31 75' C. for I hour. Nonsaponifiable lipids tvere extracted rvith t-120 3 21, t-522 076 petroleum ether and raC rrdioactivity wa,s counLecl. Counts were revised by cell protein ancl indicaecl with DPMlmg protein. Iohibitory aclivity of compouncls was inclicatecl with
-% of lipoprotein clelcient serum (I-pDS) prepared by
Hep G2 cells at over 5th passage were seedecl to 12 rvell plates ancl incubatecl witf Dulbecco's nrodifled Eagle (DME) medium containing IOdh of letal bovine serun (FBS) at 37" C.,57o CO. until cells were contluenr tbr aboul 7 rlays. Cells were exposed to the DME medium containing
cs-sl4
14 x l(l e 90x 10-
IC50.
35
Test C: Inhibitioo of cholesterol biosynthesis in vivo Male Sprague-Dawley rats weighing atrout. 1-50 g were td normal Purina chow cliet rnd lvatcr ad libitum, and cxposecl
Structures of relerence compouncls:
(1) Mevinotin
o o
o o
I
to 12 hours lightll2 hours clark lighting
acetate at volume of 0.2 ml per one. 2 Hours later, Lrlood samples were obtainecl rnd selum were separated immecliately Total lipicls were extrrctecl accordiog to tlle methocl of Folch et al. aocl saponified with EIOFI-KOI. Nonsaponilable lipids nee extractecl with petroleum etber anci radio activity incorporated inlo nonsapouifla[rle lipicls was
countecl.
At 90 minutcs after sample aclministration, rats wcre _^ injected intraperitonealty wittr t0 rCi of 2-ttclsodirrm ''']
PIVI-2:00 AM clark) prior to use ttrr in vivo inhibirion test of cholesterol biosynthesis. Animals were separated gnrups consisting <f fve raLs l,s tr- be average mean bocly weight in each groups. Test compouncls at dosage of 0.02-{.2 mg/kg body weight (0.4 rn|100 g body weight), rvere dissolved in ,. \tater or suspended or in O.5Vo methyl cellulose and orllly '' administered at 2-3 bours befoe mid-clark (8:00 PM), while cholestcrol biosynthcsis rcacbcs ro maximum in rats. As control, rats r,ere orallv acminislered only water or vehicle.
partern (2:00 ,,. *"
otr
tI
CL
tLC
(2)
c--s-_514
-"
__
orr
Inhibitory ctiviy was inclcatecl as percent decrease of counls in tesling groups (DPM/2 ml serum/2 hours) fronr that in control group. With respect to the compouncls o[ Lhe prcsenL invention, tbe inhibitory activities against the cholesterol bkrsynthesis in which HMG-CoA reductase sewes as a rate lin.itiog
o
u.
H,C
o
H
CH
enzyme, were measurecl by the above Test A and B The results ae shown in Tables, 2, 2-2,3 r.:rcl 3-2. Further, the results of the mcasurcmcots lry 1'cst C arc also prcscnlccl.
o_s
Filed 04/09/14 Page 22 of 50
5,856^336
l5
TABL.L 3
Inlibitorv autivilies bv'lst ts-I
Corrrpound
t--o
16
Example l-b
-3 - hyclroxyme t hy l-2 -( l'-me tbyle thyl)clLrioolitre (compound VI-I) 5.4 g(0.016 mol) of compounct VII-1 was dissolved in (lry toluene uncler a oitrogen atmosphere nd coolecl in ice lrath lo 0" Cl. 'lb this solution, 40 ml of a 16 wt 7c dirsobutylaluminium hyclricle{oluene solution rvas clroprvise aclclecl, and
4-(4'-fluorophenyl)
(ntolar conccntratio)
(Coorpound cf the PlgscL Lrverlronj

I--51
I x 1l)-'
35
(Refcrcncc conrpor:nd)
cs-514
x l0 I
the mixture r'as stirrecl at 0" C. for two hous. After confirming the coml)lete clisappearance of compouncl Vll-l 10 by thin liLycr ohromatography, a saturatecl ammonium chloride solution rvas added thereto at 0o C to terminate the
rerction. Ethyl ether rvas acldecl to the reaction mixture, nd
In f'alle 3-2, tlle elative activilies are shown basecl on tlre activities of CS-514 Lreing evaluatect ro be 1
the organic layer tvas separatecl.
A gelled
product was
T
(-'ompound I-116 t-_20 II-)0
BLE 3-2
Relative activities by Test B- t lelLive acLivities

19 + 20 0 20 o'
clissolved b;r an acldition of an aqueous sodium hvc'lroxicle t-s soution and extractccl anew with ethyl ethcr.'l'he erhyi ethcr extracts wee put toeether, clriecl over anhydrous magnesiunr sullrte and lterecl. The solvent was distilled ofL. The resiclual oil unclerwent crystallization when left to stand It was recrystullizecl frcrm ethyl acelate-n-hexane Lc. obtain 3.3 uo g of wbite crvstals Yielcl: 70%. Melting point: 136"-137" C,
superior to the relrence compouncl such as CS-514 o Mevinolin in Test A, and exhibitecl activities superior ro CS-514 in Tests B and C. Test D: Acute toxicity AO.57o CMC suspension of a test compouncl was orally aclministered to ICR male mice (group of three mice). The acule toxicity was determinecl based on the mortality after seven ilavs. With compounrl I-57, I-58, I-59, 1-5\1, I-512, I-5 13, I--51:1, I-.51.5, I-.517 and I--523 of the presenr inventon, Lhe rlortali[v was 09la even rvhen they were onLly aclminislered in n amount of 1000 mgikg.
th yl) -q uin o lin-3-ylcarhoxyalclehyde (compouod V- I ) 2.0 g (9 3 mrnol) of prricliniurn chlorochromate zrncl 0.4 g 25 Test C of anhydrous sodium acetate was suspencled in 10 ml of clry The percent decrease of counts atter the oral administr-aclicbloromethane To this suspension, a solution obtained by ion of 0 (l-5 mg/kg of compouLrcl I-520 was 55Va rcla,Live to clissolving I g (3.4 mmol) of compouncl VI-1 in 10 ml of dry tbe mcasured valuc of thc control group. I'he pcrcont dictrloromethane, rvas immecliately aclcled at room temeradecrease o[ counts atier the oral administration of l0 mgftg of CS-514 was 557o uncle the same condition. The ccrm- 30 ture. The mxture ws stirrecl tbr one hour. Then, 100 ml of etbvl etber rvas acfded thereto, ancl the mixture was throughly pounds of the pre.sent invention exhiltited activities
Example 1-c 4-(4'- uorophe nyl)-2-( t'- me thyte
I{csults of the rlcasurcment of the inhibitory activities by
mixed. The rcaction mixlure was lltered unclcr sucl.ion through a silica gel layer. The flltrate was driecl uncler
35 ether, ancl
recluced pressure. The rcsiclue was dissolved in the isopropyi insoluble substnces we re fltered off. The filtrate was again died under reduced pressure, and ttre resdue was
reclystallizcd from diisoprop]l ether to obtain 0.7 g (Yield: 70%) ol slightly yelkrw prism crystals. Melting point:
124"-126" C.
4t)
3
[xample l-d
(3'-elhoxy-l'-hydroxr-2'-propenyl)-4-(4'-fluorop heny'l)-2(1'-methylethyl)-quinoline (compound IV-1)
Examplc I Ethyl (E)-3,5-clihyclroxy-7-[4'-(4"-luorophenyl)-2'-1 t "me
a-s
(prepared by steps
thyethyl)-quinolin-3'-y1]-hept-6-enorte (compound I- 1 1) of Example [-a through Example I-q) Example
1-a
witb
the
Ethyl 4-(4'-fluorophenyl)-2-( L'-rnethylethvl)-quinolin-3-ytcrboxylate (compound VII-1) The synlhesis rvas conclucted in trccorclance method disclosed in J. Org. Chem., 2899 (1966).
50
6.45
g (0.0-l mol) of
2-amino-4'-fluorobe(lzopteoone,
2-amino-4'-fluorobenzophenone by thin leyer

cltromatography, the reactioo solution was cooled to room lempecaLurc, ancl a mixLure o[ 4-5 ml of conc. queous rmmonia ancl 120 mi of lr.ater cooled with ice, rvas gr.adually adclecl thereto- A sepalated oily srLbstance rl.as soliclificcl when let to stao(l overnight in a retrgerator. f'his solicl was recrystallizecl [ror a small amount of ethanol to obtiin 6.47 g (55b) of whitc powclcr. Mclting poinr: 8'-70.5' C
5.53 g (0.035 mol) o[ cthyl isobutyrylecctalc ancl 0.1 ml of conc. sulfuric acicl were clissoh'ed in -30 ml of glacial acetic acicl, ancl thc mixlure was hcatc(l at 100" C. tbr about t0 hours. After conflrming the substantial clisappearance of
-s
oo
I 13 g (3.13 mmol) of cis-1-e1hox5,-2-(td-o-but.vlstannyl) ethylene was dissolvecl ir: 8 ml of dry tetralryclrofulan, accl the solution was coolecl to -78" C. in a nitrogen stream. To this solrrtion, 2 nl (3.2 mmol) of a 15 rvt % n-butyllithiumn-hcxane soluton was dropwisc adclccl. 'lhc mixture was stirred f<lr 4-5 minutes. Then, a solution prepared by clissolving 0 76 g (2.ti mmol) o[ compound V-1 in l0 ml of dlir terrahydrofurao was clropwise aclcled thereto. The reaclion mixtule was stined at -78o C. fo two bours. Then, 2 ml of saturated ammonium chloride solulion was adcled therelo fo trminate the reaction The organic layer wa-s extracted with dicthy.l cthcr, ancl thc dicthy'1 clhcr cxtract was v/ashcd with a saturaled soclium chloricle aqueous solution aucl clriecl over anhy(lfous mrgnesium sulfate, The solvent was distilled off uncler reduced pressure. The resiclue was separated with -hexane and acetonitrile. Thc solvent was rlistillecl oll' under reclucecl pressure tom the acetonitrile layer, ancl an oily substaoce thereby obtaiuecl was purifled by siica gel column chromatography (eluent: 2.5c/a meLha.o|cbloroform) to obtaio 0.91 g of the clesiecl comporrncl in a ruriled oily tbrm.
tI-lvlNR (CDCI-) ppm: LI(t,311,7Iz) 1.37(ct,6lIJ:
7
6.5
z)
3.1
(n,lI1);
3.1
(q,2rI,t =71-Iz) 4 7 5(t, ttt,THz) 5 1 (n,
1FI) 5.9s(m,1H) 7.0s-8.2(m,8H)

5,856.336
Filed 04/09/14 Page 23 of 50
l7
Example
18
psti
(E)-3-[4'-(4"-iluorophenyl)-2'-(1"-meth lethyl)-quinolin-3'yl]propcnaldchyclc (compound lll-1) 0.91 g of compound lV-l rvas dissolved in 20 ml oI tetrahydrofuran, and -5 ml of water s
l-e
aqucous sclution was dropwise added Lhereto. The mixLure
wis stined at room temprature tor further one hour,
ancl
elbanol w,s clistillecl off rnder reclucecl pressure. Then, 5 ml o[r,ater lvas adclecl thereto, ancl rhe mixnrre was extracted with ettryi ether. The aqueous layer was freeze-clriecl to
chloriclc Example 3 l0 (E)-3,5-dihycoxy-7-14'-(4"-fluorophen'l)-2'-(1'^" methvlethyl)-quinolin-3,-1rl]-hepr6-enoic-acid-(compouncl puriflecl by silica gel cohrmo chlomatography (eluent: I-21) chlorol'orm) io t-btain the tlesirecl product as rvhile prism 110mg(0244mmol)of compouncl I-.L1 wasclissolvedin crystals. 0.4 g (SOC/o). Melting point: 127"-t28" C. l0 ml of ethanol lhen, O.j9 mlof a 0.5Nsoc.lium hydroxicle 1-i aqucous solution wa Example I-f Erh),1 (E)-7-[4'-(4''-fluorophenyl)-2'-(1"-meihylethyl)- was stirred 1l ::]octhanol was distiiled quinolin-3'-yl]--5-hyclrox.v-3-xohpfo-6-enoat" 1.-puita ' of water was addeci II-1) The aquetrus lt,er ',vas weakly acicliled -5 mg o r07a socliunl hydride wa lute hydrochoric aqueous solution and perroleum elhe:r an<,I clried uucier a nitrgg es with ethyl ether. Tbc etbyi ether layers iuspeoded in 5 ml of clry retrahyclrofui and dricil ovcr anhvtlrous magocsium was coolccl to -l5o C'. inl nirrogen atm solvent was clistilled off under reclucecl mg (0.92 mmol) of erhyl aoetoacetate 90 mg of slightl.v ycllow oily substancc. threto, ancl the mixtul.; rvas stirrecl tbr .) ppm: 1 36(d,6HJ=7Hz) 2.4(m,2Fl) 0. mt (0.92 mmol) ol a 15 ivt 9zc n-bur solutiori was rtropiise aclclecl thereto, a 'IH); 3.8-a'6(m'2H) 5.40(dd,lH,J1= 5 (d,1H,J=l9Hz'l 7 tI-8.3(m,8FI) stirrecl tbr 30 minutes. Then, a solurion p ing 160 mg (0..5 mmol) of compound III- t in tr rtr clrv Y Examplc 4 tetrahvclr.lurn, lvas clropwise adclecl th ophenyl)-2'-("-methvlethyl)-quinolin-]'ture was stirre(l fbr one hour.'ri the rea :xy-3'4' 5'6-tetrtthyclro-2H-p'r-)-en" of a satrratecl amnronium chloricle aqrL
cl soclium
queos solutiou ancl driecl over anhvclrous masnesium sulfatc. Thcn, thc solvcnt wasdistiilect off. Thc rcsiclue was
so ex
obtain 40 mg (67t'/o) of hygroscopic whitc powder. lVlclting point:207o-209" C. (decomposed).
wlh
witb
atlcled at
a
dierr,),I erher. rhe crietrryr erher
-15"
C. Then, the mixrure rvas c
saturatccl sodium chloriclc quoous over anhvdrous magnesium sultite The s rate(l to clryness uncler reducecl pressure. The residue
so
#",rL,"[12 ",ii"i::#J.t'.:l a Dean Slark apparat*s.

E
recrystallized tom diisopropyl etber o obtain 1:!l obtain 40 mg (yiekJ: 59otL) <.f white crystals. Melting point: 99" l0l"^m^g C. lS2._1S4 . . l,xample
was
L-esiclual
,tillccl off uncle I rucccl prcssurc, and thc solicl was recrystallizecl from clsopropyl elher to of coloilcss prism crystals. Mciiing poi't:
dcsired procluct as a pure colorless
''- ''' absoqrtion spots close lo each other attributable to the mcth-vlcthyl)-quinolin-3 '-yl]-hcpt--cnoatc (compouncl diastereomers. (Developpiog solvert: 3c/o netha,oolchloroform) I-11) These clasterorners wore separated aod isolated by silica 110 mg (0.245 mmol) of compound II-1 lvs rlissolvecl in -5 ml ol ethanol irr a nitrogen atmosphere, ancl the solution ,. gcl thin laycr chromatogrphy, [Developping solvcnt: was cocrle< i)" C. Ihen, l() mg (0.263 mmol) ol sorlium "-' t-BuOlVleihexane,'/acetone=7i2i I (vlv), Rf=0.6 ancl 0.7 (olrtainecl weight ratio: 1/2)l borohvclride 'was added, ancl the mixturer r.vas stirrecl f.or one Rtt().7; trans lactoLre hou. Therr, I ml of t't l0o1o hydrochloric cicl aqueous H-NMR (CDC13) ppm: 1.40(cl,6HJ=7Hz) L6(n,2H) soiution was adclecl therer6. nd the mixture rvas extracted three times wilh elhvl erher.'l'he ethyl ether sohrtion *0. --,. 1.6.5(m,2FI) 3.48(m,1H); a.20(m,tH) 5. l-5(m,1H) -5.37(cld, washod i'irh a saturatc(l soclium chloridc aqucous solution ''' lH,Jr=131r,Iz='lqz) 6.68(cl,1H, I=L9kIz.) 7.1 S.2(m,8H) Rf=0.6: cis lact ne ancl dried over anhyclrous magnesium sulfate. Then, the H-NIVIR (CDCI3) ppm: 1.40(d,6HJ:1Hz) 1.6(m,2i-I) solution was evaporatecl to ctryness uder recfucecl pressure. The csclual oil was purified bv silica gel column chroma- 265(m,211) 3 4.3(m,1FI); 4.20(m,1H) a.5(m,1FI) -5,40(dd, tography (eluent: 592 methtntl-chlorotbrm) ro obtai the -- lFI,Jr=l8tIzJ.=7117 6.66(m,1FI) 7.0-8 {m,BH) -"
Etbyl (E)-3,5-dihyclrox_v-7-[4'-(4"-fluoropbenyl)-2'-(-t
oily substance. 70 mg
1-g
Bv siliea gel thin chromalographv, the prodtLcl gave Lwo
(Yielcl: 647a)
il-NMR (cDC].) pprn: 1.30(r,3il,J:8trz) 13e(c1,Il,J= 8FIz) 1.4-r.8(n.z;').+z1tr,zri,t=trz 3.3.8'("',irO
' 6.5e(m,1Fr) 7.r0-8.i8(m.sH)

