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Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 1 of 61

Anthony J. Viola Andre K. Cizmarik Jennifer L. Dereka Zachary W. Silverman EDV/ARDS WILDMAN PALMER LLP Attomeys for Plaintif Kowa Company, Ltd., Kowa Pharmaceuticals America, Inc., and Nissan Chemical Industries, Ltd. 750 Lexington Ave. New York, NY 10022 (212) 308-44t1

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UNITED STATES DISTRI SOUTHERN DISTRICT OF NEW YORK

[v ,?ffiffi "1,"#

Kowa Company, Ltd., Kowa Pharmaceuticals America, Inc., and Nissan Chernical Industries, Ltd.,

Civil Action No.

Plaintiffs,

COMPLAINT
V

Zydus Pharmaceuticals (USA) Inc., and Cadila Healthcare Ltd. (dba Zydus Cadila), Defendants

Plaintiffs, Kowa Compan Ltd. ("KCL"), Kowa Pharmaceuticals America, Inc. ("KPA"; (collectively, 'oKowa"), and Nissan Chemical Industries, Ltd. ("NCI") by their undersigned
counsel, for their Complaint against defendants Zydus Pharmaceuticals (USA) Inc. ("Zydus

USA") and Cadila Healthcare Ltd. (dba Zydus Cadila)("Zydus Cadila")(collectively,"Zydus"),


allege as follows:

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 2 of 61

Jurisdiction and Venue

l.

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. $g 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,

including Livalo@.

5. 6.

Upon information and belief, Zydus USA is incorporated in Delaware having a

place of business in Pennington, New Jersey, and is a wholly owned subsidiary of Zydus Cadila.

Upon information and belief, Zydus Cadila is a corporation organized and

existing under the laws of India having its principal place of business in Gujarat, India. Upon information and belief Zydus filed ANDA No. 20-6047.

7.

Upon information and belief, Zydus USA sells generic drugs, manufactured and

supplied by Zydus Cadila, throughout the United States, including in at least New York.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 3 of 61

8.

Upon information and belief, Zydus USA 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.

9.

Upon information and belief, Zydus derives substantial revenue from interstate

andlorinternational 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. Further,

Zydus USA and Zydus Cadila have availed themselves of the courts in the state of New York by

filing suit in New York. By filing its ANDA, Zydus has committed, and unless enjoined, will
continue to commit a tortious act without the state of New York, thatZydus expects or should reasonably expect to have consequences in the State of New York including in this Judicial

District.

The New Drus Application

10.

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).

11.

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.

12.

The approval letter for Livalo@, with approved labeling, was issued by the FDA

on August 3,2009.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 4 of 61

13

Certain amendments to the approved labeling for Livalo@ have subsequently been

approved.

The Patents in Sut

14.

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,lggg to inventors Yoshihiro Fujikawa, Mikio Suzuki, Hiroshi Iwasaki,

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, hyperlipoproteinernia or atherosclerosis, which comprises administering an effective amount
the pitavastatin drug product.

of

15.

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.

16.

united states Patent No. 6,465,477 ("the'477 patent"), entitled "stable

Pharmaceutical Composition," a true and correct copy of which is appended hereto as Exhbit Bo
was duly issued on October 15,2002 to inventors Toyojiro Muramatsu, Katsumi Mashita, Yasuo

Shinoda, Hironori Sassa, Hiroyuki Kawashima, Yoshio Tanizawa, and Hideatsu Takeuchi, and

jointly

assigned to plaintiffs

KCL and NCI. The '477 patent claims, inter alia, pharmaceutical

compositions containing pitavastatin salts.

17.
'477 patent.

Plaintiffs KCL and NCI have been and still are the owners through assignment of

the'477 patent, which expires on December 20,2016. KPA holds a license from KCL for the

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 5 of 61

18.

United States Patent No. 8,557,993 ("the'993 paterft"), entitled "Crystalline

Forms of Pitavastatin Calcium," atrue and correct copy of which is appended hereto as Exhibt

C, was duly issued on October 15,2013 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 eli4 crystalline polymorphs or the amorphous form of pitavastatin
or processes for preparing the same.

lg.

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 pateft and KPA

holds a license from KCL for the '993 patent.

20.

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.

21. 22.

Plaintiff KCL manufactures the Livalo@ drug products

as sold by KPA.

Plaintif Kowa and NCI will be substantially and irreparably harmed by

infngement of either of the '336,'477, or '993 patents (the "Livalo@ patents"). There is no
adequate remedy at law.

COUNT

I
$ 271(e(21(Al

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

23.
each

Plaintif repeat and incorporate herein by reference the allegations contained in

ofthe foregoing paragraphs.

24.

Upon information and belief, defendant Zydus filed an Abbreviated New Drug

Application ("ANDA") with the Food and Drug Administration ("FDA") under 21 U.S.C. $

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 6 of 61

355(D (ANDA No. 20-6047) seeking approval to market

I *9, 2^9,

and 4 mg tablets

comprising pitavastatin calcium.

25.

By this ANDA filing, Zydus has indicated that it intends to engage, and that there

is substantial likelihood that it will engage, in the commercial manufacture, importation, use,

offer for sale, and/or sale, or inducement thereof, of Plaintiffs' patented pitavastatin drug product
immediately or imminentlyupon receiving FDA approval to do so. Also by its ANDA filing, Zydushas indicated that its drug product is bioequivalent to Plaintiffs' pitavastatin drug product.

26.

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

manufacture, use, import, offer for sale, and/or sell, alleged generic equivalents of Plaintiffs'
Livalo@ pitavastatin drug product prior to the expiration date of the '336 patent.
27

By a letter dated March 7 , 2014 (the "Notice Letter"), Zydus informed Kowa and

NCI that Zydus had filed a certification to the FDA, pursuant to

2l

U.S.C.

355(iX2XA)(vii)(N). On or about March 8,2014,KP4 received the Notice Letter. On or about


March 10,2014, KCL and NCI received the Notice Letter.

28.

The Notice Letter, purporting tobeZydus's Notification Pursuant to 21 U.S.C.

355(iX2XB)(ii), asserts that in Zydus's opinion, "no valid claim of [the '336 patent] will be infringed by the manufacture, use, or sale of the Zydus ANDA Product."

29.

Zydus's filing of ANDA No. 20-6047 for the purpose of obtaining FDA approval

to engage in the commercial manufacture, use, importation, offer for sale and/or sale, or
inducement thereof, of its proposed pitavastatin drug product before the expiration of the '336 patent is an act of infngement under 35 U.S.C. $ 271(e)(2)(A).

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 7 of 61

30.

Zydus's manufacture, use, importation, offer for sale, and/or sale, or inducement

thereof, of its proposed pitavastatin drug product


at least one claim of

will directly infringe or induce infringement of


g 271(e)(2)(A).

the'336 patent under 35 U.S.C.

31.
product

Upon information and belief, Zydus's proposed label for its pitavastatin drug
and

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

atherosclerosis.

32.
remedy at law.

Unless Zydus is enjoined from infringing and inducing the infngement of the

'336 patent, Plaintif will suffer substantial and irreparable injury. Plaintif have no adequate

COUNT

II

INF'RING

OF THE METHOD CLAIM OF THE 0336 PATENT UNDER 35 U.S.C. S 271Ib)

33.
each

Plaintif repeat and incorporate herein by reference the allegations contained in

ofthe foregoing paragraphs.

34.

Upon information and belief, approval of ANDA 20-6047 is substantially likely to

result in the commercial manufacfure, use, importation, offer for sale, andlor sale, or inducement

thereot of

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
and

ANDA,

prior to the expiration of the '336 patent.

35.
product

Upon information and belief, Zydus's proposed label for its pitavastatin drug
the treatment of at least one of hyperlipidemia, hyperlipoproteinemia or

will include

atherosclerosis.

36.

Upon information and belief, Zydus is aware or reasonably should be aware,

of

the widespread use of pitavastatin as an adjunctive therapy to diet to reduce elevated total

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 8 of 61

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 Zydus (e.g., including, without limitation, physicians, pharmacists, pharmacy benefits management companies, health care providers who establish drug formularies for their

insurers and/or patients). Zydus will be marketing its pitavastatin drug product with specific intent to actively induce, aid and abet infringement of the '336patent. Zydusknows or
reasonably should know that its proposed conduct

will induce infringement of the '336 patent.

37.
remedy at law.

Unless Zydus is enjoined from infringing and inducing the infringernent of the

'336 patent, Plaintif will suffer substantial and irreparable injury. Plaintiffs have no adequate

COUNT

III

OF TIIE METHOD CLAIM OF THE '336 PATENT UNDER 35 U.S.C. S 2711c)

38.
each

Plaintiffs repeat and incorporate herein by reference the allegations contained in

ofthe foregoing paragraphs.

39. 40.

Upon information and belief Zydus's proposed pitavastatin drug product

comprises pitavastatin calcium as referenced in the claims of the '336 patent.

Upon information and belie{ Zydus's proposed pitavastatin drug product will be

especially made for use in a manner that is an infringernent of the '336 patent.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 9 of 61

41.
patent.

Upon information and belief, Zydus knows that Zydus's proposed pitavastatin

drug product will be especially made for use in a manner that is an infringernent of the '336

42. 43. 44.