Example Soclium
3.-st(m,lH) :.u-+.o(m,zt 4.20(q,2H,J=.3FIz-; ;.:-sim,rnj ''---' 0 ... salt oi (L,)-3,-5<tihydroxi,-7-[4'-(4"-tuorophenS4)2'-(1"-methylethyl)-quinolin-3 '-yl]-hcpt-6-enoic acicl
llllllLll'l-119'-v ('iPj'.1'l,t:?.
9j.*".1-*..;,OT:10""'
uinolin-3'vran-2-one
pallclium-uarbon was cldecl theret<. The mixture was stirecl uncler a hyclrogen tmosphere. Al'ter conlrming t.l-re clisappearance of the starting substance ancl the appearance (compouod I--51) o-s ol'a new spot by lhi layer chromatography, the pailaclium60 mg (0 1-3-3 mmol) of cornpou ncl I-11 was dissolvecl in carlon ws frlterecl off, ancl ethnol was cistillecl oft'tr obtain J ml of cthanol. I'hcn, ().26 ml of a 0 5N sodium hvclroxidc color.lcss oil.
,"#.ic*.TlT'"*,ir, of erhanot, ,n ,i.lt;rl ""d

5,856.336
Filed 04/09/14 Page 24 of 50
t9
This oil was puritecl by preparative thin layer chromatograpby !o obtain 16 mg of the clesired product as pure
cololess oil.
20
TABLE 5
(Comporrnds
5
MS(nrie): 408(lvf*+H), 407(M*), 366, 292, 278 In tbe same mnner as in Exam.ple l-a, compouncls VII-2 fo YII-27 were preparecl lhe physicai properties of these compounds ac sho',vn in lblc 4. (In thc lhblc, Ir, I.2, R3, Ra, R5 ancl R21 corresponcl to the suLrstitients of compouncl
i this'lble are compounds o[ lormula VI wherein R is hydroqen.)
Lhe
Compound
Yf-2
VII.) TBLE 4
(Compourds n this Tble are compounds of VfT Rd is hvdropen I ComLhe
vt-3
10 vt-4
vI-5
VI-6
vl-7
VT8
pound RL
H VIt-3
H
mP.
vI-9 t-s vt-10

VT-I I
Rr
H
H
Rr
Rr
R5
R2'
('c.)
vI-1?
VII-4 vII--i
VII-6
H
6-Ct
H H
H
6-Cl
FI
7-
VII-7
VII-8 VII-9
II \Ie
H
FI
II
H
vtI-10
VII I]
vtI-11
VII-13
H
TT
vII-14 vII-15
II II
H
6-C
FI
II
H
vtlvII-
t6
17
vII-1S vII-1)
vlr-20
\II-t.1
vIt-22
vIl-2-r
FI H I FI 6-Cl U HH4-F H rI 6-Cl .\-Lll

-cl
6-Ct
6-OMe 7-OMe
4-F TI CI3 CrtL 1,11,-1)2 H H CFI:. CrH. 102-10? 5 H H i-Pr C.It 85i5.5 HHCE. CrHt 100 5-101 5 H H i-Pr CrI! 105 5-106 5 ]-F It i-Pr czfls .10 r 0-102 0 H H i-Pr C"H. oil 4-Cl H i-Pr crt{_. 134 0-r36 5 +-O^\4e H i-Pr CrHt 88.C-49,0 4-Me H i Pr c2Fls r08 5-t09.5 :-CI H i-PI CrI! lu11 0-103 0 4-CFj fI i-Pr CJI" 117 -s-_119 0 3-M +F i-Pr c:Irs oil 3-Ve 5-Me i-Pr C.Ht oil
4-F 4-F 4-F 4-F
4-OPh
vI-13
vI-14
\rl
15
rn -"
v[-1 vL1-l
vt-I8
VT-19
yl-)J,
VI-20
yt-12
25 wzt
w-24 vI-25 vf-76
vI-27
30
H
H
H
i-Pr CrHt 96.0-93 r) C"H. cH3 139 0-139 n-Pr i-Pr c-Pr c2Fls c:r5 oil
94 -s-95 5
Rz R:' HHp-FHCH' II FI H FIHHHi-Pr 6.CITIHCII. 6-ClHHHi-Pr H [I 2-l' r--NleHHHi-Pr H t{ 4-Cl HH4-OlvlcHi-Pr FI Il 4-Me 6-ClH2-ClHi-P H H 4-CFj H lf -: Me H FI 3-Me 6-N1e 7-OMe 4-F IH4-FHCrH5 HH4-FHn-Pr 6-Cl H 4-F HH4-l.Hc-Pr HH4-OPnHi-P 6-Cl s'Cl 4-F 6-CIHHHPh 6-Cl U II tI I 4-F 6-Me !1 4-t 6-OMe 7-OMe 4-F
Rr
R4 TI H H ll
5-Me
Rs
cc,)
149-15i
130-130 5
t39-1,47 1Ci8-169
CH.
iP
140.5-141.0
15-.0-157,0 192 0-1q5 0 186.0-138 s 161.0-_r64 0 122.O-12+.O 183 0-186 0 t6 \.D-162.s t-17 0 1-18 0 14 0-.165 0 14:L -5-143,5
iPr
iPr
i-P i-Pr i-Pr i-Pr
I 4-F
H tl H Il II H H
146.5-148.5 i-Pr
1'110-\7).O
720-126
15J 0-154,0
PL
9S_5-10-? 7'11 S-t12 3
c-Pr
sec-BL
.c4.0-36.0
119
0-121.0
i-Pr
c-Pr
t0.0-161 5
16?.0-16-3,0
H
H H
cH.
113 5-.116.-s
i-Pr
i-PL
Pb
C.Hu oil
4-F
H
H
H H
H
t:I
vIt-24 vII-2s
H
4-F
4-F
o-P
scc-
C.Ht 96.0-98.0 C.Ht 113 8-119 CH' 97.0--9S 5

CH.
oil
In thc samc manncr as in Examplc 1-c, compouncls V-2 to V-2'7 werc prcpared. (In 'lhb1c 6, Rl, Rr, R3, la and l{5 correspoocl 10 the substitueDts of compound of V)
35
TABLE
vlt-7i
vil-26
6-Me II
6-O\4e
7-OMe
tI
H
+-F
Bu i-Pr c-Pr
crtls cH.
109 0-111.0 153.0-15-1 -
(Compounds iD this Tbe are cornpoulds of the Rd is hydrc'cen )
VII-8
4ll
conrpo.n,l Rl
v-2 v-3 Y,4
v-_s
R2
H H H H
LI
Rr
Rs
rn.p
('c_)
t2-5-12S 143-1,46
II-NMR (in CDCJ ppm: O.92 (,3II,J:7IIz), t.4l

(cl,6H,J=Hz); 2.a7 $,3H),3 27 (HeptdpleL,I[J=6Hzl 3.96 (q,2H,t :1 Hz), 7.0-7, c3(m, sH)
H
FI
p-
TI
F]
H
tT
(I,3H,.T:7H2.), 1.42 (d,6FI,J=6FIz); 2.-18 (s,3HJ:3Hz), 3.25(Heptapler, lH,J= 6LIz) 4.()4 (q,ZII,J=7flz), 6.9 -A.I(m,7llz)
VII-14 H-NlvIR (in CDCI.) ppm:
45
l.0l
v-ri
v-'7
6-Ct 6-Ct
TI
tr
v-8
7-Me
FI
H H
H
l-F
FI
\,'9
v-10 v-11
5rr
VII-I5
FI-NMR(in CDCU ppm: 0.97(t,3H,I=7Hz),1.43 (d,6H, l=6LIz);2.29 (s,6H) 3.25 (Heptaplet, lHJ:6Hz) a.OO (q,2H, I=1Hz), 6.8-3.0(m,7H)
H
FI TI
I
H
6-Cl
v-12
v-1-?
v-1,1
H.
H
6-OMe H
4-Cl 4-Ole 4-Mc 2-Cl 4-CFr

3-Nfe
H
H 7-OMe
Il crl l H CH. H i-Pr u cHl Il i-P H i-Pr H i-Pr H i-Pr H -Pr H i-Pr FI ;Pf H i-Pr +F -Pr
5-Me
H i-Pr
91-93 t4-140
5
t2) 5-1210
1{J5._t-109.2 747 0-14i.8 '1-15.6- t36
11,9.4)1A 4
t0_5_8-106 9
't63'7-\64.2
VII-I8
H-NMR (in CDCI.) ppm: 0.98 (t,3H,J=7Hz),
(f ,3H J =7
v't6 Hz); 1.6-2.3(m,2r\,

2.
v- t5
N4e
4-F
i-Pr
8-3. 1 (m,2H)
4.
03 (q,2 FrJ=
1,.O2 _- v-18 :r
v-20 v-21
v-77
H
I
H
6-Ct
H
v-19
fI 8-C
H
H
4-F 4-F
H H
CrHt
n-Pr
4-'
,1-F
H
H H H
i-P
c-Pr
7Hz), 6.9-8.1(m,BH)
vu
21 1
(d.6H,J=6Iz); 3.25(Heptapet. IFI,J=Hz), 4.05(q,2H,J=
H-NMR (in CDC13) ppm:

13H)
03 (t,3HJ=7Hz),
I4I
6-Cl
6-Cl
6-C
FI
H H
161.:l-108 1 1f.3-122,3 't64 4-165.2 1+3.1 1442 150.2-155 3 t64 5-1ri5,3 150.1-151.6
4-OPh
i-Pr
106J-107 7
.t35.0-13-i 7 174.8-175 _1
157 125 155 200
4-t
H TI
iP
Ph
\r'-23
0,,
H
H
LI
TI
c-Pr
scc-Br
5-158 0
0-12rt - 0-15 7 0 0-200.5
7Hz),6.8-8.t(m, vtI-25
(
v-26
v-27
6-Me 6-OMe
H H
7-OMe
4-F 4-F 4-F
i-Pr
c-Pr
FI-NMR (iu CDCI.) ppm: 0.97 (cl,6FI,J:6Hz), 2.O-2 6 m,l H); 2.85 (c1,2H,J=7FIz), 3.-s t(s,3H), .s-8. I (m,sH) In the sare manner as in l,xample L-b, compounds VI-2 Lo YI-27 werc prepar..d. (In Table -5, Rt, R2, R3, R'+ aLrcl R5 corcspond to thc substihtcnts in compouncl VI )
6s
In Lbe same manner as in Exitmple 1-d, compouncls IV-2 to IV-6 rvere preptred. (In Table 7, Rr, R2, Rt. Ro and Rs cofresponcl to thc substituents oI compou(l IV)

5,856.336
21
TABLE 7
(Coorpounds itr
Filed 04/09/14 Page 25 of 50
)7
TABLE 9-continued
the
-)
this tbte are compocrnds o[ fV R s hvdroprr I
(Cornpounds in this lble are coopou0ds of he tormua ot lf wherein Rd s hvdroqe.)
Conrpouud
lv-2
IV:3 IV-4 IV-5 IV-6
Rr
R2
Rr
R5
CH.
rn.p (.C,t I1'7-t /9
Com-
H FI +' H HHHHCH. IHIHi-Pr 6-C HHHCL tt-Cl t'I II tI
pound Rl
'10 II-12
II.1O tI-11
R2
H
Ri
4 O\,fe 4-O\4c
2-C1
R{
H
R_-
1l
rr P,
cc.)
5
H H
6-Cl
iPr
tsPr
C.H, 78.0-78
tt
TI I
H H
i-Pr
II- 1 -l
In the same manner as i Example l-e, compounds III-2 lo lll-27 were prepared. (In Table 8, Rt, Rr, R3, R'and R5
corfespond to the sutrstituents of compound IIL)
II-14 tl-15
H H
FI
4-C[i5
II
+F
5-Me
TI
3-\4e
---\4e
i-P r-Pr r-Pr

r-Pr
crI{. oil
c2[Is
73.0--8.1.0
c,H-
75.0-7S 0
C.Ht
C],H. c2H,.
66 0-71 0
H
7-OMe
tf t7
1_i tI-18
II-19 II-]O II-21
tr-22
IT-23
tt-16
6-OMe
TABLE
lCbnrpountls in
II
H
H 6-Cl
4-F 4-t4-F
c"Its c,H.
o-Pr
iPr
oit
s3.0 90 0
94.0-97--0
H
TI
II
I
c-u-
oil
111
12.1
4-['
4-F
4-OPh
H
H
8
the
tiis lhblc are cornpoun<Js o[ lbrmula fll rvheei R'j is hvrlrout,rr.r

R2
F
,n
nr P-
II-14
6-Cl 8-Ct 6CI H 6-CI H HH4.F
4-F
H
H
T
i-Pr c-Pr i-Pr i-P

Ph
CrIt
CrH.
0-113.-.
91.0-9,3.0
c.H,
C.HCrHt
c'2[r_s
0-125
oit oil
69 0-,1 ), t)
H
H H
c-Pr
sccBu
C.H. oil
CrHt CrH.
oil
Comround Rt
('c
4-'
TI
tlI-]
ITI.3 TII-4
II-]6 lL)1
6-lvle H 4-F 6-OMe 7-OMe 4-t
i-Pr
c-P r
oil
H
H 6-Cl 6-Cl
FI
H
TI
III-5
TII-6
TTI.7
II
H
H
II
tI
l-1,'
TI
t{
CTL CH" i-P
t94-:t96
1'70-171 5
107-10s.5
25
Il-',z
II
H H H
H H
cIl..
i-P
i-Pr
\92-t94
125 5-.127
,30
H
7-Me
FI
1-{0.2
3
I:6Hz);
III-3
III.9
lTr- r0
}I
H
4-Cr 4-OMe
4-NIe
TII-11 Itr- t2
III-
L-I
rt-cl H
TI FI
II
H
11
I'I
2-CI
+cF.
_?-Me
-l- fe 4-F
H
I
i-Pr i-Pr i-P i-P i-Pr
D1.t-t22
r48
1_tl 6-11-].1
0-t49 l
)37.+-'140 I
s-r.8-s4,-s
:o
ppm: 1.21(t,3HJ=7tIz), t.32(ct,6H, 2.2-2.4(m,2H), 2.5 2.7(m,IH) 3.28(s,1H), 3.34 (Hep taplet, 1H,J=6Hz) 4.t)8(q,2H,I =7 lz), 1.34.6(tn,IH) 5.28(dcl,llI,J:6Ilz,J: IfIzl, 6.-s3(dd,rtIJ:1 .51Iz,J =15llz), 6.9-8.0(m,8H)
H-NMR(in CDCL)
1l-12
iPr
i-Pr i-Pr i-Pr
tII-14
TIT.1.5
4-F
\26 2-\28.8 t24.3-1'Jb 4
t{
7-ONle
5'Me
T
117t:0-l
8-150.9 3-718 5 117.S-111 5 1-15 2-135.9 141.3-144 r
147 124
oiL
IIt- 1 6 fiI- t1
ITI-13 IIT-]I9
6-OlvIe
tI
rt-ct H
{ II
H H H
+F
4-F
c.H,
n-Pr
H-NMR(in CDC13) ppm: I 25(t,3I,I=7Iz), r.33(ct,6H, =6Hz) 2.2-2.4(m,2H), 2.s-2. 8(m,1 H) ; 3.32(s,2H), 3.38 (Hep tapler, lFI, J=6 Hz) ; 4.1 3 (q,2H J =7 Hz), 4 24.6(n, lH) ; 35 5 34(dd, 1H,J -6H', J=1 5Iz), 6.53(r,lcl,rHJ=1 5FIzJ:1-5Hz),
t
+F
4-F 4-OPh
fi
FI
III-]0
IIT-21
tt
6-Ct 6-Cl
H
H
H
II 22 III-].]
IlI-24 III-25
TII-}6
s-cl
H
+F
H
H
i-Pr c-Pr i-Pr i-Pr

Ph
117-122
141 8-144 3 161 0-161 5
6-Cl
tI
-te 6-Or\le
II
H 7-()Me
I{
+F
4-F
ill-li
H H H H
H
7.0-4.0(m,7H) II-15 II-NMR (in CDCIr) ppm: 1.23(t,317,1=7llz),1.35(d,6[I, I =6Hz'); 2.2-2.4(m,2I), 2.3 l(s,6H); 2.6-2.8(m,rFf . -3.32(s. 40 2H) : 3.35(Hep1ap1ct,IH,J =6llz), 4. l2(<1,2H,J -7 Hz) ; 4.34.7
c-Pr
sec-Bu
(nr,rH), 5.-30(dd,1HJ=6Hz,I =l.6Hz\:

16Hz), 6.7-8.0(m,7H) II.TB
6.5 1(clcl,rH,J= lFIz,J=
78.0-.3t 0
1-r7 0-137,_s
4-y
i-Pr c-Pr
189,5-191_0
ilt-22
H-NMR (in C-DC1_]) ppm: 1.00 (t,3HJ:iHz), 1.26(t, +s 3ll,I =7tlz); 1.6-2..3(m,2l\, 2.12 (d, 2lIJ:6fIz): 2.61.2(m,
H-NMl{(in CIDCL) ppm: 1.40(d6H,J=7FIz), 3.44