Upon information and belief sale of Zydus's proposed pitavastatin drug product

will result in direct infringement of the'336 patent.


Upon information and belief, Zydus's proposed pitavastatin drug product is not a

staple article or commodity of commerce which is suitable for a substantial noninfringing use.

Upon information and belief Zydus knows that Zydus's proposed pitavastatin

drug product is not a staple article or commodity of commerce which is suitable for substantial

noninfringing use.

45.

Upon information and belief approval of ANDA 20-6047 is substantially likely to

result in the commercial use, manufacture, offer for sale andlor sale (or the inducement thereof
or contribution thereto) of a drug product which is especially made, adapted, marketed, sold, and approved exclusively for use in a method claimed in the '336 patent, immediately or imminently

upon E)proval ofthe ANDA.

46.
remedy atlaw.

Plaintiffs will be substantially and irreparably harmed if defendants are not

enjoined from contributing to the infringement of the '336 patent. Plaintiffs have no adequate

COUNT

IV

INFRINGEMENT OF THE '477 PATENT UNDER 35 U.S.C. S 271(el(2)lAl

47.
each

Plaintiffs repeat and incorporate herein by reference the allegations contained in

ofthe foregoing paragraphs.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 10 of 61

48.

Zydus's Notice Letter, purporting tobe Zydus's Notice of Certification under 21

U.S.C. $ 355X2)(BXi, indicates that Zydus intends to manufacture, use, sell, or offer for sale,
its proposed pitavastatin drug product prior to the expiration of the '477 pater..

49. 50.

The Notice Letter asserts that in Zydus's opinion, "no valid claim of lthe'477

patent] will be infnged by the manufacture, use, or sale of the Zydus ANDA Product." Zydus's filing of ANDA No. 20-6047 for the purpose of obtaining FDA approval

to engage in the commercial manufacture, use, importation, offer for sale andlorsale, or the
inducement thereof, of its proposed pitavastatin drug product before the expiration of the '477 patent is an act of infngement under 35 U.S.C. g 271(e)(2)(A).

51.

Zydus's manufacture, use, importation, offer for sale, sale, and/or importation

of

its proposed pitavastatin drug product will directly infringe or induce infringement of at least one claim of the '477 patent under 35 U.S.C. g 271(e)(2)(A).

52.

Unless Zydus is enjoined from infringing the '477 patent, plaintiffs will suffer

substantial and irreparable injury. Plaintiffs have no adequate remedy at law.

COUNT V

INFRINGEMENT OF THE '993 PATENT UNDER 35 U.S.C. I271(el(2XAl

53.
each

Plaintif repeat and incorporate herein by reference the allegations contained in

ofthe foregoing paragraphs.

54.

Zydus's Notice Letter, purporting tobe Zydus's Notice of Certification under 21

U.S.C.$ 355(tX2XB)(ii), indicates that Zydus intends to manufacture, use, sell, or offer for sale, its proposed pitavastatin drug product prior to the expiration of the '993 patent.

55.

The Notice Letter asserts that in Zydus's opinion, "no valid claim of [the '993

patent] will be infringed by the manufacture, use, or sale of the Zydus ANDA Product."

10

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 11 of 61

56.

Zydus's filing of ANDA No. 20-6047 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 infringement under 35 U.S.C. $ 271(e)(2)(A).

57.

Zydus's manufacfure, use, importation, offer for sale, sale, andlor importation

of

its proposed pitavastatin drug product will directly infringe or induce infringement of at least one claim of the'993 patent under 35 U.S.C. $ 271(e)(2)(A).

58.

Unless Zy,ts is enjoined from infringing the '993 patent, plaintiffs will suffer

substantial and irreparable injury. Plaintiffs have no adequate remedy at law.

WHEREFORE, Plaintiffs request the following relief:


(a)
a declaratory judgment pursuant to 28 U.S.C.

2201et

Sgq. that making,

using,

selling, offering to sell and/or importing Zydus'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)

declaratory judgment pursuant to 28 U.S.C .

2201et S9g. that the making,

using, offering for sale, selling andlor importing of Zydus'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;

(c)

a declaratory

judgment pursuant to 28 U.S.C . 2201et !eg. that the making,

using, offering for sale, selling andlor importing of Zydus'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;

11

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 12 of 61

(d)

a declaratory

judgment pursuant to 28 U.S.C. 2201et Seq. and an order

pursuant to 35 U.S.C. $ 271(e)(a)(A) providing that the effective date of any

FDA approval for Zydus to commercially make, use, sell, offer to sell or import
its pitavastatin drug product or any drug product containing pitavastatin be no
eadier than the date following the expiration date of the last to expire of the
Livalo@ patents (as extended,

if applicable);

(e)

a permanent

injunction restraining and enjoining against any infringement by

defendants, their officers, agents, attorneys, employees, successors or assigns, or


those acting in

privity or concert with thern, of the Livalo@ patents, through the

commercial manufacfure, use, sale, offer for sale or importation into the United
States of Zydus's pitavastatin drug product or any drug product containing

pitavastatin, arrdlor any inducement of or contribution to the same;


( (e)

Attorneys' fees in this action under 35 U.S.C. $ 285; and


Such further and other relief in favor of Plaintiffs and against defendants as this

Court may deem just and proper.

l2

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 13 of 61

Dated: New York, New York


Apn,l 17,2014

Kowa Compan Ltd., Kowa Pharmaceuticals America, Inc., and Nissan Chemical Industries, Ltd. By their attorneys,

Viola Andre K. Cizmarik Jennifer L. Dereka Zachary W. Silverman EDWARDS WILDMAN PALMER LLP
750 Lexington Avenue New York, NY 10022 (212) 308-4411

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 111 Huntington Avenue Boston, MA 02199 (617) 23e-0r00

13

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 14 of 61

EXHIBIT A

Case 1:14-cv-02760-UA Document 2


l

Filed 04/17/14 Page 15 of 61


us005856336A

lllll ililllll ilil1ilffill llu illlilil1 llllililfiilil ]lllilil llllililt


[1 1]

Llnited States Patent


Fujikawa et al.
[-54] [7,5]

rlel

Patent Number: Date of Patent:

[4s)

5,856,336 Jan. 5,1999

QUTNOf,INE TYPB MEVALONOII\CTONIS Inventors: Yoshihiro Fqiikawa; Mikio Snzuki; Hinrshi lwasaki, all of Funabashi; Mifsuaki Sakashita; Masaki Kifahara, bolh of Shiraoka-mcbi, ali of Japan
Tokyo, Japan

,Atrorney',

Prinnry Exaniner-1.au [,. Stockon Agent, or Firnr4fllon, Spivak, McClelland,


Maier & Neustadt,
P.C.

[s7)
F

ABSTRACT

u31 Assignee: Nissan Chemical Industries Ltd,,

A compouacl of the formula


tAl

l21l Appl. No.: 883J98


[22]

Fliled:

May 15, 1992

7.

lelated U.S. Application l)ata


1621 [301

Divisiou of Ser. No. 631,,092, Dec. 19, 1990. which is continuatiou of Ser. No. 233,152, Aug. 19, 1988.

fbreigp Application I'riority Data


1981

N 62-201224

c-Pr

Aug.2O,

.Ian. 26, 1988 Aug. 3, 1988

pPl pPl

FPI

Japan

z:-cH(oH)-cHx-cH(OH)-C
have

H2-CO O.%Ca

IIIVIG-CoA inhibiting ects, making them use-

r,s21 u.s. cr. [58] Field of Search

[51] Int. Cl.6

A6lK3tl47;

CQTD 21.5i12

...........

sl4l3lI;546173
5461173: 514/311

ful as inhibitors of cholesterol biosynthe,sis. The compound may be preparecl as a pharmaceutical tbr recluc-

ing hyperlipidemia, hyperlipoproteinemia


atherosclerosis.

or

[56]
5,1 53 "(r7

References Cited U.S. PAIENT DOCUMENTS

5/1998 lMaLtanasin

..................... ......... 5 14/3Ll

2 Clairns, No Drawings

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 16 of 61

5,856.336
1

QUINOLINE'TYPE MEVALONOT-ACTONES
RU

752, frled Aug. 19, 198B. s The present invention relates to novel mevalonolactones having a quinoline ring, processes for their production, pharmaceutical conrpositions containing them ancl their pharmaceutical uses particularly as anti-hyperlipidemic, hypolipoproteinemic and anti-atherosclerotic agenls, and ..inrmiates useful for their production and prcesss for i0 thc production of such intermediates.
compactine, CS-5'14,

Ser. No. 07163I,092, flled on Dec. 19, 1990, which is a continuation of (t7 233,

l'his is a division, of application

o
O

R17 R18

Y
o

Rt1

CO:Rrz

v
2

Some fermentalion metabolic products such as Mevinoli or semi-synthetic deriva15

tives or fully synthetic derivatives thereof are known to be inhibitors against HMG-CoA recluctse which is a rate limiting enzyme for cholestcrol biosynthesis. (4. Endo J. Mecl Chem., 28(4) 40L (1985)) CS-514 and Mevinolin hrve been clinically proved to be potentialy useful anti-hyperlipoproteinemic agents, ancl lhey are considered to be c{fective f'or curing or preventing diseases of coronary artery sclerosis or atherosclerosis. (IXth It. Symp. Drugs Affect. Lipid Metab., 19B6, p30,
p31, p66)