(Heptaplet,lHJ=7FIz); -5.93(clcl,1 Il,J:8Hz,J=1 6Hz), 6.8-a. I (m,14H) e.34(d,1 FI,J=8Hz) In the same fianner as n Example 1-1, compouncls II-2 to ll-27 wcrc prcparcd. (In 'lblc 9, Rr, l2, R3, l{+ ancl l{5 correspond lo the srbstituets of compound II.)
3H), 3 3s(s,2FI) a (t2H):7ttz).4.3-4.7(n,1H) 5.27(dd, 1.H) :6Elz,J=76H2) 6 46(dc,1H,J:1 -sllzJ:lLlz), 6.9-S.0 (m,8H)
-so
tI22 H-NMR(in CDCI3)
ppm: 1 26(t,3H,J=7Iz), 1.-13(d,6H,
TABLE
(ConrpounrJs
J=6lrlz); 2.43(c1,2l,I:6Hz), 2.6-2.9(m,lFI) 3.36(s, 2H), 3.44 (Heplap le t, 1 FI,J=6 Hz) 4. t 3(q,2H,I :7 Iz.), 4.34 7 (m,1 H) -5.30(dd,1H,J=6Hz,I=I6tI), 6.53(dd,1H.J:1 sHz,I = L6Hz),
9
Llre
7.0--7,6(m,6II)
-ss tI-23
H -N
t-otrnua Cornpound
ir llis lble lre compounds o[ of [I wherein Rd is hvdrogen.) Rj

p-F H
Ml{(in CDO.)
ti ppm : 1.23(r,3
I=6Hz); 2.4-2.6(m, tH),

a.
H ) :7 trtz), 2.2 I(cl,Zt:t, 3 2-5(s,2H) 4 09(q,2LI,J:1Hz),
R,
H
FI
R2
H
FI
Rr
H
FI
R.i
il
oil 15-:t0(i 88 5-90 5 77-S2 96-9S oil 65.5-74 0 I 1.0-94 t)
1-a.4(m,1H) -5.08(dcl,IFI,J=6 Hz,I:16l'z), .26(dd,1Fl,J: 5Hz,l=l6Hz), 7.0-8.0 (m, L3H) H-NMR(in CDCIJ
ppm: 0.96(d,6H,.1=6Iz),
It-2 tl-3
TI-4
II..S
H
6-Cl 6-Cl H
7,
tI
H
II
H
FI
II
FI
l I
TI
II-6
l-1
tI-8 If-9
'i-v-
\{e
H
H
H 4-Cl
CH. C.H, CH. C:FI5 i-Pr C:FI5 cflr c.tL i-Pr C.H, i-Pr C:H, i-Pr C.H. i-Pr CrH.
60 II2-5
I =7 H ), 1 . 8 2.4(m, 1 H), 2.43 (cl,2H,J : 6Hz), 2.6-2.9 (m, 2.8 8(rt,21 | ) :7 f I z), 3.3 6(s,2ll), 4. I 4( q,zf I ) =7 IIz). 4.3
t.26(f,3H,
(rn,lFl), 5 0--5 5(ur,lFl), 6s II-26

J
3-6 7(m,1H), 6 9 8.(rn,3FI)
\H),
.7
FI-NMR(n CDCI3) pp: 1.25(r,3H,I=7Hz), 1.32(<t,6H.
=6LIz), 2.32(s,3l), 2..39(c1,2H,
=7
Hz), 2.-3.1(m,
r H),

5,856.336
23
7H) II-27 H-NMR (in CDCI") ppm: 0.8-1.5(m,ag, 1.26(t,3H,J: 7 Hz), 2.0-2.9(m,4H), 3.42(s,2H), 3. 7 I (s,3I), 4.00(s,-lH), 4.20(q,2H,I :7 Hz), 4. 4- 4.8(n, 1H), 5.-3--5.8(n, I tI), 6.44 9 (rn,1H), 6.s8(s,1H), 7.0-7.s(m'5H) In the same manner as in Example l-g, compouncls I-12 Lo I-727 *,ere prepared.
3 3 6(s,2FI), 3.41 (Hcp taple t, LFI,J = 6Hz), 4 Ll\t1,2H :7 flz), "I 4 34.7 (m,Ill), 5.0-5.s (m,1 FI), 6 3 -6.1 ( m, II), 6.8-7. 9( m,
Filed 04/09/14 Page 26 of 50
24
3.49(Hep taplel., 1H,J=6
4.20(<1,2L1 J =1
Flz)
3.
Hz),
(m,1 FI) 7.ii-8.2(m,8FI)

5
4.3 -4.5(
m,7H) s.2-s. s (m,1 tI),
6-3.8(m,1
H),
3.
9-4.2(
m,
l.
H)
6.-5-.8
l=6Hz); 1.5-1 6(m,2H), 2.3-2.5(n,2H) 2.8--1.0(m,1FI), 3.4-3.6(m,1H) 3.-52(Hep t aplet, t H,J:6Hz), -3.8.9(s,-3H) 3.9-4. r(m,lH), 4.20(q,2H,J =1Hz) 4.3 4. 5 (n,LH), 5.3-s.5
2H); r 3 9(d,H,J =6Hz),
2.3 -2.5
I-110 FI-NMR (in CDCI.) ppm: 1 .29(t,3H,J=7tIz,),1 .40(d,6FI,
10
(m,1H) 6.s-6.7(m,1H), 6-9-s.1(m,8H) H-NMR (in CDCI-.) ppm: 1 30(1,3H J=7}]rz),1 3-1 -s(m,
TABLE
RJ
10 l-1
OH
H) 3.50(Heptapict,l H,J=6 Hz). 3.5-3.7(m, Il) 394.2 (m, I H), 4.L9(q,2H,t =7 Hz) 4.24.5(m,1 H), s.2--s.6(m, I H)
(m,1
(m,2I) 2.43( s,3H), 2.8-3
t)
Rj
6.4-6.8(m, I H), 6.e-8.2(m,8FI) t- Il.2 1-s H-NMR (in CDCI) c\pprn: 1.30(r,3H,I:7Hz),1.-l-1.6(m,
2Ll);1.37(ct,6H,t=6Iz),2.3-2.s(m,2r)2.912(m,ttI),3.41 --
R
OH
R5
Conpound R1
m.p ('c
Nfass
zs (m,lH) 7.2-8.2(m,8H) I-IT4

7
lH,I =6Iz) 3.5-3 -8(m, 1H), 3. 9-4. 1(m,1H) 4. 19 (q,z}l,l =7Hz), 4.2-4.s(m, tH) s 3-5.7(m,1FI), 6.5-6.8(m, 1H) 7 1-8.1(m,7H) ?0 I-113 H-NMR(in CDCI.) ppm: 1.0-J..3(m,2FI), 1.30(I,3FI,J= 7Hz) ; I 40(1,6H,J=6Hz), 2.3-2.4(m,2H) 3 3-3.s(m, 1H), 3.49 (Fleptaplel, rH,J=6Hz) 3.6-3.7( m, f H), 3. 9-4. 1(m,1H) 4. I 8(q,2FI,J=7FIz), 4.2-4 -s( m, t r! s. 1 --5.s(m,1 FI), 6 -5-6.8
(FIep taplet,
Rr
H
R3
4-F
R+
Rs
Rr2
spectrum
t12
t-13
l- 14
H II H H H H H H U H H H +F
ClHr
Hz);
H-NMR (in CDCI.) t\ ppin: 1.2-1.4(r,2H), 130(I,3FI,J=

t.39(d,6H,I
=
6Hz),
2.
32(bs,3
Fl)
2.3-2.
(m,2H),
Cl.15 oil
M/e
+23- 292
't64,249
t-15 {-1
t,17 t-1s
t-19 t-110
I-1I I I-112
I-11-
t-1't
t-1 15
II II HH 6.CI H -cl FI HH 1-Me lI HH II II HH 6-Ct H HH HH HH t.I II HH 6-CI H HH IH 6-cl S-Cl 6-CI II 6-Ct t{ FIH 6-Me H
6-OMe
7-OMe
fI
H
I
TI
2-F
H
4-C.l
4-OVe 4-\4e
2-Ct 4-Crl," -f -Me
3--\4c
I-116 t-1i 7
I-1ls
t-1 Ic)
4-F 4-F
4-
t-130
4F
4-OPh
121
4-F
f-t-'l
T.114 I- t25
II
4-F 4-F 4-F
-726 L t),1
6-O!1e
7 OMe
CII3 CrtI5 92-105 i-PL C,L 97-10r) CHr CrH, oil i-P C.fI, oil i Pr C,I,. oil i-Pr CH. oil i-Pr CrHs 98-104 i-Pr C?tIr 94-98 i-Pr Cl,Hs 79-l-s i-Pr CrH, oi i-Pr C:flj 117-113 i-Pr C.,I- 85-92 5-Me i-Pr CrH. oi H i-Pr CrH. gum [I C,tls C-II5 oil H l-Pr C2H5 oil H i-Pr C2I{, 79-32 H c-Pr CHr 100-104 H -Pr C"H- oil H i-Pr CzH 133-143 tI Ph Crtls gum cH Pr CrH-, oiJ FI sec-Bu C,tI. oil H i.Pr CrH, oil H c-Pr CrH= gum
0-3.3(m,1H) 3.50(Fleprarlet, LI,J =6Hz), 3. 6 3.8(m,1H) .o -1.8-4. 1 (m,1 H), 4.21t(q,2H,J =7 Hz) 4.3-4. 6(m, r H), 5.2-s, 6 (m, I H) 6..5-6.8(m, 1 H), 7.O-8.2(m,7FI)
3
I-115
1
35 2 7-3.I(m,lH) 3.5r(Hcptaplct, IHJ:Hz), 3.6-3.7(m,1H) -1.8-a 1(m,1H), 420 (q,zH,J=TIz\ 4.2-4 6(m,1FI), s 2-s.6 (m,1 H) .4-6.8(m,1H), .8-8.2(m,7Fl)
I-116
H-NMR (in CDC1.) ppm: 1.1-1.4(m,2II), 1 30(t,3ll,J= z); 1.40(d,6[I.J=Hz). 2.2 2.5(m,2H) 2.35(s,6H),
H-NMR (in CDCI.) ppm: i.30(t,3H):7Hz). r.37(d,H, +o I=6H2.); 1.-5-1.8(nr,2H), 2.3-2.5(m,2H) 2.9-3.2(m,1H), 3 46 (HepLapler,tFI,J=6Hz) 3 6-3:8(m,rH), 3.7-5(s.3H) 3. 9-4. 1 (m,1 H ), 4.07(s,3I I ) 1.2{t(q,2Il,J :7 l7z), 4.24.5 (m, 1H) -5.1-5.s(m,1H). 6,4 5.8(rn,2H)
7.
t-7.5(n,sH)
4-{
J
r-11,7
H-NMR(iLr ClDCl3) ppm: 1.30(r,3FI,J:1Hz), 1.37(r,3H,

=7
Hz): L4-1.1 (n.2H), 2.2-2.6(m,2H) 2..e-3.2(m,3H), 3 6-3.9(m,1H) 3 9-4.7(m,.lu), -s.2--5 7(m,1FI) 6.3-67(m,
lFI)
7 0-8.2(m,8H)
50
I-118
I-1,7
H-NMR (in CDCI.) ppm : I .29(t,3tI,t=7H2,),
.40(d,6I,
-\f,
H-NMR (in CDCI') ppm: 1-01(1,3HJ=lLIz), 1.27(L,3tI, tlz) ; t .4-2.1(m,4H), 2.3-2. 6(m,2H) ; 2.8-3.3(m,3FI), 3.6-3.3(m,1H)r 3 9-4 l(rn,tH), 4 18(q,2FI.J=7[Iz); 4.24.5 (m,1If , 5.2-5.6(m,1 If ; 6.4-6.7 (m,Lfl), 7.0-8. l(rn,B II);
I =7
I-119
1
J=6Iz); 1.4-1 7(m,2FI), 2.3-2.5(m,2I) 2.9-3.2(m. rH),

(m,BI)
r-18
3.49(l Iep raple t, 1[I,J:6lIz) 3.5-3.8(m,1 fl), 3.9 4.5(m,2II) 4.20(q,2H.I =1 Hz), 5 .2-5 .7 ( n,1 FI) 6.s-6. 9(m, 1FI), 7 0-s 2
Hz).
-1.49(Heptaplet,lH,J=FIz); 3,6-3.8(m,IFI), 3.8-4,2(m,1H); 1.2tt(q,2Ft,I =7 H z), I 34.5 (m,1 F{); -5. 2-.5.6( m, I H), 6.4i.8
H-NMI (in CDCll.) ppm: 1.2-1.-5(m,2H), r 3[(r,3H,J= t .37 (c1,6t,l =1 Hz), 2. 3-2. 6 (r;lt,2l) ; -3. i)-3. 4( m, I FI),
H-NMI{ (in CDCI.) t\ ppm: 1.(1.4(m,2H),

7
(m,1H); 7.0-8 (m,7H);

1
Iz)
3.
t-3.4
31(I,3FI,J:
1
6l)
1.39 (',6tl,J =
( m, I
6r'z),
FI)
2.3 -2.
(m,2H) 2 52(s,3r),
FI)
I-r20
H-NIvlR (rn CDCI3) ppm: 0.-1.8(rn,6l), 1.-10(r,3FIJ=
7
3.48(Hep taplet, rH,J6 FIz),3.5-3.8(m,

=7
-1.8-4. 1(nr,1
FI), 4.2O(q,2H,J
tIz) 4.2-4.5(m,1,\, 5 .2-5 6

65
Hz); 2.1-2.6(m,3FI), 2.e-3.3(rn,1Il); 3.4-3.7(m,rH).

63
(m,1H) 6.4-6.8(m,rH), 7.0-8.0(m,8H)

I-19
3.8-4 6(m,2FI);42{t(q.2.H,J=7FIz), 5 4-5.8(m,LH); 6.4 (m,1 H), 6.8-8.0(m,BFI);

r-121
FI-NMR (in CDCI,) pprn: 1.29(t,3l,l=7lH^z),1.38G1,6H, J :6IIz); 1.4-1.8( m,2l I), 2.3-2.s{m,2II) 3.2-3.a(m, 1l f,
I=6H2,);
FI-NMR (in CDCI.) ppm: 1,29(1.311,J:7Hz),1.39(cl,6H, 1 .4-l .9(m,2t), 2 3-2.5(m,2ll); 21-3 2(m,1H),
Filed 04/09/14 Page 27 of 50
5,856.336
25
3.5
26
H), 3942(m,7H} [I); -5. 2-s. ( m, I I D, .4-6. 8
S(m.
1
l(Hept
ap le
4.19(q,2Il,J :7 rlz), 4.34. 6(m,1 (rn,l$; 6 9-8.2(m,13I);
1,1l J =6Hz); 3.6-3
l-125
l-122
7
H-MNR (in CDCI.) ppm:
Hz);
1.4
I(II,6H,J
3.50(Hepraplet,7H) =6tIz); 3.6-3.8(m,rH), 3 9--4._5(m,2H); + 20(q,2H.J:7Hz), 5.1-5.(m,lH); 6.1-.8 (m,l H), 7.1-7.3 ( m,.5 FI); 7 .7 2(d, IH,t =6tlz); r-723
Hz)
1 l-l 8(m,2FI), 13r(r,3HJ= =6Hz), 2.3-2 5(m,2H); 2.9-3.4(m,IH),
(m,1
H-NMR (in CDCI.) ppm: 0.8-1.-5(n,zI),7.29(r,3H,I: ; 2 2-2.4 (n,2H), 2. 6-2.9(n, IH); 3.2-3.6(m, IH), 3.7 4.3(m,2Ll) ; 4. 17 (q,zfI,J =7 llz), 5.0-5.4(n 1 I I) ; 6.1 -6.-s
7
'"
NMR (in CDCI3) ppm: 0.94(d,6FI,t=6llz), 1.0-1.7(m, 1 .27 (t,3H,I =7 tIy,), t 9-2. -( m,3H), 2.9 0(d,2H ) =7 Hz.), 3.3-4.4(m.3 FI), 4. 12(,2L1 ) ='|Hz), 5.G-5.5(m, 1 I), 6 2-6 1 s (m,1II), 6.9+.0(m,8II), I-t26 H-NMI( (in CDCI.) ppm: 1.0-1.(m,3H), t.zl(r,3H)= 1Hz), 1.34(d,6FI,.I:Hz), 2.3a(s,3H), 2.37 (d,2H,J :7Hz), ,,, 2.e -3.7 (m )FI), 3.8-4.s( m, 2H), a. (q,2H,I =7Hz), 5 .0-s 5
3ll),
(m,1H). 6..1-6.7(m,tH). 6.9-8.0(m.7H).
t-r27 II-NMR (in CDCI,) ppm: 0.8-1.9(m,BII), t
29(L,3LI,J= 4.02(s,311),
S
FI), 7.t.2(m,1 3H);

(
lHz),
I-124
FI-NN4R
7Hz), 2.2-2 6(m,3I), 2.8-3.2(m,rg, 3.3-3.7(m,1H), 3.9 - 4. s(m,ZH). 4. t 9 (q,2H,J =7H2.), 5.4-5 .8(m, 1 I{), 6.s-6 8
(m,1H), 7.1-8.0(m,8I),
in CDCI.) ppm: 0.8-l .8(m,6H), t .29(t,3H.I=
1-s
2.I-2,6(m,3H), 2.8-3.2(m,IH),
3.7
2(s,3H),
t9(q,2H,I =7 Hz), 4.3 4.6(m, rH), 5.a-5.8(m, 1H), 6.4-6 (m,1FI), 6..56(s,1H), 7.0-7.4(m,sH)
4.
In
the same manner as
in Exmple 2, compouncls
I--52 to
l-527 were preparerl. TABLE