(whercin Q is

-C(Ol-, -C1Rr]1oH)--; h,vdrogen or Cr_. -C(OR13)2alkyl; Rrz is hydrogen or Rra (wherein R1'r

is

-C(0)-, -('(OR112or

or

-CFI(OH)--; Rrr is

10

is physiologically hyclrolyzable alkyl or M (wherein M is NHu, soclium, potassium, Vzcalcium or a hvdrate of lower alkylaTinc. rli-lower alkylamine or tri-lower alkylamine)); two R" a_r^e inclepenclently primary or secontlary Cr_o alkyl; or two^l" togcthcr t'orm {C}lr)ror -{(H.).r-; lrt and I{18 arc indcpcndentl' hydrogn or Cr_. alkyl; ncl ll5 is hyclrogen, Cr-u alkyl, C.-. alkenyl, Cr_., cycloalkyl,
Re

However, with respect to fully synthetic clerivatives, particularly hetcro aromatic derivatives of inhibitors against HMG-CoAtecluctase, limited information is clisclosecl in ttre

23

following litertures:
86

wPI ACC NO. B4-158675, 86-028274,

86-09B816,
30

-33207 0, 87 -1245 19, 87 -220987, 88-0778 1, 88-008460,

798 and 88-112505. The present inventors lave tbuncl that mevalonolactone clerivatives having a quinoline ring, the correspondig dihydroxy cartroxylic acids and salts and estes thereof have high inhibitory acfivitios against cholcstcrol biosynthcsis whccin HMG-CoA reductase acts as a rate limiting enzyme. The
8B-091

a,

phenyl-(CHr),,CH(CH")- (wherein n is 0, 1 or 2). Various substifients in the ttrrmula I will be clescribeci in detail rvith reference to specic examples. Howeve it shoulcl be unclerstoocl that lhe present invention is by no
means restrictecl by such spccific examples. Cr-u all tbr I{r, l{2, Ilr. l{4, Ru ad R" inclucics, f'or

chloro, bromo or trifluoromcthyl), phenyl-(CH.)_(wherein m is 1, 2 or 3), -{CHr)"CH(CH.)-pbenyl or

(whcrcin l{e is hydrogen, C,-o

alI, C,-.. altrioxy, fluoro,

present invention has been accomplishecl on the basis of this discoverv.

The novel mevalonolactone derivatives of tbe present invention are represented by the following formula I:
Rj
R1

,n '

cxamplc, mcthyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Cr-. alkoxy t'or RI, R2, R3, Rr and Rd t'or example, methoxrv, ethox n-irropoxy and lnc1udes,
1-propoxy. Cr_, a1kyl l'crr

(r)

Rrr inclucles, f'or example, methyi, ethyl,

n-propyl an<l i-propyl.

Cr-, alkyl for R13 inclucles, lbr example, methyl, ethyl, n-prop!{ and i-propyl. 4,s Alkyl tbr R1a includes, tbr cxample, methyl, ethyl,
Rz

Y-7.
N
Rr
Rs

n-propyl, i-propy1, n-butyl and i-butr1. M is a metal cai;able of fbrming a pharmaceutically acceptable salt, and it inclucles, for exzrmpie, sodium ancl

s0

-COrH. (primary to [crtiaty lowcr-COZNH4 alkylamine such as


trimethylamine). Cr-o alliyl for I{5 inclucles, for examplc, mcthyl, ethyl,

potassium. CO,M inclucles, t:r example,

aod

wherein R1, R2, R3, R. and R are indepenclently hrdrogen,

-C'FI:CH-CH"-;

i-propenyL Phenyl-(CFI"),"- for l{5 includcs, tbr examplc, benzyl, located at the ortho position to each ofher, Rr and R2. or R3 l--pheuylethy{ ancl y-plienylpropyl. and Ra together tbm or when Phenyl-(CHrl,CH(CHr)- ttrr Rs inclucles, lor example, -{H:CH-CH:CH-; located al the ortho position to each other, Rl and R2 a-phenylethyl and cr-benrylethyl. together fbrm R'5 ancl R1 are Cr-u alkyl frr R7 ancl RB inclucles. lor example, methyl, independently-OC(R1-5XR16)O-{wherein hydrogen or Cl_j aikyl); Y is o,s ethyl, n-propyl ancl ilropyl. -CII2-,or Further, these corpounclsmay have at least one or h/o -CH'CH:-, -CH:CH-, -CH2-CFI:CLIancl Z is -Q-CHTWCH2-C(]2112, asymmetric cartron toms and may have at least trvo to tbur

butylsiiylox hyclroxymethyl or

Cr-u alkyl, C=-u cycloalkyl, Cr-. alkoxy', n-butox7, i-butoxy, n-propyl, igopyl, n-butyl, i-butyl, sec-truryl, t-butyl, sec-butoxy, RtRsN- (wherein R7 arcl R8 are ndependentiy s5 n-penlyl and n-hexyl, hyclrogen or Cr_, alkyl), trifiuoromethyl, trifluoromethoxy, C.-u cvcloalkyl tbr Rs includes, tbr example, cyclopropyl, difluororethox fluoro, chloro, lrromo, phenyl, phenoxy, cyclobutyl, crclopenty_l ancl cyclohexyl. Lrenzyloxy, hydroxy, trimethylsilyloxy, dphenyl-tC-_. alkenyl t'or R' inclucles, for example, vinyl ancl
(.,vherein

-O(CH.),ORre Rle is hydrogen or Cr_3 alkyl, ancl lis 1,2 or 3); or when

60

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 17 of 61

-CH:CFI-may qrrinoline ring. For exarnple, N'shown by e.g. 1'or 2' examplesTorZ,tbeaboveprelrredexamplesforZma.rrlre inclicates the position of the substituent on the phenyl l-s mentionecl. substituted at the 4-positit-rn of the quinoline ring (the carbon Norv, still turther prelrrecl subslituents of the compounds cennected to the quinoline ring is clesignaterl as 1'). The <,rf lhe present invention will be described. As examples for meanings of the respective substituents re fhe same es the l{1, l{2 and l{ , whcn both I2 and 116 are hydrogcn, lr is hydrogen, -methyl, -ethyl, 6-tifluoromcthyl, 6-hydroxy, alove-mentioned meanings. Preferrecl substituents tbr Rr, R2 nd R are hydrogen, z0 6-methoxy, 6-chloro, 6-bromo, 6-n-buty1 ancl fluoro, chloro, bromo, C-'r-, alkyl, Cr-, alkoxy, C.-u 7-dimethylamino_. cycloalkyl, dimcthylamino, hyclroxy, hyclroxymethyl, When only R is h.vclrogen, Rr and R2 represent 6,8hydrox'ethy1, trifluoromethyl, trilluoromeihoxy, clichloro, 5,8-dimethyl, 6,8-dimethyl, 6,7-ctimethox 6,7diethoxy, 6,7-dibromo, 6,8-dibromo, 6,7-difluoro and 6,8difluoromethoxy, phenoxr and [renzyloxy. Further, when R is hydrogen, it is preferred that Rl nd zs difluoro. As still further pret'erred examples tbr R3 ancl Ra, rvhen R3 R2 together form methyleneclioxy. is hyclrogen, Ra is hyclrogen,4'-chloro or 4'-fluoro, or R3 and ,4s prelerrecl examples for R3 ancl Ra, when Ra is hydrogen, R3 is hydrogen, 3'-lluoro, 3'-chloro, 3'-methy1, I{a togethcr reprcscnt 3'-methyl-4'-fluoro. Stili further prel'erred exernples t'or R5 inclucle etfi.vl, 4'-methyl, 4'-chloro and 4'-fluoro. Other prelened combinations of R3 and Rr inclucle -30 n-propyl, i-propyl and cyclopropyl. Still further preferred examples for Y include (E)3'-mcthyl-4'-chloro, 3',5'-dichloro, 3',5'-difluoro, 3',5'CH:CH-. climethyl ancl 3'-methyl-4'-fluoro. hcferrecl examples for R5 incfucle primary ancl seconclary ,As stilt further preferred examples t'or Z the aboveCr-u alkyl and Cu-u

optical isomers. The compounds of the formula I include r11 dimethyl, 6,8-<Jimcthyl, 6,7-dimethoxy, 6,7-cJieLhoxy, 6,7of these optical isomers ancl all of the mixtures thereol. dibromo or 6,8-clibromo. ,Among compounds having carboTlic acid moictes fallWhen I1, R2 ancl R6 are no hydrogen, thcy togcther ing outsicle the delnition of of the carboxyiic represent 5,7-dimcthoxy-S-hydrxy, 5,s-dihlo;o-6acidmoietyofsubstituentZof -C0-l{12 theccimpounclsofthepreent 5 hyclrox-v,6,7,8-trimethox.u, A,ld,ti*"nyi,6,7,8-trichloro, invention, those which un<lergo physiological hyclrolysis, -5-fluoro-6,B-dibromo or 5-chloro-6,8-dibromo. after intake, to produce the corresponcling cartroxylic acicls As more preferred examples for R3 and Ra, when R3 is (conrpounds lvherein the moiety is are lrydrogen, R" is hydrogen, 4'-rnerhyl, 4'-chloro or 4'-fluoro. -COrH) -CO-Rtz equivalenl to the compouncls of the present invention. When both Rt and Ru are ()t hydrogen, they logether No*', pret'erred subsliluenls of the compouncls o[ the rr represenl 3',5'<limethvl or 3'-meth,1-4'-iluoro. prescnt invention will bc described. As morc prcfered examples for Rs, the above-mentioned In thc following prcfcrrccl, morc prcfcrrccl sti1l furthc prctncd e xamplcs of I{s may bc mcntioncd. perfrred nd most pretrred examples, the numerals ibr the As pref'errecl examples tbr I and (E)-CH,-CH.positions of the substituenls indicale the positions on the lre mentionccl. As more preferred

34

5,856,336

Prelerred examples lor

c.vcloalkyl. Y include
ror Z

-CI:CI.I-. Prererrecr examples


FIO

incrude

-CH2-CH.o

ancl

35

mentionecl preferre<l example

[or Z may be mentionecl.

Now, the most preferred sutrstituents tbr the compounds

of the present invetion will lre clescriled.

o o

"Y'-r

o.fJl""'i.t:::S.::iti,1"ri,;!""]T,.;ri:
6-chloro. When only R6 is hydrogen, R] and R2 together represent, lbr example, 6,7-dimethoxyAs the most prelrred examples 1'or R3 ancl Ru, R3 is hydrogen and Ra is hydrogen,4'-chloro or 4'-fluoroThe most pretrrecl examples ltr R-- iuclucle i-propyl and O) 45 cvclopropyl. The most rreferrecl exarrple for Y may be

v"

40

-CH(OH)CFI2C(OR Norv, more 1:relrred subsiituents of the compounds of the As the mosl. pret'errecl examples for Z, the abovepresent invention will Lre clescribed. menlioneci preferrecl examples for Z may be mentioned. As more preferred examples for Rr, R2 and Rd, when both Norv, particularly pretrred specific compounds of the R2 and R6 are hvdrogen, Rt is hyclrogen, 5-fluoro, 6-fluoro, 50 present invention wili be presentecl. The following com7-fluoro. B-lluoro, 5-chioro, -chloro, 7-chloro, 8-chloro, pouncls (a) to (z) are shown in the tbrm of carboxylic acicls. 5-bromo, 6-bromo, 7-bromo, 8-bromo, 5-methyl, 6-methy1, 7-methrl, S-methyl, 5-methoxy, 6-methoxy; 7-methoxy,

orcH2ctI:(oII)I-cr( CH2CO,R'' ancl

co2R12,

t:r)2CH2CO2R 2. -cII(oH)cFIrC(
r

(E)-cH:cH-.

8-merhoxy, -5-trifluoromethyl, 6-trifluoromethyl,

7-trifluorollethyl, 8-trifluoromethyl, 6-trifluotonethoxy. -difluoromethox B-hydroxyethyl, 5-hydrox 6-hydrox1.,

However, the present invention incltde ot only the cornpounds in the ttrrm of carboxylic acids but also the corresponcling lactones tbrmed by the condensation of the cars5 boxylic acids with hyclroxy at the 5-posilion, and soclium
sals ancl lower alkyl esters (such as methyl, ethyl, i-propyl and n-propyl esters) ol the carboxi,lic acicl"s, which can be physiologically hydrolyzed to the carboxylic acids.

7-hyclroxy, B-hydroxy, 6-ethyl, 6-n-butyl


7-climcthylamino.

ancl

When Rd is hyclrogen, R1 and R2 together represent (a) (E)-3,-5-dihydroxy-7-14'-(4"-lluorophenyl)-2' -(r" 6-chloro-B-methyl, 6-bromo-7-methox),, -methyl-7-chioro, 6o methylethyl)-quinolin-3'-yl]-hept-6-enoic acid 6-chloro-8-hydroxy, 5-methvl-2-hydroxy, 6-methoxy-7(b) (E)-3,5-dihyclroxy-7-[4'-(4" -fl uorophenyl)-2'-( 1 "chloro, 6-chloro-7-melhoxy, 6-hyrlroxy-7-chloro, 6-chloromcthyicthyi)-'-chloro-quinoli-l'-yl]-hept-6-enoic acid 7-hydroxy, 6-chloro-B-bromo, 5-chloro-6-hydroxy, (c) (E)-3,5-dihydroxy-7-[4'-(4" -fluoroplienyl)-2'-(1 "6-bromo-.9-ch1oro, 6-bromo-8-lrydrox 5-n-rethyl-8-ch1oro, methrlethyl)-6'-methyl-quinolin-3'-yl]-hcpt-6-enoic acicl 7-hyclroxy-B-chloro, 6-bromo-B-hyclroxy, 6-methoxy-7- 65 (d) (E)-3,5-clihyclroxy-7-[4'-(4"-fluorophenyl)-2'methyl, 6-chloro-8-Lrromo, 6-methyl-t-trromo, 6,7-r1ifluoro. (l "methylethyl)-6',7'-dimethoxy-quinolin-3'-yll-hept-66,8-difluoro, 6,7-mcthyicncclioxy, 6,8-dichloro, -5,8enoic acicl

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 18 of 61

5,856,336

(e)
(

5 (E)-3,5-dihyclroxy-7-[4'-(4" -fluorophenyl)-2'(

6
-continucd
R4

cyclopropyl-quinolin-3'-y1]-hept-6-enoic acid

f)

E) - 3,

-5

-d ihy

dro

xy -7 -14'

-(

4 " - fl. uo r o p h e n y l) - 2'

cyclopropyl-'-chloro-quinolin-3'-y1]-hept-6-enoic acid

(g)

(E)-3,5-dhydroxy-7 -14'-(4"-fluorophenyl)-2'(E)-3,5-clihyclroxy-7-14'-(4" -fl uorophenyl)-2'-enoic


1 "

cyclopropyl-6!-methyl-quinolin-3'-yll-hept-6-enoic acid

(h)

cyclopropyl-6',7'-dimethoxy-quinolin-3'-r1]-hept-6
acid

Rr

CHzOH

(i)

(E)-3,5-dihy

ctro xy -7 -14'

-(4" -chlorophenyl)-2'-(

ro
N
R5

-F->

methylethyl)-qu;noin-3'-y1l-hept-6-enoic acid C) (E)-3,-5-dihydroxy-7-[4'-(4"-chlorophe nyl)-?' -( l" methylethyl)-6'-chloro-quinoli-l'-y1l-hept-6-enoic acicl (k) (E)-3,-5-clihyclroxy-7-14'-(4"-chlorophen yl)-z' -(1," methylethyl)-6'-mcthyl-quiolin-3'-yll-hept-6-enoic cid (l) (E)-3,-5-dihydroxy-7-[4'-(4"-chlorophenyl)-2'-( l "methrle thyl)-6',7'-climethoxy-quinolin-3'-yl]-hept-6-enoic
acid

VI
RJ
1,s

R4

(m) (E)-:,5-dihy<lroxy-7-[4'-(4" -chlorophenyl)-2'-

cyclopropyl-quinolin-3'-yl]-hept-6-enoic

(n)

(E)-3,5-dihydroxy-7-[4'-(4"-chlor,ophenyl)-2'(E)-3,5-clihyclroxy-7-[4'-(4"-chlorophenyl)-2'acicl
zs

acid

2a

cHo

cyclopropyl-6'-chloro-quinolin-3'-y1]-hcpt--cnoic acid

-->

(o)

(p) (E)-3,5 -dihydroxy-7-[4'-(4" -chloroph enyl) -2' cyclopr<-rpyl-6'7'-dimethoxy-quinolin-3'-yl]-hept-6-e noic


(q) ()-3,-5-dihyclroxy-7-[4'-phenyl-2'-(1"-methylethyl)quinolin-3'-yl]-hept-6-enoic acid
acid

cyclopropyl-6'-mothyl-quinolin-3'-yl]-hcpt-6-enoic

N Rl

R5

Ri

R1

(r)

(E3,5-clihy<froxy-7-[4'-phenyl-2'-(1"-methylethyl)- :o
Rr OH
35

6'-chloro-quinolin-3'-yl]-hept-6-cnoic acid (s) (E)-3,5-clihydroxy-7-14'-phenyl-2'-(1"-methylethyt)6'-methyl-quinolin-3'-yl]-hept-6-enoic acid ( (E)-3,5-clihydroxr-7-[4'-phenyl-2'-( 1"-methylethyl)6',7'-dimethoxy-quinolin-3'-yl]-hept-6-enoic acid

oEr

-D->

(u)

(E)-3,5-dihyclroxy-7-i4' -phenyl-2'-cyclopropyl-

N
Rr
RJ

R5

quinolin-3'-yi]-hept-6-enoic acitl

IV
Ri

(v) (E)-3,5-clihydroxy-7-14'-phenyl-2'-cyclopropyl-6'+o

chloro-quinolin-3'-y1]-hept-6-enoic acicl

(w) ()-3,5-clihydroxy-7-14'-phcnyl-2'-cyclopropyl-6'-

mellryl-quinolin-3'-yl]-hept-6-enoic acicl (x) (E)-3,5<tihydmxy-7-[4'-phenvl-2'-cyclopropyl-6',7'dimetboxy-quinolin-3'-y1]-hept-6-enoic acicl

cHo

(y)