RJ
11
I-i(RLz=al
or
(l{6 = H)
otr
Rt
R5
Compound R1
t--i2 t-53 t--i4
t--55 t-.56
Rr
t{
H
TI
Ri
R{
H H H
FI
mP
R.-
('c
Na
Na Na
H
TI
EI
+F
FI
CH,. CH,,
t38-t42
(decomposed) 't30-1,32 (dccomposcd) 196-197 (decornposed)
H
H
l
i-Pr
ct
6-Ct
H
H
H
CH.
N
Na Na
Nr
21,t-a
(decomposed)
I
tl
H H H
FI
iPr
i-Pr
9i-193
(decornposed)
r-57 I-58
t{
7-Me
FI
2-F H 4-Cl
193-2.n1
(decompose,l)
H H
H
i-Pr
t7i)-I'?5
(deconrposed)
I59
I 510 t-5:tl
L-5
iPr
i-Pr i-Pr i-Pr i-Pr i-Pr
Na
193-202
(decomposed,l
4-OMc 4-Mc
Na
Na iria
175-193
(decomposed)
H
6-Cl
H H
H
H
l
H
H
18?-?00
(decomposed)
t2
3
103-f0r)
(dccomposcd)
t--- I
+cttj
j-Me
-l-Me
.1-F
H
4-F
Na Na
20tt212
(dccomposcd) 195-100 (clccomposcd) 19-197 (decomposed)
t5 t4
t-51-5
FI TI
H
6-OMe
5-Me
I
i-P i-Pr
a
Na
t-516
I--s
7-ONle
TI
239:245
(decornposed;
I7
II II
4-F
TI
c.Il.
-Pr
Na Na
230-23i
(decorrposed, I9-3-200
(iJecomroserl)
t--< L8
II
+F
II

5,856,336
27
'lABt.E ll-continued
Rj
Rr
Filed 04/09/14 Page 28 of 50
28
oIt
I_-i (Rrz= N)
=H)
Rl
OH
f{
R5
n,pCompouucJ I-519
t--s20
Rr
6-Ct
TI
Rr
H
TI
FI
Rl
+F +F
+oPb
4-F
TI
R4 f{ u
H
H
TI
Rj
i-Pr
Rtz
Na
fc.)
19J-198
(decomposed,
c-P
Na
N_a
\97-l99
(decontlnsed!
13{)-139
(deco mposed)
I-521 l-521
r--i23
i-P
i-Pr
Ph
6-Cl 6-Cl 6-Cl

tT
8Ct
Na Na
Na
lg3-187
(deconrposed)
II
H
190-196
(decomposed)
I-5X4 I-525 -526 I-527
H
H
c-Pr sec-Bu i-P c-Pr
2t)A:l])
(decomposed)
6-Nfc 6-ONle
H H
7-OMe
+F
+F
4-F
H H
Na Na Na
204-208
(decomposed)
134-)38
(deconrposed)
I-57
31-43(m,aH). 5.3-5.(m,lH); 6,4-6.7(m,1H),
(in DMSo-dd) ppm: 0.e 1.2(n,2H), 1.37(ct, -- 6H,I=7Hz); r.7-2.r(m,z), 2.zoa,zU,t=Z'ttz); .0 .4(r, !\J7lHz);1.6-2.\(m,ZH),3.4B(Heptaplet,lH,J:Hz); 3FI),3.5l(Heptaplet,ttl,t=tlfz;3.9-4.3(rn,rF,5.3-5.6(m,
H_-\\4R.
35
FI-NMR (in DMSO-d6) ppm: 0 9-1.-3(m,2 H), 1.35(d,
8H); I--58 I--59
7.r-8.1(m.
rH); 6.3-6 6(n:r,1H), 6,9-8.1(m,7H);
tt-s1-5
7.1-7.9(m,8H); 6.3-6 6(m,1H), li.B-s.0(m,7t): I--516 H-NMR (in DMSO-d6) ppm: 0.9-l 3Qn,2H), 1.33(cl, FI-NIvIR (in DMSO-d6) ppm: 0.9-1.-3(rn,2H), 1.31(ct, 6H,J=7LIz); I.6-2.2(m,2H), 3.48(Heptaplcr.tH,J=7Hz). 4s 6H,J=ltIz); L1-2.O(m.2H), 3.:-3.l(m.aH); 3.62(s.3H), 3.5-a.6(m,4FI). 5.2-5.6(m,2H); .3-6 6(m,1H), 7.r-8 1(m. 3.9-4.2(m,1FI); 3 94(s,3H),5 1-5.5(m,rH); 6.2-6.6(m,1H). 8H); 7.0-7.5(m.H); I-510 t-511 H-NMR (in DMSO-dl ppm: 1.0-t .3(m,2H), L32(rl, H-NMR (in DMSO-ct6) ppm: 0.9-t.-5(m,2H), 1.34(r,3H,
-5.2-5.6(m,lH); 6.3-6.6(m,tH), 6I-l,J=7Hz);
H_Wti (rn DMSo-d) ppm:0.9-1.2(m,2Fr), 1.31(cr, *'' 6H,J=7Hz); 1.6-2.2(m,24),'i.:-s1s,oH;; .0-:.'1.,:lrg, 6H,I:1Iz); 1 7-2.2(m,2H1, 2.-50(s,3H); 3.-l-4.5(m,.5H), 3..51(Heprapter,lH,.T:7Hz); +.O-+ 3(m,tH), 5 3-5.6(m,tH);
H-NMR (in DIVtSO-ct6) ppm: 1.0-1.2(m,2H), 1.35(d,
L6 2.2(n,2I), 3,0-38(ur,4FI); 386(s,3H), sa J=7Hz); t.6-22(nt,2l{), 27-3.4(m,4H);
3.6-4 3(m,2I{),
4.0-4.3(m,1LI); -5.3--5.6(m,1[I),6.3-6.6(m,1II);6.9-8.1(m,
8H); I-511
5
5.2-5.1(n,1It);6.1-6.(m,1I!,6.9-8.1(m,BII);
I-s18 FI-NMI{ (in DMSO-(J) ppm: 0.8-1.3(m,2H), 1.01(r,3H,
H-\MR (in DMSO-d6) rpm; 0.9-1.-3(m,2H), 1.3-3(cl, J=7Hz); t.6-2 r(r1,4l), 2.i4 8(m,5H); 3.9-4.3(m,tH), 6l,J=7Hz): 1.7-2.1(m.217), 2.4r(s,3H); 3.2-4.3(m,5H), 5s -5.2-5.7(m,1H); 6.3-6.6(m,1H), 7.1-S.1(m,SFI),
3-5.6(m,1H); 6.3-6.6(m,1H),
l-512
7.0-8.3(m,BH);
I-.5
l9
7.t)-8.1(m,7H): I-sL3
LH)=1Ltz),3.9-4.2(m,rFI): 5.3-5 7(m,1H), 6,3_6.7(m,1H); oo 7.2-8.1(m,7Ll);
II-NMR (in DMSo-ctd) ppm: 0.9-1.3(m,2ll), 1.33(d, 6fI,I=7Ilz);r.6-2.2(m,2),24-.sm,tnS; 3.49(Ileprapler, 6l)=7Hz); L6-22(rn,2H), I 1-3 8(n,3FI); 3.48(Hepraplet, 1H,J=7FIz),4.0-4.-l(m,1FI); 5.-3-5.6(m,1H), 6 -3-6 6(m,1H);
H-NMR (in DNISO-d6) ppur: 0.9-1.3(m,2FI). 1.33(cl,
F-NMR (in DMSO-cl6) t\ ppn: 0.8-l 3(m,21-I), 1._i4(ct,6Fl, (m,2H); 2.3-27(n,t[), 3 0-J.9(m,3H); 4.0-43(m,tFI), J=7Hz); 1.6-2^2(m,2H),2.1-3 9(m,3H); -3.219(Heptaplet,lFI, 5.5-5.8(m,1FI); 6.:+-6 7(m,1FI), 7.2-S Q(m,SFI); I=7Ht,), 3.9-4.3(m,1 FI); -5.2--5.6(m, I H), 6.3-6.7(m,lFI); o-s J--52 t
I-52o FI-NMR (in DMSo-d") ppm: 0.8-1.5(n,6I), 17-2.2
7.1-8.1(m,.eFI); r-st4
H-NMR (in DMSO-d") ppm:09-r-5(m,2FI),
1.36(cr,
6rr,I=7ftz); t.7-2.3(m,2rr),3.0--3.9(m,3ll); 3.50(tleprapler,
Filed 04/09/14 Page 29 of 50
5,856.336 29
tH,J
7
:6Hz), 4.0-4
30
6(m,
3(rn, lH)
0-8.1 (m,13II);
; s.2-s.
rH)
6.4-6.7 (m,
It) ;
.IABLE
R:t
R4
13
t--1
I-522
H-NMR (in DMSo-d6) ppm: 0 8-1.3(m,2H), 6ItJ :7Ilz); L 6-2..2(m,2I), 3. 1-3.9(m,3rI); 3.51(Heptaplet, LH J :7 Hz),4.o-4.3(m, lH) ; 5.3-5 7(m,1 H), {t.3-6.1 (m,tH) ; 7.1-8.0(m,6II):
I-523
l r 37(d.
10
RL
OII
FI)
(m,Zlr);
r-524
FI-NMR (in DMSO-d6) ppm: 0..9-1.4(n,2H), 1.6-2..1

2.9
1-.4(m,1FI); 7 1-8.2(m,13H);
-3.7
(m,3II),
3.7
-4.1(m,ll\
5.
1-5.4(m,1
l!,
R5
1-5
('ompound I-,r2
I-_r3
R2
H H H
6-Cl 6-Ct
E.
R3
4-F
TI
Rr
H
I
R-s
II-NMR (in DMSo-d6) ppm: 0.8-L.5(m,5rl, 1.6-2.2 (nr,2H); 2.3-2.1 (nt,2H), 3.0-3.S(m,3H); 3. 9-4.3( m, 1 H), -5.4--5.8(m,1H) ; 6 3-6.6(m,7H), 7.t}-s.0(m,SH);
r-525
cFr3
FI
cFIs
20
I-34 I-35 I-.i6
H H
FI
H H
iPr
H H
f]
CH.
i-Pr
3.9-4.2(m,1FI); 5 2-5 6(n,IH), 6.2-6.6(m,1H); 7.1-8 1(m, 8H); l-526
H-NMR (in DMSO-dd) ppm: 0.9-1.6(m,2H) 0.96(cl,6H, 6Hz) ; t .t -2. 6 (m,3tr), 2. 89 (d,2 H, J -7lz) ; 3. 0-3 8 ( m, -1FI ),
.
FORMULAITON EXAMPLE
zs
TableLs
Compound I-51
lictose
10 e
5.0
3..1-3.t(m,3H); 3.9-4 2(m, 1H), -5.2--5.6(m, 1 H); 6.3-6. 1H), 7.0-8.0(m.7H); I-527
t 1 -z.tt(m,2H),
H-NMR
(in
DMSO-cld)
ppm: l..lo(d,6H,J=7Hz),
6
2.34(s,3H), 2.a-2.
(m,tIH}
3.
(!-3.3 (m,
2H),
6(
"
_^
m,
Crvstal celluLose porvder Con stuch Hvdroxvpropyl celluose CMC-Ca
s.0
1.0
30 e
c
!
15
Magnesiun srearate
Total
35
20.0 g
FI-NMR (in DMSO-c16) ppm: 0.7-1 .-5(m,-5H), 1.S-2.2

(nr,2I), 2.2-2.6(n,2H), 3. r-3.3(m,2H), 3.se(s,3FI), 3.94.2 (m,2I I), 3.e1(s,3l I), s.4-s.7(m, , 6.3-6.(m,ll I), 6.52(s,
Thc above components were mixed by a usual method

and then tabletted to produce 100 tablets each containing nrg of thu active ingredient.
lI{),
llf
l[)
7.0-7.4(m,sH);
IIORMULAI'ION EXAMPLI I-22 to

40 Cnpsules
In
the same manner s in Example 3, compouncls
I-26 can be prepared. TABLE

Ri Rl
12
L-j
Compound I-51
Lactose
1.0 g 10.r) g
otI
Crvstal cellulose porvder Magnesium steruLe

To
0.i 1-s0I
tl
:
Rl
FI)
OFI
50
Tbe above components were mix ecl by a usual method nd then packed in No- 4 geatin cipsules to otrtain 10[) crpsules each contrining l0 mg of the autive ingredient.
I.
OI{MULAIION BXAMPL
N
R
-\) Soft epsules
Compound
t-12
R
H
RJ
R4 H
H
H
+F
H
CH,
t-23 t-24
t-?5 t-16
II
6-C 6-C
H
TI FI
II
I't
f{
II tl
II
cH.
i-Pr CII-. i-Pr
6U
Conrpound I-51 PEG (polverhvlene gLvcol) 400 Saturated fattv acid triglvceride Peppermt oil
PolysoLbate 8l) Totl
1-00 g 3S9 c :l-5 00 g 0.{)1 g
0l{Jg
20.0t) g
6-5
In the same manner irs in Example 4, compouncl^s I-32 to I-36 can be preparecl.
The above compouents were mixed ancl packed in Nc
soll gelatin capsules y a usual method to obtain 100 solt ctpsules ech containing l0 mg of the cLive ingreclient.
Filed 04/09/14 Page 30 of 50
5,856.336
31
FORMULAIION EXAMPLE
Ointenl
Compound f-51
32
4
FORMULATTON EXAMPLE
Graoules
Liquid rarafrn
Ccta trol
10 _e (100 l0 0 g (10.0
s)
c)
g,r
rhite vaseliue
EthylparLreo
L-merthol
'fhr^
I
68,4 g (s9.4 0.1 g (0,1 g) 0 -i g (0,5 g)

.10
Compountl I-51 Lac!osc Crystal cellulc powder Con stach Hydroxypropvl cellulose MagesilLm stearate Tot^
1,0
ri0
-5
50
1.0
100 l) g
20.{) g
The above componnts were mixecl
b5r a
usual methocl to
1-\
obtain a L'/o (l(l7o) ointment.
F'OIMULAIION EXAMPLE 5
Suppos
itory
The atrove components were granulated by a usual method and packaged to obtain 100 packages each contaoing 200 mg of the granules so thrt each package contains l0 nrg oF the active ingreclient.
We claim: A compouncl of the fomrula,
F
Compound I-51
\\'itepsol Il15' Witepsol V/35'

Polvsorbate 80
t-o g 46.9 g
0.1 g 100.0 g
10
1.
Totr "Tradcnak tbr triglyccridc compouud
tAl
25
The alrcvc componenls were mclt-mixecl bv a

cach containing l() mg of thc activu componcnt.
usul
30
melhoc[ and poured into suppository containers, fbllowecl by coolitrg t'or solidifrcation lo o[r1aio 100 suppositories of 1 g
I.OI{MULAI]ON E)IAMI'LE
Injeclioo [ormulabion
Compound I-51 Dislilled wate tbr
N
35
Z=-CH(
mg
H)--CHa--{-H( OH)-CH,-CO O.%Ca.
rl
iljection tbrmrLlatioI
ao defined in claim 1.
The tbrmulation is prepared by clissolving the compound in the tlistillecl wter whenever it is require<l.
2. A mcthod tbr reducing hypcrlipidemia, hyperlipoproteinemia or atberosclerosis, which comprises administering rn clfecive rmount of the compounrl of lormula A s
Filed 04/09/14 Page 31 of 50
EXHIBIT B
Case 1:14-cv-02497-PAC Document 2 Filed 04/09/14 Page 32 of 50 I ilt ilililt ilt ililt ill] llllt llllt ]ilt ll]t llilt lll|t ilIil llf ilt ilt
us00855 7993 B2 (12)
United States Patent

Van der Schaafet al.
(ro) Patent No.: 1+s; Date of Patent:
us 8,557,993 B2
Oct. 15,2013
CRYSTALT,INE FORVIS OF PIT.{\ASANIN C\LC]IUM (71) ;\pplicant: Nissan Chemical lndustries, Ltd,
(s4)
FOREIGN P.{TENT DOCLTMENTS

EP EP
Too
(t2)
(JP)
EP
lnventors: Paul Adriaan Van der Schaaf. Hagenthal-le-Flaut (FR); Fritz Blatter, Reinach (CH); Ma rtiu Szelagierdcz. Muenchens tein (OLl); Kai-Urve
Schoening. Obc'nvil (CH)
ltP
EP
F]P
(73)
Assignee: Nissan (lhemical Industries [.td.,
Too
(JP)
(*) Nolice: SLrbject to anv <lisclaimer,

LI.S.C. ls4(b) by 0 days.
tre terLn of Lhs patcnt is exteudcd or adjustcd undcr 35
JP JP JP JP JP JP JP JP
wo
wo
WO WO WO
!vo
(21) .A,ppl No (22) Filed:

(6s)
L3/664,498
Oct. 31,2012
0304063 21989 406 t2;t992 I 099 694 ri200I t 412 227 l,'2004 t 472228 11,',2004 I 691 3)6 9i2006 6t-\11460 8,'1986 05-148231 5i 199- 6-92970 4i1994 8-12674 l,'1996 2005--s00382 1i2005 2005-5 1604 6,'2005 1005-5208t4 7t2005 2007-5169i2 6i2007 03/016317 2i2003 03j064382 8i2003 wo 03i06439? 812003 rd/O 0310707t7 8;'2003 03'0t7091 1012003 WO 2004i072040 8i'2004
o 520 OTI-IER PUB LIC,.\1'IONS
Prior Publication
US 2013/0053413
Dta
Al
Feb. 28. 2013
Related U.S. Application Data
(63)
Continuation of application No. 13,i280.^131, filed on Oct.25,201.1. now abaudoned. whichis a continuation ofapplication No. I21331.086. filed on Dec. 9, 2008, norv abandonecl, which is a conLinuation of applicaLion No 10/544,752. filcd as applicarion No. PCTiDP20011050066 on Feb. 2, 2004. Dolv
abandoned.
(JP to ptesent appLication) w-ith English trarslation. lvlu , 20 t 0 Subrni ssion of Ref'erences in .lP 2006-_50 l gg7 (.IP counterpil't to present application) with Inglish traslation NI,26,2010 Subrnission ol Retrences in .lP 2006-i01997 (JP counterpzul to present application) with English traaslation.
Jn 21, 2010 Subrnissior of References in .rP 2006-501997

counterpilt
Jun 29, 2010 Office Action in .rP 2006-50199? (JP counteart to

present ppl;cflrion) u'ith English translrion Aug. 23. 2010 Submission of Refrences in .IP 2006-501997 (JP eounterpilt to ptesentpplication) with English translaLion. Dec 27, 2010 Subrnission of References in JP 2006--501997 (.rp counterpaft to present application) rvilh English trmslation Jan 21, 2010 Subrnission ot References in JP 2006-520594 (.IP counterpart [o related U S .{ppl No 13t487.289) with English rrmslrtion. Mro, 3. 2010 Submission of Rclbrenccs in JP 2006-520594 (JP counlerptrt to relted U S Appl, \o, 131487,289) with nglish trmsla-
(30)
Foreign *\pplication Prio rifv Data

03405080
Feb 12.2003 (EP)

(sl
)
tiun.
(s2) (58)
21s/38 USPC
I.JSPC
Int. CI. c07D u.s. cl.
(2006.01)
NIa 26, 2010 Subrission of Refer.ences in ,IP 2006-52C1594 (JP corntcrprtlo rclatctl Li S Appl, No 11,'487,289) with English tralslaton.
s46n0l
546i t01
Ficld of Classification Search

Scc application fllc
lor comp.lctc search history
(.56)
Rcfercnccs (litcd
L] S. P,{TENT DOCLIMENI'S 3,175,944
5,0il,930
A ^ r
A
3,'1965 Floeksema
4;199
,\pr t2, 201 t O1lce Action in.lP 2006-520594 (JP counterpzur ro relacd L; S Appt No l-;487,289) rvith English trmslarion. Akiba et al . "Six-vfonth Repated Oral Toxicity StrLdy ot \K-104 ia Rats." The.Iournal olToxicological Sciences. vol 2-, Supplernent!', 7 t3-720. t998 Aug. 26, 2004 Interntionl Search Report in E,P 2004-707232 (EP counterpart to present ppl iceton) Mru 14, 2006 C)fficc Action inEP 2004-70i 232 (EP counrcJpfr ro present application) Dec 14,2006Thirtl Party Submission in EP 2004-70723? ([Pcounlerpilt lo present applicalion)
(Continued)
5,284,953 A
FL'ikaua et
aJ
54611 0
^ _s,856,i36 A
5,-514,804
5.40'7.929 -s.471.075 A
2i t994 C)hra et al 4i t995 lLl.hashi et al

+
5,919.552 A ^ 6.315.449 Bt
6.528.66
5.872.130
82
6,8:5,8:i8 B2 7 ,3i t .86s B2 2002i0099224 2003,,0 t0_5i59 ,\ Ît

2003,,021i00
2004006i961.\l
200510110978
A1
Al
2I)i0245200
^t
Ohrua ct al Ohaa et al. Ii t999 lrjikrwa et a1 ., 2i 1999 Ft!ikau,a et aJ. 8i t999 lkeda et l ti2002 Ohara et al 3/2003 Niddan et al. t2t2004 C'hen et al. _s,/2009 Acernoghr et l i'2002 Niddar el rl. 6i2003 !'n Der Schnaf et al. I2t2003 Storz 42004 V'u Der Sch:rat et al 6i2005 Yutla et al 9t lot2 Ohaa et al
121
t995
Prirnar;, Examiner
-sr'1996
(74) .4ttorne-t.
-5l4j3l I
5
-l) iVI Sezunan gent. or Firnt

&
Neustadt. L,.L.P
McClellancl, Maier
-Oblo.
Spivak.
t4ri
il
(s7)
ABS'IR{CT
Thc present invention is directcd to ltL-\4' crystllinc lorus of Pitavastatin hemicalciurn salt, reJrred to hereinafter as polymolphic Fomrs A, B, C, D. E ancl F. as well as the amorphons f-om. Furthennore, the present inventiol is directed to proeesses ft)r the preparation ol-these ostalljne lrms trnd the anorphou s t'orrn and pharruccu ticl cornpo sitions cornpris ing these orvstallinc fomrs or the arnorphous i'onns 39 Clairns,9 Drarving Sheets
Filed 04/09/14 Page 33 of 50
us
(56) References Cited OTIER PUBLICATIONS
8,557,993 B2
Page 2
EP 2004-807807 (EP colnterprt to related
11. 2008 Tiird Prty Submission inEP 2004-707232 (EP counterpart to present application) Feb 17. 2010 C)ffice Action inEP 2004-70i232 (EP counterpzur ro present application) Sep 29, 20 I C fhird Party Submission in EP 2004-707232 (EP counterpart to present applicaton) Jan. 25, 20 I I C)ffice Action :P 2004-701232 (EP counterpat to plesent applicatiotr) Jul 15. 2005 Inrernatonal Search Report in EP 2004-807807 1EP cunterprt to related U S Arpl No 13/487.289) Sorbera et al "Nll-104: Ilyolipidemic llMC-CoA Redrrctase Inibitor." Drugs ofthe Futule 1998,23(8). pp. 847-859 Nov 14. 2005 lnternational Prelirninary Report o Patentability in
Aug
Ogata, How lo Operte Chernicl Experirnent, vol. l. 1963, pp 154-155. 185-199 (Feb 5, 2013 t)ffice.\ctior in JP 20ll-260984) Dec. 10, 2012 Submssion of l(elr'ences in .fP 2006-50t997 (JP counterprt to prescnt appliction) witl English nsltion Nov 6. 2012 Submission ofReirencesir JP2006-520594 (JPcomterpalt to relted LI S ppl. No. t3i487,289), with Englsh tra.nslatron.
"lfedical SrLpplies Lnten'iew Forn: HMG-Co.{ reductase inhibitol designated rfrrgs LIVALO Tbtet 1 mg and LI\ALO Tablet 2 rng," .Ipnese Society ofHospital Phalmacists. Sep. 2003, with Englsh
trnslation. Aug t9. 2010 Subrnission ofReferences .in.rP 2006-501997 (JP counterprt lo present application) wiilr paltiaI Englrsh trmslation \,la', 8. 20ll Ofce Action in JP 2006-501997 (JP cormterpart to present application) lr,rth English kanslation pr' 26. 20ll Subrnission of Retr'ences in JP 2006-501997 (JP
US Appl
No
19,200i Ollce Action in EP 2004-807807 (EP counterpart to reltedU.S Appl No 13148i,289) Apr 4. 2008 Office Acrion n FP 2004-807807 (EP counterpart ro relted U.S, Appl. No 131487,2ti9).
ln.
tlir'487,289).
counterput to pr esent applicaiion) Sep 30. 2010 Subrnission of Refelences in JP 2006-520594 (Jl counterpilt to lelatetl Ii S Appt No 131487,289), u'ith ptil English translation Introductor,v Chemistry Course 2, Ph.vsical Chemistry. pp. 321-341, Aug. 28, 1997 (Sep 30..10 I I Submission of Relerences in JP200652U594)
Aug 2, 2010 Ofce Action in EP 2004-807807 (EP counterpzut to

elateclU.S
;\ppl No
13,487.239).
(EP cotur-
Tlird Palry- Subrnission in EP 2004-807807 terpatorelatedLIS Appl No 13t487.289)

Sep- 29. 2010
r
Apr. 26, 2011 Strbnssion of References in JP 2006-520594 (JP counte4)fl.I1 to related U S ppl. I'io 131487,289), with partial
English trmslation Japmese Phalrnacopoeia, Foruteenth Editon. pp 49-51 ivfr 30. 201 t (Apr, 26. 2011 Submission ofRetrences in JP 2006-520594). Mu 27, Z0l? Ofce AcLion in JP 2006-520594 (JP cornter!ilt to related Ll S Appl No 13i487,289). with English taslation Informtjon Oftr Fol ln dispatchetl Apr. 6. 2010 in Japmese Patent Application No 2006-500 1997 (with EnglishJanguage translation). lnfonnation L)fi'cl Form dispatchcd Fcb. 73,2010 in Japmesc Patcnt Application No 2006-501997 (rvith English-language trmslation) Information Offer Forrn dispalched Apr. 27. 20 [0 in Japa.nese Patent Application No 2006-501 997 (rvith English-lmguage translation). Official Action dispatched Jnn. 29, 20 l0 in Japalese Patent.,\pplication No. 2006-501997 (with EnglishJanguage trurslation) M Suzuki et al, Fist Systematic Chiral Syntheses ofTwo Pails o[
Enantiorners u,itl 3.5-Dihy'droxyheptenoc Acid Chain, .4,ssocited ri,itlr a Potent Snthetic Statir NK-104, Biorganic & Melicinal ChemistD; Letters, 9, (1999), 297i -2982
Feb 8.2011Office Action n EP 2004-807807 (EP coLmterpart to elated Li S Aprl. \o 1J1481 .289) Apr. 1 1. 201 I Thild Paty Submission n EP 2004-807807 (EP cormrer?rt to relafedlj.S, Appt No t3l48?,289).
By.rn el al , Solid State Chernistry of Drugs. 2d ed.. SSCI. Inc , 1998,
pp 59-64
The United States Phalmacopeia20l l. TheNtional Fonnular_v. USP
34NF29,vot I
Brittain. Polyrnorphism in Pha.nnaceutical Solids, 2cl ed, Iform Healtlrcae USA, 1999, 2009 Berse et al , "Phannaceutical Salts." Joulal ofPhmuaceutical Sciences,
vol.66. No
Takahasbi et
al, "Synthesis of
l. Ja l9ii. pp I to 18
an .Aiificial fMG-CoA Reductase
Ihibitor NK-104 vi a Flytirosilylation-Cioss-Coupling Reaction,"

Bull. Chcm, Soc. Jpn , 68, 2649-2656 (199-s) Miyachi et aJ., '\ Novel Synthetic Method of HlvfG-Co Reductse Inhibitol NK-104 Vi:r a Hytlroboration-Cross Corrpling Sequence," Totrahedron Lcttcrs, vol 34. No -5 l, pp 8267-8270, 1993 Bhattacharya, et al . "Therrnoa.natical and Crystallographic N,lethods." Polyrnorphsrn in PhamaceLrticl Solids. Bittarn H. ed . 2d ed,. Informa Healtlcare USA, Inc , 2009. pp 3 t 8-31-5 Ivso,ic, et al.. "Uses ol'X-Ray Powtlel DilTaction in the Phumceutical Industry," Pham Fom Qnal , 201 l, pp 30-33. Evaluation Rcports for App'oval for Prcscription Drug: Pitavastatin Calcium, LI\LO tablet I mg, LI\I{LO t:let 2 mg, http:r,'www infopmdagojpi. nrade public Sep t0,2003. rvith pzutal English tlalslarion Feb 5. 2013 Office Actio in JP 201 I-260984 (JP counterparr ro relatetl U S Appl No t3;487.289). wittr pzutial English trmslation.
Tlirct Pafy C)bsenation Subrniitecl on Aug. 21, 20t0 in JP 2006501 977 (including excerpt trorn .IP-A-2005--520814) Englsh Lmguage Translation of rrg 21. 2010 Thitd Put). Observtion Submitted in JP 2006--501977 (inclu<ling excerpr -orn Wo 03t064932. which is a counterpari to .fP-A-2005-.5208 t4) Suzki. Mikio, Development \York fot HMG-CoA Reductase Inhibitor NK- [04, (200 t), (partial English trmslation altachett) Ceriifcate for Lrbrruy \2lterial stoled in the National Diet Libr.ary, Dcvcloprncnt Work for HMG-CoA Rcductasc Inhibitor NK-104. Published (200 I ) lblurne Heisei- I 3. Chiel' L ibrr irn ol' Kansai-km ofNational Diet Library, KaarrkiYiutaguchi (prutial English trms-
laton attachcd
* cited by examiner
Filed 04/09/14 Page 34 of 50
(1 (t)
1500
tD
r .t.
(-f
1250
1000 IIITTNSITT COUNTS 750
n
L'I
.J
(r)
500
V)
(D
tD
250
\c
0 0
5
10
15
20
25
30
35
{0
Fs,
THTT AIGT.T
e (
so
;J \o \o (,
b,J
UI UI
Filed 04/09/14 Page 35 of 50
U.S. Patent
oc.
15,
2013
Shet 2 of 9
us
o -.
8,557,993B.2
tf) c.
C)
a-ct
GI
Rg
fr:
r . (9 z
H
Gf
Fl
o Fl
o oc)ooc>c'cre'c>ct oc)c>c>ooc'oc> r.O ctt c) r F rrl -t c-D G Fl
EA
Filed 04/09/14 Page 36 of 50
U.S.
Patent
oct.ts,2ot3
sheer3 of 9
us 8,557,993 B2
o
<{.
rl (fl
o
(f
<\l
f-
ff
ct z
or< c{H
F.
GI
lf Fl
e Fl
q
-f)
,$ \
o o
-1.
o o
o o o rl
o e o @ o o \cl o o
-t
o e <\l
e z=. tx
tsi
Filed 04/09/14 Page 37 of 50
U.S.
Patent
ocr.
15,2013
sheer 4 of 9
us
ct .{.
9,557,993 B2
rrl (f
o l
rD
GI
fl Fl (9
od <\
=
Ei
H c\l
a.l
o r--l
r-l
el
-$
\
o o <. Fl
o o GI
Fl
c>
o o
o o @
o o r.o
o o r<.
o o t
e s H
Filed 04/09/14 Page 38 of 50
U.S.
Patent
ocr. 15,
2ot3
sheer 5 of 9
us
o
-1.
8,557,993 B2
<fi
r)
o o.
<\
rt
ET
o c{
<9 d
F. rd
Fr
sf
r.r
r{
e Fl
r-ct
o t Gf
FI
o
o Fl
o o r.) r oo oLll o
C{ 1l^D
e f-t X
=,=
Filed 04/09/14 Page 39 of 50
U.S.
Patent
ocr. 15,
2013
Sheer 6 of 9
us
o -t.
8,557,993 B2
(rD
rl
6.'
a.tt
rf (9
R* r
rJl
|< =
?
Fl GI
t.rt
o ct o
FI
o o
o o \l
H-^ tsr Y: cr2 = gta =e.