(E)-3,5-dihyctroxy-7-[4'-(4"-lluorophenyl)-2'-(1"-

methylethyl)-6'-methoxy-quinolin-3'-yl]-hept-6-enoic

(E)-3,5 -dihyclroxy -7-[4'-(4" -Iluoroph eny l) -2' cyclopropyl-6!mcthoxy-quinoll-3-yl]-hept-6-enoic acicl


TLe mevalonolactones of fhe fonnula I can Lre prepared try the following rcaction schemc. Thc enal III can also be preparecl by processes K, L ancl
Rl
s0
R3

(z)

acid

4s

-E->
N
Rs

fil
R4

M.

o
COtRt'

RJ

R4

OH
R2

RI
CORl

-F-> -A->
60

N
Rt

R5

R5

II

\{I

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 19 of 61

5,856,336
7
-continued
R3 R4

I
-continued
OH coRtz
R3

co2R
OH

R:

-->
N
Rt
R3 R5

T->
10

N
R1

Rs

I-1
R4

VIII
R3 R3

OH

Co3r:
ot{

]-s

cHroH 7
R2

-E->
N N
R1 Rs R5

T>
Rr LX
R3
R4

r2= H) I-5 (Rr:- Na)


I-2

25

R:

R4

OH

cHo
30
R2

R2

T->
?<

N
ITI

Rs

N
R1

I-3

R3 R4

R4

OH CO{{rz

Ri

40

o
45

T->
N

Rj
I-1
R4

N r-4
R3

R5 R3

OH CO]Rr

50

s5

R:

cEo

-R->
60

N Rl I-6

R5

Rl

In the above re&ction scheme, Rl, R2, R3, Ra, R5, R6 aud Rt2 are s delned ahove with respect to the formula I, and
65

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 20 of 61

910
Rrt ancl R22 indepen<jently represent Cr-u as methyl, ethyl, n-propyl, i-propyl or

5,856,336

cabon in a solvet such as methanol, ethanol, telrahydrofuran or acelonitrile at a temperaure of from O" to 50" C., Step A represents a eduction reaction of the ester to a preferably from 10o to 25" C. primary alcohol. Such recluction ection cn be conducted Step K represents a reaclion for the synthesis of n by using various metal hydrides, preferably diisotrutylalu- s c,13-nsaturad carboxylic acid ester, wbereby a trans-form minium hydride, in a solven such as tetrahydrofuran or cr,B-unsaturated carboxylic acid ester can be obtained by a toluene al temperat.re of from -20o to 20o C., preferably so-called Horner-Wittig reaction by using an aikoxycariro-

n-butyl.

low*r alkyl

such

oxiclation reacrion or the primary alcohoi to an aldehrcle, r.vhich can be conclucted by using 10 tetrah!drfuan at tenperatrre of from -30o to 0" C., various oxiclizing agents. Pret'erably, the reaction can lre pret'erblv from -20" to j15. C. conducted by using p,vridinium chlorochromate in meth1l St"p i represents a recluction reaction of the cr,p_ ene cbloride t.a temperatue of fiom 0o to 25 " C., or by uo"ur,rui"d acid ester to an allyl alcohol. "fhis using oxal-vl chloide, ctimethyf sulfoxicle anci a tertiary reduction reaction "rOoxyli" ianbe conclucted by using various metal amine such as triethylamine (Swern oxidation), or by using 1-- hy<jrides, preferably cliisobutylalumnumhyriclen in a sol_ a sulrr trioxide pydine complex' vetrt such as dry tetrahyclrofuran or toluene at temperamre Step C represents a srnthesis of a 3-ethoxy-1-hydroxy- of f.:m _10" t 10o i., preferatfy from _L0. to 0 C. 2-propene derivative, n'hich can be prepared by reacting a ", an oxidation reaction of the allyl compound V ro lirhium compouncl which has u."r, p...'t'iil ^,^t^it Y^:"t::"snts thi" oxidation eacton can be conilucted narily formed by rrearing cis-1-erhoxy-2-(rri-n-uutyrrtnoniil , """') lf:.T]:"-::.11 elbylene wirh t)uryl lithium in retrahydroturan ll-T*,Y::ii'::dl':9,-1^s1.1,1"i:.1:-'.Y::]i:"J.i:

i'S.'8",li!r

:Jifili::y::h]tl',.:*ii:t1"tJ'J"

Step G s a step for hydroiyzing the ester.'l-tre hydrolysis can tre conductecl by using an equimolar amtlunt of a lase, prctbrably potas-sium hydroxidc or sodium hydroxidc, n a

-50'c.

Further, the reduction reaction may be conducted by using zinc borohyclride in dry ethyl ether or dry tetrahrclrofruan at a emperafure of -100" to 25" C., pretrably tom -80o to

1 can be preparecl by the process of the prcscnt III ancl an acetoacetate. Such condensation reaction is preferably conclucted by using soclium hyctrids 35 invention. In Tabie 1, i- means iso, sec- means seconclary and c- means crclo. Likewisc, Me means methyl, Et means and n-butyl lithium as the base in letrahydrofuran at a ethyl, Pr means propyl, Bu means butyl, Pent means pentyl, temperature of lom -80" to 0o C., preferably tiom -30" to _10. C. Hex means hexyl and Ph means phenyl. Step F represents a eduction reaction of the carbonyl group, which can be conudcted by using a mctal hydride. +o TABL,E 1 preferabiy sotliu.m borohyclricle i ethanol at a temperature I-2 (Rr2=H) of from -L0" to 25" C., prelerably from -10o to -5" C. Rs R4 I-5 (Rrz *)
between the enal

" acerone, crhvl crher or crhvl ace tare ar rcmperarruc or from n" j: tY c'' preferably t-rom 15" to '50" c' srep D represcnis a synthesis of an enal by acidic hyclrolysis. Ai the acid catalysi, i is preferred to employ p-iolu".re zs Pt"p T represents a reaction for the synlhesis of an sulfonic acid, hydrothloric acid or sulriric acid, and the cr,,p-unsaturatecl keione by the selective oxidarioo of the reaction may be tonducted in a solvent mixtue of rvater and dihyrlroxy carboxylic acid ester- Th.is eaction can be conduc'tcd [ry, using activatccl manganese clioxide in a solvent tetrahyctrofliran or ethanol at a te.mperature of from l-0o to 25" C. -the 3-ethoxy-1-hydroxy-2-proo"ne derivative such as ethyl elher, tetrahydrofran, Lrenzene or toluene at a obtaned in Step C can t.r" u"" io stlp o wiihout purico,ion r tem rerature of lrom 2{}' to 80" C., preferably from 40o to i.c. by simply removing tetrr-n-butyl tin formd simulra- 80" C' In addition to the compounds disclose d in Examples given neously. Step E represens a clouble anion conclensation reaction heeinafter, compounds ofthe formulas I-2 ac1 I--5 given in 'Ihble h;-.;;"r*;,;'r#i ;i dr#:bi;;:"?ii
1'v'"r

Edtt trlutu, rlt d utvut uu a Lt[l4uvqtolullut_

+s
R6

oH

t(-

solvent mixtue of lvater and methanol o ethanol t a 5{-r temperturc ol trom 10" to 2-5o C. "Ihe tiee acid hercby obtained may be converted to salt with a suitable base. R1 Step H is a step for forming r mevalonolactone by the deh.rrdration reaction of the tiee hydroxr acid I-2. The R1 clehydration reaction can be conclucted in trenzene or loluene s5 6-OMe unde reflux while remor"ing the resulting water orby adding 6-OMe a suitable dehydrating agent such as molecular sieve. G.Br F\rther, the clehydration reaction may be conductecl in dry 7-Olle methylene chloide [ry using a lactone-foming agent such as carbodiimide, preferably a \'ater soluble cabodiimide such oo 6-Br

R:
H H
H
S-Me 8-OMe

R3

TI 4-F

[f
I

4-rr 4-F 4-F

H
i I

i-Pr i-Pr i-Pr i-Pr i-P


i-

H
F

H
4-F

H
H

Pr

H H
H

as N-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]

caboclinicle p-toluene sulfonate at a Lemperalure of from 10" to 35 " C., preferably from 20" to 25" C. Step J represents a reaction tbr hydrogenating the double bond connecting the mevalonolactone moiety and the quinoline ring. This hydrogenation rerction can be concfuctecl by using a catalytic amount of palladium-carbon or rhodium-