FIH =. =v
e o :
o o st
<>
Filed 04/09/14 Page 40 of 50
U.S.
Patent
ocr.
15,2013 sheer 7 of 9
o <.
us
8,557,993 B2
<fl
r-(
o (Yl
Lr
r+ od
Gl
z
f-
(.'
LT' Fl
ct
t-t
o
o o <\l FI
o o o r{
o o E ?H
e o (o
s> AE
oo oo
=t
r'I= =e.
Filed 04/09/14 Page 41 of 50
U.S.
Patent
oct.
15,
2ot3
sheet
I of 9
o
-f
us
8,557,993 B2
(n-
rt
Llr GI
ff F <9
4 H fI
Fr GI
rrD
Fl
a.t
={
$
|,\
e o \,
o c>
l)
o o rEl.
H
o o cf
>
C\I
o o rl
s =e,
G=
>< zv t{
Filed 04/09/14 Page 42 of 50
f.].S.
Patent
ocr.
15,2013
sheer 9 of 9
us
o .sl.
8,557,993 B2
.l2
fI . <9
Rg g
GI
= 4
o H
:$
\
o o (O
o o rrt
o o <r
ct o >{
crl
o o
Fl
c o
Filed 04/09/14 Page 43 of 50
polymorphism. Polymorphism is oommonly delned as the ability of any snbstance to have two or more diftrent crystal strucfures. Drug substances may also encapsnlate scrlvent CROSS REFERENCES TO REL,{IED molecules u,hen crystallized. These solvates or hydrates are -5 refed to as psendopolyruorphs. It is also possible that the .{PPLIC.{TIONS arnorphous fonn is encounterecl. Differcnt polyrnorphs, TLis applicatioL is a continualitn of LI.S. patent applica- pseudopolymorphs or the amorphous fon differ in their ion Scr. No. 13i280.431, filccl Oct. 25,2011, which is a physic:il propeitie int, solubiliry etc. contimmtion of lI.S, patentapplcationSer. No. 12i331,086. These can apprec.i cer-rr.ical properties
(iRYS'l'ALLtNl,l 'ORIS Ot'PI.I'AVASIAl'IN
l2
us
9,557,993 82
CILCIUII
fileclonDec.9,2008.no,wabandoled;whichisacontinuation
olU.S, patent application

Patcnt Application
Ser. No.
i0154
3
l,) suchasirru,tiun
8, 2005. uow abandoned; *.hich ivas a
2004i050 2004, and clairns priority to luropean Pat 03405080.7, fi1ed on Feb. 12. 2003. all of
No PCT/EP
l'alec lerelI Dy retereucc ll tnelr entlfelle The preseLri invetio is directecl to ei anrl the amorphous fom of Pitavastati'
.l!isalsoeconomi_ t theproduct is stable forextendeclperiods leed t-or specializcd stomge conditions lt ant to evaluate polynorphism of dmg subre. the discovery ofnew crystalline polya dnrg enlarge the repefclire o1 materils
scientist has w'ith lvhich to design a phar-
: lonn o[ a c1rug
forthcprcpartiouthercoiandphannacq ^ comprising these forms. rre present invention relates to ne\.v cl" the au-rorphous fomr of pitavastatin calci also known bi the uames NK-t04, Itavas tin. Pitavastaiin calci.m is lor.rvu by th (3R.5s)-7-[2-cyclopropyl-4-(4-fluoroih"r j,-s-irr--vr^y_-e(E)lh"pt"',oi. acid hmic astatin calcitun has the follorving formula.
3
"vith ;ircdcharactcristcs lv-cnowhavcsu4rrisc4,sta1line forms of Pitavastatin calcium, as fonu A' B, c' D, E ald F, and the rf Pitavastalh calcimn' e present ivention is diected to the pol,vD'E ancl F, and the arnorphr'rus fomt
:rum salt (2: l)' re inve.ntion is a crystalline polymorph
a targetecl release
P'C,
of
)propyl-4-('1-fluorophen'l) quinolin-3yll -3,5 <lihydrox.v-6(E)-heptenoic acid hemicalcium salt. herein clesignatecl as Fonn A, which exhbits a characteristic X-ray porvder cliffiaction pattern wilh characteristic pealis expressed in cl-vahres () aud in 20 as given in Table 1
(vs-rzery strong intensiry s=strong intensity. rn:rnediurn intc-nsify. rv=veak intensity, \ :very r"'eak intetsity).
OH
Crl*
T,{BI,F,
I
-A
rl-crrino< rn,l ) tslcs lrr Form d-spacing []

41)
-gLe
l20l
Rel lntensitv
s s s
t].6
t-l
)
.5.0
9t-
6.8 9.1
8li Pitavastatin calcium has recently been developed as a new

8.4
8.1 6.7
lr)-0
to.-
tl
trl
S
chernically synthesized and pou,erlrl statin by Kowa Corn-
I 1.0
1-1
paly Ltd. Japan. On the basis ofreported data, the poteucy of 4i

Pilar,astarin is dose-dependent aud appears to be equir,alent to that ofAlorvstatin. This new statiu is safc ancl well toleratcd in the treafinent of patielts rvith hypercholesterolaemia. Siguificant interacLions with a mrmbe of other commonly trsed drugs can be crrnsidered to be extremel,v- low Processes ttrr the preparation ofPitav'statin are clescribed in EP-A-0304063 and EP-A- 10!)9694 antl in thepublications
6i
137
6_i
r40
14.1 9
0
557
i25
5, 17
Ii
t7r
18.4 19 l 10.3
r6.9 m
1S
50
4,81
464
42i
4.2t)
by N. Ivfiyachi et al. in Tetrahedron Letters (1993) vol. 34. pages 8267-8270 and by K. Takahashi et al iu Bull. Chem. Soc, Jpn. (1995) i.ol. 68.2649-2656. These ptrblications describe the synthesis ofPitavastatir in great delail but do not clescribe the hemicalcium sa.lt of Pitavastatin. The publicaSorbera et al. in Dmgs of the Furure (1998) r.ol. 23, pages 847-859 and by iVI Su:mki et al. in Bioorganic & Vfedicinal Chemistry Letters ( I 999) vol. 9, pages 2977 -2982 describe Pitavasiatr calcium, however. a precise procedure lor its prepzLration is not given.,,\ lull synthetic pmceclure lirr
the preparation
l.l
t;
m
ln
410
387
.t5
2l
22-L)
3't4
J. /
)i7
242
25.2
llt
fn
s
i.i:1
-l
tions by
LA
l9
)1
1,02 2.95
296
-1(),2
60
6-1
340
Another object of the invention is
crystalline polvrnorph
of Pitavstatin calcirun s described in l,lP-A65
0520406. In the process described in this patent Pitavastatin calciunr is obtained by precipitatioLt fr'orn rur aqueous solutior as a rvlie c4;stallirre material witha melting point of I90-t 92 C. Il is know-n that phiurnaceutical substance-s can exhibit
(3R,5S)-7-[2-cvclopropyl-4-(4-lluorophenyl)quinolin-3y1l-3,5-dih'droxy-6(E)-heptenoic acid hemicalcium salt, herein designated as Form B, which exhibits a characteistic X-rav ptrrvcler diflraclion pattcru lvith characteristic peaks expressed in d-values (,4.) and in 20 as given in Table 2.
Filed 04/09/14 Page 44 of 50
us
3
'ARL.2
j-{n .in.r. 1n;r 1 illsles lor Fonrl R
d-spaciag []
19 ()
8,557,993 82
4
]ABI,F] 4
-cr-i^-.,,, )a
nsles f'' For f}
,turgls
[20]
Rel Intelsity
d-spacing []
t7.-5
I _3._5
,AJgle
4.6
166 142 l 1.i

9-6 9.2
i.3
6.2
s
[20] i0
6.5
Rel Intensity
u m
s
t2
1rl.-i
77
ll.0
r0. t 8.8 8. 8.2 6.8
6._\5
68
8.7 10.0 1!i.2
m
m
m
Il ill
96
I 1.3
B5
'l.i
7.8 7.6
r08
1
I1.1 126
13 t)
1
3.1
-5
l3
ln
s
6.8
6.21)
14.3
64 6o
594 566
43 5.22
_5
i.9
t-
_5.78
l_i..i
14
1-t
14_9
lj6
I 6.3
t1
17.0
5-11)
ti.4
l3.r) 187
2t) tn
5.52 ,\.28 4.87 4.80 4.66 4.46
t61
1
6.8
1B 2
t8 5
19.0
19.9
m
nl
4.92
474
4.59
4.34
4.23
4.OC)
20.5
ltt
s
r9.i
2f_)
fn
s fIt
443
4.26 +.19
210 217
22.3
20._s
3.99
3.8C,
20.8
?3.4
2t2
2r.5
111
sltou der m
s
2-5
3.1C
24()
25.6 26.2
n
m
4.r3
3_9i
3.47
3.41t
224
23.2
383
3.73 3.64
236
24.4
m
lrod
252
3.4)
li7
26.O
l0 of
.{nother object of the inveution is a cr_vstalline polynorph
to +
27 l') 2-r.9 28.9
,10
It9
3.09
li
(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophcnyl)quioolin-3yll-3,5-dihydroxy-6(E)-heptenoic acid heuicalcium salr, herein designate<l as Fonn E, which exhibits a charcteristic X-ray powder diffraction pattem with characteristic peaks e'xpressed in d-valnes () an<l in 20 as given in l'able 5
of
v1l
't,\uf
,r-t s
or
d-.^^;^-. "- )a nols

40 d-spucing []
2at-o
Fonr F Rel. htensiLy
herein desguated as Form C. which exhibits a characleristic X-ray powdcr cliffractiou patlcrn witlr chrractcristic peaks cxprcsscd iu d-valucs (A) ancl in 20 as givcu in Table 3.
-gle
[20]
t]
TABLE
3 rl-sninos qnrl lA atsles t'or Fornr C d-spacirg [-4]
44
5.0
s
s s s
13.4
6tj
8 89
10.0 L0 -3
l-l I
4i
l() (l
88
8.6 8.2
tJ.6
m
s
Argle
2t6
I _s.9
[20] 4l
5,6
Rel Intensity
m
s
l(1.8
I
i.i
ul
s
6.5
tt4
l0-6
8.6
78
8.3
m
JN
6j
50
136
14.0
1.5.2
nl
s
i.84
5.56 5 -.9 5.24
4-91)
r0.3
17
5.06 4 9,s
il6
175
1i
164
16.9 t,1 8
18.3
t7
r)
414
455
4.31
4.1-1 4.r-)6
187
19.5
L
s
4.84
55
lll
vs
4.69
?06
21.9
m m
m
60
439
4.-34 4.3( I
9 20.2 2t).4
20--!
l8
m
nl
m
i.84
17t
3.58
)3
4.24
4.21 4.12 4.08
20.9
24.0
2l.l
216
2r.7 223 m
il
m
248
399
3.17
nl
m 24.t
v
herein designated
as Form D, which exhibits a cluracteristic X-ray powder dilfraction pttu'ru with characteristic peaks
65
i.69
1.60
i._5
241 254
26.6
335
Il
expressed in d-r,alues () and in 20 as given in Table 4.
Filed 04/09/14 Page 45 of 50
us
5
'll\B[,F,5-continued
r1-"-ncino"-
8,557,993 82
6
t,urthennore, lhe present invenLion is directerl to processes t'or the preparation of Fomr A, B, C, D, E and F, and the amorpholrs trn of Pitavastatil ca.lcium. Form A can be geuera.lly prepared from Pitavastatin -s sodium npon reaction ,with CaCl, in an aqueous reaction mediun. Al ernatively, Form A of the inventon mav also be obtailed iu situ liorn tile flee acid ((3R,5S)-7-[2-cycloprt p.vl4-(4-fl norophenyl)quinolin-3 -y.ll -3.5 -didroxy-6(E)-heptenoic acid) or the corresponcling lactone with Ca(OH)r, advautagcously als( in an aqucous rectio1l mcdium. The ,,, " aqucous rcaction mcdiru usrnll-v corrtaius at least 809/o b.w.. o1 w'ater; prefrably it is water or ,n'ater containing rninor arnounts of solvents and./of reactanls from prevous steps. Form A rnay contain Lrp to l5%o water. prelerably aboul 3 tcr l2oto, morapreferabl, 9 to I l9lo ul'water. l-\ Fonu B can be generally prepared by suspending formA in ethanol containing *,ater as a co solvent. The aruorut ofr/ater is preferably about 1 to 50%. Forln C can be geuerally prepared by suspending formA iu sopropanol contaiuing r:r'ater as a co solveut. The amouut of 2r) water is preferably about I to 50%. especiallv 1 to 20? aud more preferably about 57o. Forur C can also be prepared hom a mixhre of isoprop:utol and a ketone solvent. corrlainiug wter as a ccl soh,ent. Preferably, the ketone solvert is acetone- an<l the amount ofketone solvelt are abort 1 to 30%, 2,s lnore prelerably about l0%. The aurount of water is preferablv about I fo 2oyo. more preferably about 57o. Folm D can be generally prepared by suspending fonnA in
absolnte ethalol. Form E can be generally prepared by suspending fbrm.4. in r0 1,4-djoxane containing water as a co solvent. The amount of lvate is prelrably about I to 5070. Folm F can be generally prepared by suspending formA n ruethurol coutaining water as a co solveut. The arnorurt of ,'vater is preterably about I to 507o. Ii ln the above trleffioned processes sm.ll rnounts of seecling crstals of the desied crystalline t-orm may be added to the reaction rnixture. Preferably srall amounts are about I to 20 weiglrt 7, more prelrably about 5 weiglit 9/o. Seeding crystals nray be added before or, where appropriate, alier the 40 stcp initiating the crvsrallizatiou (e. g. coolilg, additiou ol-
nrl
?t
rnols fr Fnnn F
d-specirg []
.Agle
_10
[20]
2
rJ
Rel. lnteusiry
296
264
l4
(3R,55)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3yll-3.5-dihydroxy-6(E)heptenoic acid hemicalcium salr. herein designated as Fonlr F: which .'xhibits a chamcteristic X-ray powtler dil'lraction pattcnl with charucteristic peaks expressed in d-ralues () ancl in 20 as given in Table 6.
T.A.BLE 6
l-<nnnio n 2A anlpc r F^"
of
Another objo-ct of the inv.ention is a cr)'stallinc polymorph
d-spacing
[.4]
Argle
_5.
[20]
I
Ret lntetrsity
m
s
l1
r7.2
1_\.8
56
7t)
8.3
12.6
10-r)
96
8.7
1.2
8.r
7.8
tD9
1
14
7.1,
1l
ll9 i
t.i
ol m
68 6-i
62
8.04
It
s
l- 0 t.l 7
m
s
t44
141
15
t70
570
.5
li
It
m
28
16.8
t,1 6
18..1
i.03
4.85
4.6t
4.51
19..)
It
nl
trl
s
19.7
430 418
4.08
3.91-r
206
2t.2
2
1.8
non-solvcnt ctc. as dcscribcd above). Acldition bcforc initiating the crystallizaticn is of specific teclmical interest, s The amorphous fomr cal be generally prepared by addition 3.-59 248 s oJ a uon-solvett tLt a cr)[centrated solutiorr of Pilavastatil t46 l-i.7 m 3 41) 4-; calciuru it an orgaric solvent. As ton-solvent may be taken 26.2 26 ti m 1br *nurnt" heptane t'rr methyl rercbutyl ether, whereas i tl 26.9 exarnplcs 1-or thc org:u.ric solvcnl are 1,4-clioxane, tctrahydro3.14 ?8.4 ftrran and etl methyl ketone. It is preferable rhat the uori.02 295 solvent and stlvent are miscible. The arnorphous t-crrn cur 3.tr0 298 289 i.9 IN so also be prepared b.v l"vophilization of al aqueons solution of Pitvastatin calcium. , C, D. E' F as well Snall changes in the experimental details can cause srnall substantially pure deviation ir the d-vaiues and 20 ofcharacteristic pezrks il the
1,84
3t4
2ll
22.9
s
s
2t.8
rou de
3.69
of
rl-
55
he educt specified, ' and solvents ancv
ch
Processes fbr
tatin calcium
depicted in I'lG' 7. ,rl particularly. tLre ro processes Powde X-ruy diffraotion is perlbrmed on a Philips . 7l() for tire preparati.' ef 1ar1.11i'e l-orms of pitavastatil cal_ -. por.vder X-ray diractoneter using Cu k (crl) radiation ciresieiirlly treeol-rsiclualorganicsolvetbyexposng (1.54060 ): 20 angles are recorcled with an experirnental ilre crystalline ibnn oTPitavasrarinialciun to an atmosphere errorof*O'1-0-2o.AdsctrssionofthetheoryofX-raypt'xvder with a delned relative air hrmidit-v. lVfore particularly, the dilraction patterns an be t-ound in "X+ay difi'action proce- os present invention is directed to a proess lbr rhe preparation of dures" by H. P' Klug and L E. r\lexander, J Wiley, NewYork nv crystalline lrmr or mno.pLu, lolm of'piiavastatin cal(1974)' qittn which is esseutial.ly liee of residual organic solvent.
Filed 04/09/14 Page 46 of 50
'flesecan. t'orexample.bepreparedbyexposingtheowslalline t-onn or amorphous lorm to an a rmosphere rvith a relative air humidiry of5 to 100%o. Preferably'. these are prepared bz exposue to an irer1 gas stren with a defined relative air
78
us
9,557,993 82
novel lorms to prepare such solulions is considereil to be within the contemplation of the invetion
Capsule dosages, ofcourse.
will contain the solid conpo_
huruiditytoexchangeresidualorganicsolvelrtwithw'ater.
co po oi ne-r.
general, a rclative air humidity of 5 to 100%. especially 40 to 8070' is used. Ano ther oblect o f t be present nven tion are phannaoeu tcal
Il 5
sitiourvithjnacapsulewhichmaybemadeofgelatinorother colventioual elcapsulatilg material. Tablets and powders

may be coatcd. Tablets ald powders may bc coatcd r.vith an enteric coating. The enteric coated powder forms may lrave coa tings cornprising phtirulic acid cclhrlclse aceta(c, hyd1lxypropylnethvl-cellulose phthalate, polyvinvl alcohol phthalate, carboxymethyleLhvlcellukrse. a coprrlynLer of styrene and maleic acid a copolymer of rnethacrylicacid arrd meth14 melhacrylate. and like materials, and if desired, they may be employed rvith suitable plasticizers ancL/qr extending agets
an effectiv l, I), F or F
da
phanna
'''
,,.
luiose,hvdrox,r'propylcellulose,hydroxyprupyLnetlcelu- .1.15 gr of (3R,5s)-7-[2-cyclopropyl-4-(4-fluor.opheryl) lose,carboxymethyl,cellulosesaltsardothersubstitutedand

unsubs[ituted cellu]oscs: srarch: pregelarinir"a ,n."tr; i,iur] galic cliluents like calciurn carbonare ancl calcium aiffi- r. phate and other dilue[ts knorvn to the pharuraceutical d;;try. Ye other suitable cliluents inclue waxes. ,ugur,4d sugar alcohols like man_itol and sorbitol, acrylate pllrmers an ctrpolrrners, as w-e1l as pectfu. dextrin an gelain.
As to t1'Lenovel polymorphic forms and amorphons fonn of enteric-coating. PiLvaslatin calcium it is pret-erred that these contain PrelerredLuritdosagesofthephamraceuLical cmpositions 25-100% b' weight, especially 50-100% by *.eight. of at ofthis invention rypically conrain from 0.5 ro 100 mg ofthe least one of the novel ttrrns, hase< on the Lotrl arroun[ ol' 29 novel Pitavastatin calcium tlmrs or mixtures tliereof with Pitavastatin calcium. Preferabl,; such an amount of the novel each other ol other forms of Pitavastatin calcirun. lVlore usnally. the crrrubined weight of the Poll'1to*1" fonlrs or amorphous fonu of Pitavastatin calcium is 75-100% byrveight. especially 90-100% bvweight: pitavastatincalciumibrmsofaunitdosagcarclrom2 5mg Hig1y plefrred is an amount of 9-5- 100% by weiglrt. to g0 mg, for exarnple 5. lO, 20 or 40 mg. Thecompositionsoftheinv.enlionincludepowders.grauu- u-s The i.ollowiug Examples illustrate the invetio in more lates. aggregates and other solid cornpositious cornprising at detait. Tentperatrres are gi'en i degrees Celsins. ' least one of the novel forms. In addition. the compostions that are contemplated by the present invention may f,rfiher EXAIVIpLE I inc.lude diluents, such as cellulose-derived tnaterials like powclerecl cellulose, microcrystalline cellulose. micotne o Prep:uation ofform A cellulose. methyl celhilose, eth!.1 cellulose, hydroxyerlyl cei-
hese polymorphic fomrs mav be used as single componentol'asrnixtureswithotherctystallinefomrsortheaurorl-\ Acoatedabletrnayhaveacoatingonthesurtceolthetablet pholts fi1n. or may be a tablet cornprising a porvcler or granrles wth an
acid tert-but'vl 3]l",l.L^1.y1]^],'5-dihydroxy-6(E)-heptenoic cslc.rlPitavlstatr tcrt-bulv1 estcr) ws suspcnded in 52 ml o' a nr.ixture of methyl tert-btrtyl ether and methanol (10:3). TLr
_.-,..^;_"-;
:,i -:'
*et ancl dry granulatou and di-r-ect compression Ttr this aqueous solution were added a solution ol 0.58 gr bleting processes. Excipients that also may be present in the CaCl, in 80 rnl of wator ovcr a pcriod ol I horu The rcsu.lting solid cornpositious ftlrther include disirtegrants like sodirrm 4-i suspension was stirred for about l6 hours at roonr tenperastarch glycolat. crospoviclone, low-substituted hydrox,u-pro- ture. The suspension w'as filteecl and tle oblailed solicl rvas pyl cellulosc and others. In addition, excipicnts may includc dried at 40. C. and 50 mbar for about 16 horus. The obtained tab_leting lubricrnts Iike magnesium ancl calciun stearate and proclucr is crystal Fonn A wtich is characterize by an X-ray sodium stear"vl flumarate: flavorings: sweeteners: presera/a- potvder cliffrctiou pattcm as shorvn in h-IG. 1. Funher char_ tives; pharmaceuticall,v acceptable dyes andg.lidants such as so cterization ol the obtainerL Fonn A by thermogravimetry siLicon dioxide. rhe crosages ircr.cre dosages suirabre rt r oar, bnccar, tal. parenteral (including snbcutaneous, intranuscula and reltig pqit of 95,, C. intravenous), inhalaut aud ophthalmic administration. Although the most suitable route in anv given case will s_s EX-\lvIpLE 2 depend on the nature and severitv of dre couditiou being lreated, the most prelrred route of'the present inventiou is preparation crl Form B oral. The dosages may be conveniently presented in urt dosage form ald prepared by any of the ruethods well-kuowu 100 urg Pitavastatin calcirul lor.mA was suspeuded in 2 rl intheafiofphanuacy. oo rvaterandstirreclatrooruternper.atrrefor30ruiu, f-ollowedbr Dosage l-ollns include solid dosage l'onls. like tablets, the addition of 2 ml of ethanl and additional stirrig for lB powclers. capsues. suppositories, sachets, toches an<l losen- hours '[ he suspensiou rvas lltered aml clried in ar, ,vielding ges as well as liqLrid snspensions ancl elixirs IvVhile the 36rngofFo.mrB.TheobtainedcrystalFormBisc[aracterdescription is uot intended to be limiting, the inventiou is also ized by an X-rav polvder <liffraction pattem as shown in FIG. not ilte[ded to per1ain to true solutions of Pitavastatin cal- os 2. Furt]rer chaacterizatiol of the obtained ljorm B by therciutn rvherettpon the properties that distiuguish rhe solid mogravirnetry cor-rpled with FTIR spectroscopv revaled a fomrs o f Pitavastatiu calciurrr are lost. Htrw-ever. the use of the watcr contcnt oT abo ut 1070.
used in
ta
thismixturcrvcrcaddcd2.lTurl ofa4Mqucollssolutionof urd thetestrlting yellori'ish solution was stirred fbr2.5 hours at 50' (l- 'lhe reaction nrixture was ctxrled to roc-.m Furtherexcipientsthatareu,ithinthecontemplationof the 40 tenperature followed by the addition oi50 ml water aud prescrlt invctrtiou inclucle bindcrs. such as acaci gum, prr'gc- stirring ftrr an additiolal hour. The aqueous plnse was sepalatirized starch, sodium a.lgiuate, glucose and other binders rated and once extrcted r,'t ith 20 rnl trf ruethy I terl-butyl ether.
NaOIl.
rec- :li-;tlSi"'l::Hl'r" .i:i*li":::*;ll.'j
Filed 04/09/14 Page 47 of 50
9
l',X^M
Pf ,f i
us 8,557,993 82
10
3
(
sol irl
dried in air. 'lhe obtainetl crys ta I F,'onn F is cbaracterized by an X-ray powder diffracrion pattem as show'n in FIG. 6. EXANIPLE 8
Preparation of Fomr
62 urg Pitavastatin calcitun Fonu A was suspended .in 2
isopropanol containing 50, rvater.
This snspclsiou
ml s was
of
62
m-e
Preparationofthe,{morphousFonn
of Pitavastatin calcium Fonn A rzs dissolvecl in 0.3 tris stirred sohrtion was slclu'ly addecl 2.3 ooln temperture' alrd stirred for an addi-
heated to 60" C., rvhich led to almost complete dissolntion
trrm .. ancl again coole<l tu roorn ternpeiature. Ar this perature the suspensiru r.vas stirred for 6( ing suspension rvas llterecJ, once lvashe
tem-
panor containiug 5e/o waer. a<l crystal Forur c is chaacterized by an Xtion pattern as shown in FIG. 3. Frufher the obtained Fonu c by theunogravinetry coupled with
IR spectroscop)r revealed that the sample contains about 6 isopropalol and a silrall amoult of wat
driedi
1(
.:n
,:ljTi"i'ffil)i:.il:.r.;#f,i
patten given
il FlG 7 (top).
FT- ,,. 37o
l.lx^Nlpl.: 9
preparatiou of the.\morphous Form
60 mg of Pitavastatin calcium Form.. was dissolved
EXAMPLE
prepa,.atio, of.Fonu
il
I .5
"
il"i:i:ff^JJs',""'i
jii";.,*:ili1f,i;'lLl5'ilj
6-s rng PitalasraLin calcium Form A u,-as snspended iu a about 16 rorus. The suspensionwas filtered and the obtained mixtureof0.9m-lisoproparol,0.lrnlacetoleand4Oplwater. solid.,as dried in air. Au X-ray dift-action snrdy on the Stirring this suspension for abcut t hour led to near.ll, com- 2-r prodnct sho'wed it to be amorphous, see FlG. 7 (bottom). plete dissolution. Seeding rvith 4 mg of Form C (froru Fnrthecharaclenz,ati<t't oltheobtainedpnrductbythernro-
resnlting snspensiou was stirred at room temperarure 1r
examplc 3) and stirring f'or 2 hours led to thc f'omtation of a concentrated suspension. This strspension was {iluted with te same amount tif'solvent nixfttre as abve and stirred fir all additional :10 hours. The snspension was filtered and the ]fr obtrinecl solid was dried :,rl 40u C. frr aboLrt I0 min. Anal b-v X-rar powderclflraction idicates rhe product ," b"i;: tal Fon c as shou'n ir FIG 3'
gravimctry couplccl w-ith FT-IR specoscopy rcvealed that contaned about 5.5% methrl tert-butyl ether. Diflrenrial scarLning caloriuretry showed the sample to have a glass lransition te11perature ofabout 68' C,
!h9 arnple
BRIF DDSCRIPTION OF TII[' DR{W]NGS

F IG. L is a characteristic X-ray powder diilaction pattern lbr Form A FIG. 2 is a characteistic X-ray pow'der difliaction pattem ftlr Fonn B FIGS. 3A atd 38 are tw-o characteristic X-ray powder cliiiaction natterns lbr Fornr C.
tiX:\MPl
preparation
.f,l
r;
ofForn D
t rclorr tenperature t'or 20 was filtered and dried in air. is characterized by an X-ray
ng of absolute hotus. The r

60
FormA was suspended in- I
ml
un Fl(i.
4 is a charactcristic X-ray powcler <lillraction paltem
'l he obtained crysta1
nrrnr )
fr Ftn D. FlG. 5 is a characleristic X-ray powcler diffraction pattem

FIG. 6 is a characteristic X-ray powder diifraction pattem
powder dillraction pattem as showr
in
FIr 4.
forForm E. '.'Ta:ttfl l,n
DXAMPLE
6
a
o-'
"tu for the aurorphous fomr. cliflraction pattcrn

'lhe irvention claimed
56
are
tw.
characteristic X-ray powder
Preparation of Fonn E
is: F. or the amor(3R,--sS)-7-[2-cyclopropyl-4-(4-fluorophenye)qunolin-3-yl l-3,5-dihyctroxy-6(E)-heptenoic acid hemicalcium salt wherein A) poll'ruorph A exhibits a characteristic X-ray pow'der FIG 5. i- diffraction patteru with clmracteristic peaks expressed in 20 at5.0 (s),6.8 (s).9.1 (s). 10.0(w), I0.5 (m). 11.0 (ur), EXAMPT,E 7 13 3 (vw). 13.7 (s). 14.0 (w), 1a.7 (w). 15.9 (vw), 16.9 (w'), 17.1 (vw). 18.4 (tlr). 19 I (N'), 20.8 (vs), 2l.l (m). Preparation of Forn I 2 1 6 (m). 22 e (m). 23 7 (n), 24.2 (s), 2s.2 (w). 27 . | (n), 60 29 6 (vw). 30.2 (w).34.0 (w); 60 mg ol Pitavastatin calcirun Fonn A was suspended in 3 B) polyrnorph B exhibits a chaacteristic X-ray owder rrl nrethanol containng 2Oo/o*aler, and stirretlat40" (1. Iitr di lliaction put.tem with characteristic peaks expressecl in hclur. The resulting suspension w'as slowJy coolecl to room 28 ar.4.6 (w'), 5 3 (vs), 6.2 (s), 7 7 (s), 9 2 (m). 9.6 (rn), tenperature ancl stirring ruas contiuued l-or 4 hours The sus10 3 (w). 1 1 3 (m). 11.7 (rv). 12.6 (vw). 13.0 (w). 13.9 pension was heated again to 40o C.. stirred lor 30 rr. in, slowly o: (m). 14 7 (vw), 14 9 (rv). 15.6 (w). 16,3 (ru). 17.0 (vw'), cocled to room tenpelature and stirred ttrr an addititually 15 17.4 (v*'). 18.0 (w-), 18.7 (m), t9.3 (m),20.0 (s),20.5 hours. TLre snspension was fltered ancl the obtained white (u.),20.8 (n).21.2 (,'v, shoulder),21.5 (m),22.4 (m),
60 rngofPitavastatin calcium F-orur-A was suspeuded in
luixtru'e ol l.l-dioxane and water (1:ll, and stined for 18 horus at roorn tmperatre. The resulting srrsperxion was Iltered ancl dried iu air. The obtained crystal Fonn E is characterized by an X-ray powder ditiaction patLem as shoi.vn in
phous f-orm. of
1.
A cr.vstalline polvmorph A, B, C. D. E,
Filed 04/09/14 Page 48 of 50
11
23 2 (s),23.13 (rn). 24.4
us
2 (tv. broad), 26.0
9,557,993 B2
12
process lirr preparing the crystaline polyrnorph or 26'4 (vr,'), 27 0 (w),27.9 (vw),28.9 (rv); morp.hous ft-rm according to clain l, wherein: Cl) polymorph C exhibits a chaacterstic X-ray powder the crvstalliue polymorph or amorphous form being predifhaction pattem with chamcteristic peaks expressed iu pared is the crystallirie polimorph C; and 20at4.l (tu).5.6(s).7.8(ur),8.3(m), 10.3(rn). 11.6(w), -s the process comprises suspending the crystalline poJy17.5 (rv). 17.9 (w),1S.7 (rn), 19.5 (s),206 (m).21 5 morphAinamixtureofisopropanolandakctoucsol-
(vw),25
(r.v).
7 ,{
(vw),2l .9 (m),23.I
l)) polvmorpb I) exhibits
(m),24.0(rv),248(rv); a chraceristic X-ray porvder
ll.'lhe
velt.containinglrarerasacosolvelt. process according to clair 7. lvherein the kekre
diffractionpatternwithcharacteristicpeaksexpressedin soh'ent is acetone. 20a1 5.{)(m),6.5(m),6.8(s),8.7(rrr).ttl.ttrr;, ltt.Z(rn, r0 9.-lheprocessaccorclingtoclairT,rvhereinrheketone 108 (m), 13 1 (w), 13..-i (m), 14.3 (s), 15.3 (vw). 16.1 solventispresenrinaramorutoll to30-gzobyvolumeofthe suspensioir. of (3R.5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) Qu). 16'8 (rv), 18.2 (w), 18.5 (m), 19,0 (w-), 199 (m).
25.6 (w). 26.2 (n); E) poly1sryh E exhibits a characteristic X-ray pcrw-cler
20.5(m).21.0(r's),21.7(s),22.3(w).23.4(m).2a.0@), quinolin-3-r1l-3,5-dihydroxy-6(E)ieptenoic acid hemical-
,., --
cium salt.
t0.TheprocessaccorclingtoclaimT.whereinlhewateris
in present in an amount of I lo 20%o bv volune of the suspension 20at4.4(vw).5.0(s).6.6(s),6.8(s),t9(s), l0.0Qn). ol (3R,5S)-7-[2-cyc1oprcp..1-4-(4-fuorcrphenyl)<uinolin-310,3 G). 10.8 Qn), 13.3 (s), 13.6 tn), 14.0 (s), 15.2 (vw), yll-3,5-didroxy-6(E)-heprenoic rcid hemicalcum salr. 159(w'), 16.4(rv), 16.9(vrv), 17.t3(r'w), 1f.3(m). 18.9 2 1'l .,,\processlrrpreparingthecrystallinepolvmorphor (rv). 20.2 (vs), 20.4 (nt),2O 7 (m), 20.9 u). 21.1 (vs), zunorphous f:rm accolding to claim 1, wherein: 21 6(n),21.7 (m),22.3 (ru),23.5 (m),23.8 (rn),21.1 the cr-vstallinepolymorphoranorphous trm beirg pre(rv). 2:1.7 (vN'). 2,5.4 (wv ), 26.6 (m). 30.2 (w). 34.0 (r'rv'); pared is the crvstalline polymorph D; and and tire process comprises suspencling the crystallile polyF) polymttrpir F exhibits a cluracteristic X-ray powder z.s morph A in absolnte ethauol.
dilraction pattem w-ith characteristic peaks expressed
dillractionpattemwithcharacteristicpeaksexpressedin
20 at -5.1 (m)' 5 6 v). 7.0 (s), 8.8 (rn). 9.6 (s), 10.2
(w), amorphous fomr according to claim l, wherein: 10,9(m), ll.3(w), 11.9(ru), 12.5(n),13.0(s). l3.7Qn). the cr,vstallinepolyrnorphorarnrphous fqrur beingpre14 4 (s). 14.7 (m). 15 3 (vw)- 15 5 (w), 16.8 (rr), 17.6 pared is the crystalline polyruorph E; antl (tt). 18.3 (m). 19 -l (n). 19 7 (m). 20 6 (n),21.2 (vs). ro the process colDprises susperding the crystalline poly2 I 8 (s), 22.8 (s). 23 1 (iv), 23.8 (w, shoulder). 24. I (s). morphA in I,4-dioxane conraiuilg r,varer as a cosolvent. 21 8 (s),25.7 Qn), 26.2 (vw).26.6 (m), 26.9 (w),28.4 13.Theprocessaccordingtoclaim12.u'hereinthewareris (w). 29 5 (w). 29.8 (r,rv), 30.9 (m); rvherein, ttrr each of present in the amotutt of I to 50% by volume of the suspesaid polvmorphs. (vs) strnds lbr very strong sion of (3R.5S)-7-12-cyclopropyl-4-(4-luorophenyl)qunojntelsity; (s) stands firr strong intemity; (rn) stancls 1'or rr lin-3-yll-3.5-dihydroxy-6(E)-treptenoic acid hemicajcium medium iutensitv; (w) stands for."veak inrensity; (vw) sa1t. stands for verv- weak intensit.. 14. A process lor perparing the crystalline polymorph or 2 A process l'or preparing the crystalline pol,vmorah or aLuorphous fonn accordingto claim 1. wherein: amorphous t-orm according to clim l, whereiu: the crysta.llile polymorph or amorphous form beiug preLhe r:;rystalline polymorph or amorpLrous ftrrm being pre- +o pared is the crystalline polymorph F.; an< pared is thc cr-vstalline polvrnorphA; ancl the process compriscs suspcnding the crystallinc polythe process conprses reacting (3R,5S)-7-[2-cyclopropvl- urorph A iu mehanol containinfrvater ai a cosolvni. 4-(4-fluorophenyl)quinolin-3-yl] -3,5-ctihydroxy-t(E)- .15. The process according to claim l.{, wherein the water is heptenoic acid sodiurn slt w'ith CaCl2 in au aqueous presetianamtuntofl to509/ob)rvoluteofthesnspesiq reactior medjl-rnr. 4: of (3R.5S)-7-[2-cyclopropyl-4-(4-fluoropheyl)quinolin-33' .{ process i'or preparng the crystalline polymorph or yll-3.5-dihydroxy-6(E)eptenoic acid hemicalciun salt. amorphons fbru accorclng to claiur l. rvherein: 16 Theproccss accorcliirgttr claim 2, wherein (3R,5S)-7the cr-vstallie polyrnorph or amorphons form being pre[2-cyclopropyl-4-(4-fluoroplrenyl)quinolin-3-yl]-3.5-dihypared is the crystalline polymotph B: and droxy-6(E)-heptenoic aci<l hemicalcium salt'is isolated by
dte process cornprses suspendlg the crystalline pol,v- so filtratio aud dried in air orvacuum. morph A in ethanol containing water as a cosolvenr I7. The process accorcling to claim 2, wherein seedirg s 4 Theprocessaccorclngtoclaim3,whereinthewateris carriedoutwithcrvstalsofthedesiredcrvstallinepolymorph. presellt in al1mount of 1 to 50%o by volume of the suspension 18 Aprocess preparil1g the crystalliue polymorph or amorof (3R,55)-7-[2-cvclopropyl-4-(4-fluorophenyl)qrnolin-3- phons fomr according claitr 1, wherein: yl]-3'5-dihydroxy--6(E)-heptenoc acicl heuricalciurn salt. 55 the crvstalline pol.vmorph or amorphons flcmr being pre5. A process for preparing the crystallile pol-vmorph or pared is the amorphcrus form; atd amorphous fom accorclin5 to clitn l, wherein: the prclcess comprises adding a non-solvenl to a solution of the crystalline polynoryh or zrmorphons form being pre(3R,5S)-7-[2-cyclopropyl-4-(4-lr"rorophenyl)quinoliupared is the crystalline polymorph C; and 3-yll-3,5-dihydroxy-6()-heptenoic cid remjcalcirun the process comprises suspending the crystalline poly- ao salt iu an organic solvent. nlorphA re process cornplisc's suspending the cr--vstal- 19. The process according to claim lS, wherein the noline polyrnorph .'\ in isopropanol containiug rvaler as a strlvclt s selectecl liorn heptane uncJ methyl tert-butyl ether.
12.
A process for preparing the crystallire polymorph or
coso.lveul
claitn 5, w-hereiu thewateris solvent is selected frorn l,4-dioxane, tetrahydrofuran ard presentinanamorurtof l to509byvohuneofthesuspensiou es ethyl methyl ketone of (3R,5s)-7-[2-c'clopropyl-4-(4-luorophenyl)quinolin-3- 21. A process 1'orpreparing Lhe crvstalline polymorph or yll-3'5-dihydroxy-6(E)-heptenoic acid hemicalcitun salt. amorphous fonu accordiug claiur l. wherein:
6 Theprocess according
20. The process according to claim
l8. wherein theorganic
1o
Filed 04/09/14 Page 49 of 50
13
Lhe
us
and
9,557,993 B2
r;rystalline polyrnorph or amorphous lorm being pared is the arnorphous t'omr; the process comprises drying an aqueous solution of
pre(3R, s
l4
intensity. (m) stau<ls fur me<lium intensiLy, (w.) stanils lrr
rveak intensiti,', nd (vw) stancls f'or very wak intensity
y1l-3,5-didrory-6(E)Jreptenoic acid hemicalcirun