6,7

iPr

65

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 21 of 61

5,856,336
11

l2
They may be lbrmulated into various suitable tbrmula-

TABLE l-continued
R: R4

ofi

CO2Rr:
Rd R2

OH

N
Rr R3

Rs

R4

R5

4-F

H 4-Ph H 4-PhCH? II 4-F H 4-F 6-OCH2Ph H 4-F Ft H 4-b HH4-F 6-Ct H 4-F 6-Mc2N I 4-F 6-Me H 4-F 6-i-Pr H 4-F 7-Me H 4-I.' 6-OMe H 4-F 6-8r I 4-F 6-i-Pr H 4-F 6-Ct 8-Ct 4-F 5-F 6-81 4-F -Olc 7-OMe 4-F 6-Me 7-Me 4-F 6-Ct 7-Ct 4-F HH4-F II FI 4-F 6-OMe 7-Oilfe H 6-OMe 7-Ole 4-Cl 6-OMe 7-OMe { 6-OMe 7-OMe 4-C1 6-OMe 7-OMe 4-F 6-Mc H II ti-Me II 4-Cl 6-Me t{ H 6-Me H 4-Cl 6-Me H 4-1. i'.CI FI FI 6-Cr I 4-Ct 6-C1 H I 6-Cl U 4-Cl 6-C-1 [I 4-F i-IHH H H 4-CI HTTH I{ tI 4-Ct I,I [I 4-F

H H 6-Cl 6-Cl

I H Il H H H H H H II lI H H H lI II H H H H H fI H H FI H tI H fI H H H t{ H FI lI H H FI H II Fl

i-Pr i-Pr
c-P sec-Bu

i-P
i--Bu c-Pent

c-Pclt
i-Pr c-Pr

i-Pr
c-Pr c-Pr c-Pr c-Pr c-Pr

i-Pr i-Pr i-Pr i-P


c-Br c-I-Iex

i-P
i-P c-Pr c-Pr c-Pr

i-P
i-P c-Pr c-P c-Pr

i-P i-Pr
c-Pr c-Pr c-Pr

i-Pr i-P
c-P c-P

tions clepending upon the manner of the administration. The compounds of thc present invention may be administcrcd in L2 t'? - H) the t'orm of lree acicls or in the lbrm of physiologically I-5 gtz - *o, 5 hyclrolyzable and acceptable esters or lactones, or pharmaceutically acceptable salts. The pharmaceutical compositicrn of the present ilvention is preferably administered orally in the form of the comp<,rund of tbe present invention per se or in lhe form of l0 powders, granules, tablets or capsules tbrmulated try mixing the compouncl of the present invention with a sutable pharmaceutically acceptable carrier including a binder such as hydroxypropyl celhrlose, syrup, gum arabic, gelatin, sorbitol, lragacanth gum, pol) /inyl pyrroliclone or CMC-Ca, ,-, an excipient such as lactose, sugar, corn starch, calcium phospbate, sorbitol, glycine or crystal cellulose powcler, a R6 lubricant such as magnesium siearat, talk, pol;rethylene glycol or silica, aad a rlisintegrator such as potato stach. H Ilorveve the pharmaceutical composition ofthe present invention is uot linlited such oral administration and it is n^ -" applicabie for parenteral to aclministration. I,tor example, it may be administered in the form of e.g. a suprository formtlated H by using oily basc material such as cacao buttcr, polyethylH ene glycol, lanolin or falty acid triglyceride, a rransdermal r H lberapeutic base fcrrmulatecl by using liquicl para[n, white ,H vaseline, a higher alcohol, Macrogol ointment, hyctrophilic H ointment or hyciro-gel base ntaterial, an injectiorr formulal{ H tion formulated by using ore or more materiais seiecled H from the group consisting of polyerhylene glycol, hydro-gel H -rn basc material, distillcd water, distillr:cl water for injcction and excipient such as iactose or corn starch, or a fonnulation H t{ tbr administration through mucous membranes such as an H ocular mucous membrane, a nasal mucous membrane ancl an TI trral mucous membrane. fI 8-Br .15 Further, the compounds of the present invention may be conrbinecl with Lrasic ion-excange esins w-hich are capable 8-OMe 8-Me of binding bile acids and yet not being absorbed in gas8-Ct trointestinal tract. H 'I'hc daily dosc of the compoun<l of the formrila I is tiom H 0.05 to 500 mg, preferably fom 0.5 to 50 mg for an aclult. H 4{r ' [t is administercd H from once to three times per day. The dose FI may of course be varied clepending upon the age, the weight H or the condilion ol illness of the patient. H LI The compouncis of the ttrmulas II to VII are novel, and E 0., they are importaut otermediates fbr the preparation of the H compounds of the formrLla I. Accordingly, lhe present invenH tion relates aiso to the compounds of the formrlas II to VII H H and thc proccsscs lbr thcir production. H Now, the present invention will be describecl in fu.rther I.I clctail with refercnce to Test Examples lbr the pharmaco.n I1 logical activities of the compounds of rhe present invention, H their Preparation Exampes and Formulation Examples. H H Ilowever, it should be understood that the presnt invention H is by no means restricted bv such specilc Examples. H
H

c-lr

55

PHA.I.MAT]OLOGIC'AL 1'ES'1'EXAMPLES TestA: Inhibition ofcholesteol biosynthesis fom acetate in

Furthcr, pharmaceuticaliy acceptable salts such as potas-

vitro

sium salts or esters such as ethyl esters or meth,vl esters of lhese compounds can be prepared in lhe same maoner. The compounds of the present invention exhibit high inhibitory activities agailst the cholestcrol biosynthesis wherein HMG-CoAreduclase cts as rate limiting enzyme" as sho\4.n by the test results given hereinafter, and thus are capable ofsuppressing or reducing lhe amounl clcholesterol in blood as lipoprotein. Thus, the compounds of the present invention are useful as curing agents against hyperlipidemia, hyperiipoproteinemia and atheroscleosis.

oo

Enzyme solution was prepared from liver of male Wistar rat billialr cannulatetl iLncl discharged bile fo over 24 hours. Liver rvas cuT out at micl-clark nd microsome and supernatant fiaction which was precipitable with 40-80% of saturation of ammonium sult'ate (sup traction) werc prepared from live homogenate accorcling to the moclifrecl method of

489, 119 (1977). For assay of cholesterol biosynrhesis, microsome (0.1 mg protein) and sup lracion (1.0 rng
protein) were incubated for 2 hours at 37" L-. in 200.l of the

Kauss et. a1.; Kuroda, M., ct. al., Biochim. Biophys. Acta,

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5,856,336
13
reaction mixture continingAJP; 1 mM, Glutatbione; 6 mM, Glucose-l-phosphate; 1(l rnM, NAD;0.2-5 mM, NADP;0.25 mM, CoA; O.tkl mM ancl0.2 mM l2-1'rC]sodium acetate (0.2 ,Cli) with 4 1 of test compound solution clissolved in water or climethyl sulfoxide. To stop reaction and saponifS 1 m1 oI 15% EtOH-KOH rvas adclecl to the reactions and heated at 7-5" C. t-or I hour. Nonsaponifiable lipi<ls were extractecl with pctroleum cthr;r and incorporatccl 1aC raclioactivity was

l4
TABLE 2
hhibitory actiYities bv'lst A
s Cornpound (Conr:ounds of the presnL invcnlio)

I..

(molar concentration)

counted. Inhibitory activity

with

ICso.

of

compouncls rvas indicatecl

I-l
ro

1.?5

x IO-'

t-51

I-52
I-5-3

Test B: Inhibiticn of cholesteroi biosynthesis in culture cells

1.0x10e 7.I x 10-8 1.9 x 1-7


1.4

Hep G2 cells at over 5th passage wee seedecl to l-2 well plales ancl incbatecl w'ith Dulbecco's moclifecl Eagle

(Reference corpounds) Vfevinolin


1s

(DME) medium containing ltl% of feta'l bovine serum

cs-514

9.0

x x

1ll-e
10-e

(FBS) at 37" C.,5Vo COruntil cells were confluent for about 7 dars. Cells were exposecl lo the DME medirLm containing -57o of lipoprotein clelcient serum (LpDS) prepared by In Table 2-2, the relative activities are shon based on the ultracentrifugation method tbr ovcr 24 hours. Medium was activities of CS-514 being evaluatccl to bc 1. cliangecl to 0.5 ml of fiesh 57c LpDS containilg DME before 20 assay ancl 10ll of test compound solution dissolved in watcr TAB.F. 2-2 or IIMSO were aclded. 0.2 pCi otl2-1'rC]soclium acetate (20 Reltiwe b Test A rl) was aclded at O h(B-l) or 4 hrs(B-2) after addilion of compounds. Afler 4 hrs further incubation with [2-1'rC] Conpound Relative activities soclium acetate, rnedium was relovecl and cells were 25 washcd with phosphate buftbed saline(l'lS) chilicd at 4" C. (Compounds of the Cells were scraped lvith rubber policeman ancl collectecl to Freseut i!cltrion) tubcs with PIIS and digcstecl with 0.2 ml of 0.5N KOH at I-i6 1.7-{ -37" C. Aliquot of digestion r,vas use<l for protein analysis and I-11 6 2.25 remaining was saponifed with 1 ml of 15% ETOFI-KOFI at 30 t-111 o.37 I- r2l) 3.11 7-5" C. for t hour. Nonsaponifiable lipicls lvere extracted with raC r-322 0.16 petroleum ether ancl ra<lioactivitv was counlecl. Counts were revised by cell protein and indicated with DPMlmg protein. Inhibitory activity of compouncls rvas inclicated lvith

IC50.