salt by
22.
29. -A. crystalline poly'morph C of (R,5s)-7[2-cyciopro5S)-7-[2-cyclopropyl-4-(4-fluoropherryl)quinolin-3- pyl-4-(4-fluorophem't)quinolin-3-yl]-3,5-didrox6@j-
atlroturt
.{ phamraceutical cor'tposition conrprising an eflctive of the crysralline polymorph or arnorphous fonn
lyophilization.
heptenoic acid-hemicalcium salt.-havilg un X-rny. p.d"t clilliaction partern substanlially as depicted in F'IGS. 3 ncj 38.
30.
according to clairn 1. aud a pharmaceutcallv acceptable

_
car-
-{ cr,vstalline polymorph D of (3R.5S)-7[2-c;,cloproacid hernicalciurn salt, w,hich exhibits a character-
py1-4-(4-ltrorophenyl)quinon-:-y-3,S-aifrl,arixy-6p)-
pyl-4-(4-iuorophenyl)quinolin-3-yll-3,-5-dihydroxy-6(E)- tencic acid hemicaicium sa1t,'lmving anX-ray porvclerif'-
heptenoic acid hemicalcirun saft. having an X-ray powtler +o cilraction pttern substantially as cepici-etl in t'l(i 5. diffiaction pa cnl substantialll' as dcpictcd in FlG. 1. 34. A cr-vitalline polymorphir of (3R.5s)-7[2-cyclopropyl26 A crystalline polymorph B of (3R,5S)-7-[2-cyclopro- 4-(4-fluorophenyl)crinolin-3-yl]-,-s-tryroxy-OqE-.i,pyl-4-(4-fluorophenyl)quinoliri-3-yll-3,5-dihydroxy-6(E)- tenoic acid hemicaliium salt, which exhiiits a characreriric heptenoic acid hemicalcium salt. which exhibits a character- X-ray powder diffraction patterl with characteristic peaks istic X-rzry pou'der dilfraction pattem with characteristic +s expresed in20 at 5.1 (m). 5.6 (w),7.0 (s). LS (m).9 6 (s). peaksexpressed20at4.6(w),53(vs),6.2 1s).7.1 (s),9.2 102(w). 109(m), 11,3(w), 11.9(rn), 12.5(m). 13.0(s).t3J (m).96(m), 10-j(w). 11.3(rn), 11.7(w), 12.6(vw), 13.0(w), (ru). 144(s), 14.7(rn), 15.3(vr,v), 155(w),.16.8(n),n.e 13.9 (nr), 14.7 (vw), 11.9 (w), 15.6 (w). 16.3 (m). 17.0 (vw). (w). 18.3 (m). 19.3 (ni). 19.7 (m). 20.6 @).21.2 (r,s),21.s (s), 17.-1 (vw), 18.0 (w), 18.7 (ra), 19.3 (rn),20.0 (s).20.s (w), 22.8 (s),23.1 (w).23.8(w-, shoul<ler), )+.1 Gl, )+.s";.zs.l 20.8(n),21 .2(tv,shonlder).21.5(n),224(nt),23.2(s).23.8 so (rn).26.2(vw).26.6(rn),26.9(w).28.4(u).295(w),29.8 (n),24 4 (vw'),25.2 (rv, broacl), 26.0 (w). 26.a ,w),27 .0 (w). (vr.v). and 30.9 (m), wherein (vs j shncls lor very srrong inten27 9 (.nw), ancl 28.!) (w), wherein (vs) stands l-or very strorg sity, (s) snds frrr srrong iniensily, (m) stand-s lr rneclium intensify. (s) stands ftrr strong intensity. (rn) stalds for intensity. (w) stands for weak irtensity'- and (vr,v) stads I'or rnedium intensity', (w) stands for weak intensiq,. aud (vlv) very weak intensity. stands lb verv ra'eak intensity. 5s 35. A crystallne poll,morph F o1 (3R,5s)-7[2-cyclopropyl27. A crystalline polymorph B of (3R,5s)-7-[2-cyclopr.r- 4-(4-fluor.ophenyl)quinolin-3-,1]-:,s-ail,aroxy-oe;-"ô-
33. A crystallile polymoryh E of (3R.53)_7_[2-cyclopio_ A of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophen'l)quinolin-3-yl]-3,5-dihydrxy-O(Blpyl-4-(4-fluorophenyl)quinolil-3-yll-3,5-dihydroxy-6(E)- heptenoic acid hemicaium salt,-having ariX-ra;, powder
pyl-4-(4-fluorophenyl)quinolin-3-yll -3,5-dihydrxy-6G)leptenoic acid heticaium salt.-hr,ing a1 X-ray powtler aLrd dilfracton patterl substantially as depict-ed in FtC. 4. pat32. { crystalline polymorpr E of (3R.5S)-7[2-cycloproternsubstantiallyasdepicteclirFIGS.7Aand7B z.r pyl-4-(4-fluorophenyl)cluinoln-3-yll-3.5-dihydroxy-61pj24 4 crystalline polymorph of (3R,5S)-7[2-cyclopro- heptenoic acid hemicalium salt, which exhiits a character"\ py1-4-(4-tuorophenyl)quinolin-3-yll-3.5-dihydroxy-6(E)istic X-ray po*'cler diffraction pattern with characteristic hepteuorcaciclttencalciurnsalt. lvhichexhibitsa claracter- peaks expieecl in 20 at 4.4 (v1,r,), 5.0 (s), 6.6 (s). 6.g (s). istic X-ray powcler dilliaction pattern with characteristic 8.9(s). 10.0(ni), 10.3G). 10.S(rn). 13.3 ).-13.6(mj, t+.Oisl, peaksexpressedin20at5.0(s).68G),9.1(s), 10.0(w), 10.5 30 15.2(vw).t5.9(w), 164(w), 169(vw),7.s(vw.. 18.3(m), (n), I1.0(m), 13.3 (vrl,). 137(s), 14.0 (w),14.1(rv). l5.e 18.9(w),20.2(vs),zo.inil.201@j,zo.qm),21.1(s). (vr), 16.9 (r*'). 17.1 (vw). 18.,1 (m), t9.l (n'), 20.8 (vs), 21.1 21.6 (m), 21.7 (m), 22.3 (m),23.5 (m)t,23.8 i, 2a.r (w)i, (nr),21.6 (nt).22.9 (m).23.7 (m),24.2 (s).25.2 (w), 27.1 (m). 21.7 (vw). 25.4 (vw). 26.6'(n, :o.z 1w;. and-34.0 (r,w j. 29'6(vw),30.2(w).ancJ-34.0(w),wherein(vs)sLatrds ftrrvery rvherein (vs) stands t'or very .srrong itensity, (s) sr.rn<I.s lor strongintersitv,(s)staldslirrstrongintensity,(m)stanclslbr 3i strongilrellsiry,(m) standsfbrmediumintensiy,(rv)stacls meditlm intetuity. (w) stands for weak ilrensity, and (r,rv) lr ''eak intensilv. ard (r,w) stads 1'or very *eak ntensiry.
stalds fcrr very weak 25. A crystalline polyrnorph
FIG l. polymorph B has an X-rav powder cliffraotion substantiallv as depictedinFlG.2. polyrnorph C has pora'cler clffraction pattem substantially as depicted n 3.4. and 38, polymorph l) has an X-ray powder diffraction pattenl substantiallv as depicted in FlG, 4. polynoph E has au X-ray pou'der difliactiou patteru substanlially as depicted i FIG. 5. polyrnorph F has an X-ra1'po'wder diflaction patlern substanrially as depicted in FIG. 6, the arnorphorts lom has an X-ray powder difiiact.ion
A crystal.line polvrnorphA, B, Cl, D. E, F, or the zulor- islic X-ray powcler dflraction patreru with characteristic pht'rtts l'omr. ol (3 R.5 S)-7-12-cyclopropyl-4-(4-tuorophe- purks expies.secl in 20 ar 5.0 (m). O ; 1-;. O.S (s), 3.7 (ru), 10.0 nyl)quinolin-3 -yll-3,5-dihydroxy-6(E)-hcpteuoic acid (m). 10.2 (m), l0.S (m). l3.l (rv). 13 5 imj. t+.: (s), 15.3 henicalcirun salt of claim 1, wherein pol-r'morph A has an (l,,w), 16.1 (n), 16.8 (r). f a z 6vj, tS.s fr"j, f S.o 1w1. f l.O X--raypowclerdiftiactionpaltensubstautiallyasdepictedin r-s (m).20.5(n1).21.O(vs).21.7(s).22,3(w),23.4(m;)+.0(rn\,
23.
ro heptenoic
pattcm anX-ray FIGS.
:o
25.6 (w), and 26.2 (m). wherein (vs)'stands "ry rt.or.g stauds l'or strong intensitv. (n stnds foi medium intensity.. (w) stands I'or weak intensiry, ad (vw) stancls for very weak intcnsity. 3l. A cr,vsta1lne polymorph D of (3R.-ss)-7[2-c_v-clopro-
iureit'', (s)
t*
iutensirr.
hepteuoic acid hemjcalcirun salt. having an X-ray powder fracrion patteri subsrartially as clepited in ft. 6. diftiaction pattern substantially as depicted n FIG. 2 36. Theamorphous form f (3R.SSZZ-cyclopropyl-4-(428. A crystalline polyurorph C of (3R,5S)-7[2-cyclopro- eo luorophenyl)quinolin-3-yl]-3,5-clihydrox-v-01e1-n*i""ot
pyi-;1-(4-tluorophenyl)quinolin-3-yll-3,5-clihydrox)L6(E)bepLenoic acid hemicalciurn sall. ,ur.hich exhibits a

peaks expressed
istic X-ray pou'der clillaction prem with characterisric fuorophen;,l)quinolin-3-yll-3,5_dlryclrory_k(E)_heienoi;
character10.3 wtrereiu stroug
acict hemicalcium salt.
3T. t heamoryhous lonu ol(3R,5S)-7[2-cyclopropyl-4-(4-
in20 at 4.1 (m). 5.6 (s), 7.8 (rn). 8 3 (m). acid hemioalcium sal. havrng un ,{-."y io*"r cliftiaction (m). 11.6(w)'175(rv). 17.9(w). 18.7(ru), 19,5(s),20.6(m). o-s patternsubstartiallyasdepicredinFlcS 7Aand78. 2 I .5 (vw). 21 .9 (rn), 23 ' I n). 24.0 (w ), and 24.8 (r.v), 38. .4. process I'or preparing the cr-r'stalline polymorph or (vs) slands t'or ver,v stroLrg intensitv, (s) stands fcrr amorphous lorm accrdilg to clai i, rvheren:
Filed 04/09/14 Page 50 of 50
us
l5
9,557,993 B2
the cryslalline polyrnrrrph or amorplLous l'orm being prepared is the crystalline polymorph F; and
l6
the process coruprises suspellding the crystalline poly-
lnolphA Luethanol containing water as a cosolvent. 39. The process according to claiur 38, wherein the water prcsent in an mount o f 1 to 50o/o by vohme of thc suspensi()n
o
js
_s
(3
yll-3,5-dihydroxy-6(E)-heptenoic acid hcmicalcium salr.

**,t**
R.5S)-7 [2-cyc lopropyl -4-(4-tluorophenyl )quinol in-3 -

Kowa Company Et. Al. v. Aurobindo Pharma Et. Al.

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Kowa Company Et. Al. v. Aurobindo Pharma Et. Al.

Încărcat de

Drepturi de autor:

Formate disponibile

I

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 1 of 50

UNITED STATES DISTRICT CO SOUTHERN DISTRICT OF NEW

Civil Action No.

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 2 of 50

Jurisdiction and Venue

defendants are doing business in this jurisdiction.

KCL is a Japanese corporation having its corporate headquarters and principal

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

NCI is a Japanese corporation having its corporate headquarters and principal

place of business in Tokyo, Japan-

NCI are engaged in the business of research, developing,

Upon information and belief, Aurobindo Inc. is incorporated in Delaware having

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 3 of 50

Upon information and belief, Aurobindo is currently transacting business in the

Upon information and belief, Aurobindo derives substantial revenue from

and the Southern

District of New York.

The New Drus Application

("NDA") held by KCL (NDA

Livalo@ is approved for use as an adjunctive therapy to diet to reduce elevated

total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to

HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 4 of 50

Mikio Suzuki, Hiroshi lwasaki,

has been and

still is the owner through assignment of the '336

United States Patent No. 8,557,993 ("Ihe'993 patent"), entitled "Crystalline

Kai-Uwe Schoening, and ultimately was assigned to plaintiff NCI.

The '993 patent claims, inter

or the amorphous form of pitavastatin

or processes for preparing the same.

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 5 of 50

holds a license from KCL for the '993 patent.

FDA of NDA No. 22-363.

Plaintiff KCL manufactures the Livalo@ drug products as sold by KPA.

INFRINGEMENT OF THE '336 PATENT UNDER 35 U.S.C.

Plaintiffs repeat and incorporate herein by reference the allegations contained in

Upon information and belief, defendant Aurobindo filed an Abbreviated New

355(i) (ANDA No. 20-6015) seeking approval to market

comprising pitavastatin calcium.

there is substantial likelihood that it

engage, in the commercial manufacture, importation,

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 6 of 50

By its ANDA filing, Aurobindo seeks to obtain approval to commercially

prior to the expiration date of the '336 patent.

By a letter dated February 2I,2014 (the "Notice Letter"), Aurobindo informed

24,2014,KP4 received the Notice Letter. On or

The Notice Letter, purporting to be Aurobindo's Notification Pursuant to 21

U.S.C. $ 3550X2)(BXi, asserts that in Aurobindo's opinion, the'336 patent purportedly is

Aurobindo's manufacture, uss, importation, offer for sale, and/or sale, or

infngement of at least one claim of the '336 patent under 35 u.s.c.

will include the treatment of at least one of hyperlipidemia, hyperlipoproteinemia,

Case 1:14-cv-02497-PAC Document 2

Filed 04/09/14 Page 7 of 50