35

Structues

to 12 hours lighttl2 hours clak lighting pattern (2:00

Test C: Inhbition of cholesterol biosynthesis in vivo Male Sprague-Dawley rats weighing abour 1-50 g were td normal Purina chow dict and rvater ad libinrm, and exposed

of reference compounds:

(1) Mevinolin
o,,

or

rlter sample administration, rats were - -" injected intraperitoneally with 10 pCi of l2-14C.lsoclium acette at vr:lure of 0.2 m1 per one. 2 Hous luter, f:loocl samples were obtainecl nd serum were separated immeciiately. Total iipicis rvere extractecl according to the rnethod of iolch ct al. ancl saponificd with EIOH-KOH. Nonsaponil- tt .able lipids were extractecl with petroleum ether anci rc1io activity incorporated into nonsaponifiatrle lipicls was countetl.

At 90 minutes

PlvI-2:00 AM rlark) prior [o use fcrr in vivo inhibition test of chcllesterol biosynthesis. Anirnals were separated groups conssting of hve ral.s as to be averagc mean bocly weight in each groups. Test compounds at dosage of 0.02-0.2 mg,kg bodv weight (0.4 mVl00 g body weight), rvere clissolved in ,. water or suspended or in O.5Va methyl ce11ulose and orally administered at 2-3 hours before mid-clark (.9:00 PM), while cholcstcrol biosynthesis reaches to maximum in rats. As control, rits were orallv administerecl only rvater or vehicle.

o o

II
o
CFI]

I'l3C

(2) CS--s14
oH

Inhibitory activity was nclicatecl as percenl decrease of counls in testing groups (DPMr'2 ml seruml2 hours) fr,rn that in control group. With respect to the compouncls of the presenl invenLion, the inhibitory actvities against the cholesterol biosynthcsis in which FIMG-C-oA reductase se's ls a rate limitiug enzyme, were measurecl by the atrove Test A and B. The results are shown in 'fables, 2, 2-2,3 tntl 3-2. Further, the rcsults of thc mcasurcmcnts lry 'lbst C arc also prcscntccl.

o
6

TI

o
I

CH;

o-s

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5,956,336
15
TABT.E 3

16
Example 1-b

4-(4'-fl uorophenyl)-3-hydroxymethyl-2-( 1'-methyle thyl)quinoline (compound VI-l) lnhibitorv aclivilies bv'I'st B-1 5.4 g (0.016 mol) of compouncl VII-1 was dissolved in dry 5 toluene uncler a nitrogen atmosphere and coolecl in ice bath Cornpornd [-r.r (molar conccntaton) to 0" C. 'Ib this soiution, 40 mI of a 16 wt 7o dsobutyla(Com:ouod of the luminium hyclride-toluene solution was clropwise acided, and present inventiol) the mixture was stirrecl at 0" C. for two hous. After I--51 1x:t0-7 conlirming the complete clisappearance of compouncl Vll-l (Refercncc comporud) cs-514 J.) x lu 10 by Lhin lrtyer chromatography, a salurated Lmmonium chloride solution was added thereto at 0o C. to terininate the reaction. Ethyl ether rvas acldecl to the reaction mixtue, and In Table 3-2, the relative activities are show'n basecl ot tle the organic layer was separalecl. A gelled product was ctivities of CS-514 being evaluated o be l. clissolvecl by an addition of al aqueous sodium bytlroxicle rs solution and extracted anew wilh ethyl ether. 'fhe ethyl cthcr TABLE 3-2 extracts were put together, clriecl over anhydrous magnesium sulfate and Iltered. The solvent was distilled oIT'. The Relative activities bv Te$ B--l resiclual oil underwent crystallization *'hen lelt to stand. It (,'ompound Relative aclivilies was recrystallizecl from ethyl acetate-n-hexane to obtain 3.3 uo g of white crystals. Yielcl: 70%. Meiting point: l-36"-137'C. I-116 19.4

I-520 It-20

20.O

f0.3

Exaurple carboxvaldehvde (compound

l-c

4-(4'-iluorophenyl)-2-( 1'-methyle lhyl)-quinolin-3 -yl-

decrease of counts ater the oral administration of 10 vtas 55vo uncler the same condition. rn" i)ounds of the presenr invonrion exhilited acrivities to rhe rel'erenee compouncl such as cs-514 o.

'-' 'turluuruurullurvrvrruv.2.0g(g.3mrnofofpyricliniumchlorochromatencl 0.4g 'lhe percent decrease oT counts aile the oral administra- 1! llt'tous sodium acetate sr'as suspencled in 10 ml of clry clichloromethane . To this suspension, a solution obtained by ticu of b.05 mg/kg of compound I-520 was 55vo relatire to (: + mmol) of compouncl VI-1 in 1o ml of drv 'l'hc ths measured value of t'hc corrrol group. pcrccnt 1l::1"-* ],s dichloromethane, was immeciiately aclded at room lemeraTestc
I{esults of the measurcment of the inhibitory activiti.^

V-l)

oI cs-514

TesrA,andexhibiteclcrivitiessuperiortocs-5l4i"T;; lhl:"ql
B
anc'

Test D: Acutc toxicity Al.svo CMC suspension or a resr corapouncr was administeed to ICR maie mice (group of three mice)''The ^' y"tto," prism cr.vsrars. Merring point: acute toxicity was determined based on the mortality ,i""_ruJ r?seven rlays. With compouncl I-57, I-58, l-59, I-511, -512, ,,. I-513, I--514, I--51-5, I--517andI-523of thepresentinvention, Example 1-d the mcrrtality ws $t/o even when they were orally aclminis- 3-(3'-ethoxy-1'-hydroxy-Z'-propenyt)-4-(4'-fluorophenyl)-2tered in n amount of 1tX)0 (rimethylhyl)-quiooio" (.on",pouoa

ms,4(i was stired for one hour' Then, 100 ml of .ir" 30 lure' The mixture aclded thereto' ancl the mixture was throughly superior 1!11 ?t\t,*1" mixture was lltered under suction lvt"uin.iti'., T:1; Tfu .I"action gel layer' The filtrate was driecl unde a silica

., :iff"*:ff;iH::'"::x#"$,'"'.::iii.orili"i orary ::ii,*"fl;t::i"ilff;:l:iT:f,,:


;il1ii after ;C -'' *"

(prepared by steps

methylethyl)-quinol-3'-yll-hept-6-enoate (compound I-1I) of Example l-a through Example I-q) Examp'e

Ethyl (E)-3,5-clihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1'-

Examp,c 1-a

mglhg'

rV-r

., ",,'f f;i'*li"f ff$":;i;*.iilii? rhe solurion was cor:rlecl ro -7Bo C. in a nitrogen stream. To
rhis sohrrion, Z ml e.Z mmol) of a L5 wt 7o,i-butyl1ithi.,*.Ihe n-hexanc soiution ias clropiise ddecl. mixture was

wilh n-hexane ancl acetonitile. The solvent was clistillecl oI[ 6r) uder recluced pressure lom the acetonitrile layer, ancl an chromatography, the reaction solution was ct-olecl to room oily substance thereby otrtainecl was purifled by silica gel temperature, ancl a mixlure of 4-5 mi of conc. rqueous column chromatography (eluent: 2.5Vo methanolammoniaand 120mIof rvatercooleclwith ice,wasgradually chloroform) to obtair 0.9I g of the desirecl compound in a adclecl thereto. A separated oily substance was soliclied purificd oiiy tbrm. when lelt to starcl overnight in a relrigeralor. ll'his solid wrs os II-MNR (CDCIJ ppm: 1.L(t,3ll,1flz) 1.37(d,6',,J= lecrystaliized from a srall amount of ethanol to obtain 6.47 7Hz) 3.7(m,1H); 3.7(q2HJ=7Hz) 4.15(1,IH,7Hz) 5.7(m,

2-amino-4'-lluorobenzophenone b;r thin layer

carboxylate (compound VII-1) The synthesis was conducted in accorclance with the method disclosed in J. Org. Chem., 2899 (1966). 6.45 g (0.03 mol) of 2-amino-4'-lluorobenzophelone, .s5 5.53 g (0.035 mol) of ethyl isobulyrylacctatc ancl 0.1 ml of conc. sulfuric acicl were dissolvecl in 30 ml of glacial acetic acid, ancl thc mixture was hctcd at 10{)" C. tbr about li} hours. Afte confirming the substantial clisappearance of

Ethyl 4-(4'-lluorophenyl)-2-(1'-methylethyl)-quinolin-3-y1-

,. :JJ',1r',;:of#i::,i:;i"lii".lr;ix'",1,'iiii;

tetrahydrofuran was clropwise aded thereto. The reaction mixture was stiged at -78" C. for two hours. Then, 2 ml of a salurated ammonium chioride soiution was aclded theeto to terminate lhe reaction. The organic layer was extracted with diethyl cther, and the di.cthyl ether extract was washed with a saturatecl sodium cLloride aqueous solution ancl dried over anhlclrous magnesium sulfate. The solvent was distilledoffunclerreducedpressre.Theresiiluewasseparated

g (55Vo) of whitc powdcr. Mclting point: 68"-70.5o

C,

1H) 5.95(m,1H) 7.tt5-8.2(m,8H)

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l7
Example

5,856,336
18

1-e

(E)-3-la'-(a"-fluorophenyi)-2'-(1"-methylethyl)-quinolin-3'-

aqueous solution was dropwise adde<i thereto. The mixture

in 20 mI of 5 ml trf water and 100 mg of 5 p-loluenesulfonic acid were addecl thereto. The mixture was stirre<l t room temperature fo 24 hours. The reaction
tetrahydrofuran, and
solution rvas extractecl with diethyl ether a few times. The extracts were washed with a saturatccl sodium chloride aqueous solution and dried over anhrclrous magnesium 10 -sulfate. Then, lhe solvent was dislilled off'. The residue was purified by silica gel column chromatography (eluent: chlcrroform) to obtrin the desirecl product as white prism crystals. 0.4 g (5O7o). Melting point: 127"-128" C. Example

yl]prope naldchyclc (compouncl III-1) 0.91 g of compouncl IV-l was dissolved

was stirred at room temperature tbr futher one hou ancl ethanol w-as distillecl offunder reclucecl pressure. Then, 5 ml of water was added thereto, ancl the mixture was extracted with ethyl ether. The aqeous layer was freeze_dried to obtain 4 mg 67%) of hygroscopic whitc powder. Melting rroioi zoz;i1" i. laecoposei.
Example 3

(E)-3,5-dihyclroxy-7-[4'-(4,'-fluorophenyl)-2'-(1,'methylethyl)-quinolin-3'-yll-hept-6-enoic

acid (compouncl

l-21)
LIOmg(0.244mmo1)of compoundl-11 wasclissolvedin
10 ml of ethanol. Then,0.79 rni of a 0.5N sodium hydroxide aqucol.s solution was dropwise addcd thereto. 'I'he mixturc w-as slirred tempsralure for further one bour, ancl 11 l:oethanol was distilled of uncfer reduced pressurc. 'Ihen, 10 ml of water \vas added thereto, and the mixfure was extractd wilh er.hyl.elher. The aqueous layer was weakly aciclilied (pFI 4) with a dilute hydrochloric aqueous solution and extracted three times with elhyl ether. The ethvl ether iayers

Erhyl (E)-7-[4'-(4"-fluorophenyl)-2'-(1"-metbylerhyl)quinotin--yt1'-5-hydroxr-3-xohpio-6-enoat"

l-f

ls

qCPS ppm: 136(<l,6H,I=7Hz) 2.a@,2H) 0.6 ml (0.92 mmol) of a 15 wt 7o n-butyllithium-n-h"run * ^ }-NyI solution was clropiise aclclecl thereto, ancl the rni*r,,r" vn" ?:l!**H].,3:ai(m'1H); 3'8-a.6(m'2H) 5.40(dd,lH,Jr= stirrecl t'or 30 minures. Then, a solurion preparecl by dissolv- l9FIz-I^=BHz) 6'55 (d'1H'J=19H2) 7'0-8'3(m'BFI)

1"*pa ' 5-0 mg of 60Zo soclium hydride was washed wirh dry petroleu e{her and dried unier a nitrogen stleam, and the zo suspended in 5 ml of clry retrahyclrofuian. Tt" rurp"n.io w-aicooleclto-15"C.inanitronatmsphere.Tlten, 120 w?rc put togcther and driecl ovcr anhydrous magncsium mg (().92 mmol) of ethyl acetoaetate nras dropwise ad",l sultte. Tlien' the solvent was distilled off under recluced threto, and the mixrur rvas srirrecl for 15 minures. Then, pttfYl-lo gqfin 90 mg of slightly yel1ow ofy substance' fi_f1 III-1 in dry

ing 160 mg (0.5 mmol) of

compound

_ overanhyclrousmagnesiumsulfate-Thesolutionwasevapo- 3s -Ioluenewasclistillecloffunclerreucepressure,andthe ratecl to dryness uncler recluced pressure. The residue was resiclu.al solicl was recrysrallizecl from sopropyl elher to recrystallizecl from diisopropyl ether to obtain 13! obtain 40 mg ol coloiless prism crysrals. Meiing point: ^m-g (yicltl: 59o/o) of white cryslals. Melling poinl: 99"-101o C. lB2"-184 . . By silica gel thin chromat<,rgraph', the product gave two Example 1-g *" absorption spots close to each other attributable to the Ethyl (E)-3,5-dihyclroxy-7-[4'-(4"-fluorophenyl)-2'-(1"mcthylethyl)-quinolin-3 '-yl]-hcpt-6-enoate (compouncl diaslereotners. (Developp.ing solvelt: 3c/o methtnolchloroform) I-11) Ttrese diasteromers were separated and isolated by silica 110 mg (0.245 mmol) of compound II-1 rvas dissolved in -5 ml of ethanol in a nitrogen armosphere, and the solution ,. Bcl thin layer chromatography. fDevelopping solvcnt: was ccrolecl 0" C. The, l0 mg (0.263 mmol) of soclium '-' t-BuOMe/hexaneleeroe=7/211 (vlv), Rf=0.6 and 0.7 borohydride was aclcled, ancl the mixturer was stirred for one (obtained weight ratio: 1/2)] hour. Then, I ml of a l07a hydroctrloic acid aqueous R0.7: trans lactone solution rvas addecl thereto, and the mixture ws extracred H-NMR (CDCL) ppm: 1.40(c1,6H,J=7Hz) 1.6(m,2H) three times with ethyl ether. The ethyl ether solution e5 -^ 2.65(m,lH) 3.48(m,1H); 4.20{m,tH) 5.t5(m,1H) 5.37(r1d, washcd wirh a saturatecl soclium chloride aqueous solution ''' lH,Jr=1s-zJz=71Hz) 6.68(d,1FI, J=19H2) 7.1-8.2(m,8H) Rf=0.6: cis lactone ancl dried over anhydrous magnesium sulfate. Then, the
Tlre resiclual oil was purified by silica gel column chroma- 2'65(m,2H) 3.d3(m,1H); 4'20(m'1H) a.65(m,1H) -5.40(dd, tography (eluent: 57r methrnol-chlorolbrm) to obtain ,,r. -- lHJr=IBHzJr=7Hz) 6.66(m'1FI) 7.0-8.2(m,BH) -' desired product as a pure colorless oly substance. 70 mg Exampic 5 (yreld: +To) r, /il a_.^_^--(1"-me thvlethvl)-quinolin-3'II-NMR (CDO.) ppm: 1.30(r,3r'r,J=8Hz) 13e(d,6I,J= 9;11:!0..;,01"ophenvl)-2
solurion was eyaporatecl to clryness under educecl

letrahyclrolurzn, rvas <.lropwise addecl thereto, and the mix-^ (E)-6-14,-(4"-luororhenyl)-2'-i1"-methylethyl)-quinolin-3'hrre wLs stirred for one hour. To the reaction mixhrre, I ml 30 yf*t"nyfj-+-try<lroiy-2,c, 5,6-tetrahyro-H'-pyran-Z-one of a sarurated armonium chloricle aqueous solution.was ("np"i*t f_ aclded at -15o C. Then, the mixture was extracted three 90 mg .f cc,mpounrl I-21 was dissolvecl in 10 ml of dry rvith diethyl ether. The diethyl ether solution rvas washed toluene,"and rhe solution was refluxecl under heating for 3 with saturatecl sodium chloriclc aqucous solution ancl driecl hours by means of a Dean Stark apparatus.

Example4

times

pressure.

H-NMR (CDC13) ppm: 1.4(d,6H,J=7Iz) 1.6(m,2H)

8Hz) 1.4-t.s(m2):'i.qzri.,zri=tn
6'59(m'lH)

.:.s't-,g)

3.-si(m,1H) z.o-a.o(m,zr9 4.2tt(q,21l=8Hz

ethanol, ancl 10 mg of sril; pallaclium-carbo was addecl thereto. The mixture was Sodium slt of (E)-3,5-dihydroxy-7-[4'-(4"-lluorophenyi)- stirred uncler a hydrogen atmosphere. After confirming the 2'-(1"-urethylethyl)-quinolin-3 '-y1]-hept-6-enoic acicl clisappearance of the starting substance ancl thc appearance (compound I-51) os of a new spot by thin layer chromalography, the palladium60 mg (0.133 mmol) of compouncl I-11 was clissolved in cartron was ltered off, and efhanol was clistillecl off to obtain 3 ml of ethanol. 'I'hen, 0.26 ml of a 0.5N sodium hydroxide colorlcss oil.

7'10-8'18(m'8H) Example 2

s.:sim,tui

t]:fi.ll-4-hvdroxv-3'4,5,6'teretryctro-2H-pvran-2-onc t"*;;nr'ua|,*,'r"

",

was disiolvect

in 5 ml of

of diasrereomers of compound r-3L

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5,856.336

t9

This oil was purified by preparative thin layer chromatography to obtain 16 mg of the desired product as pure TABLE 5 cololess oil. (Compouads in this 'lble are compounds of the MS(m/e): 4o8(M*+H), 4O7{M*), 366, 292, 278 lonnuJa VI wherein R is hvdroen.) In the same manner as in Example 1-a, compounds VII-2 ) t VII-27 were preparecl. The physicai properties of these n.p. Compound R1 compounds arc shown in I'able 4. (In the'I'ablc, Rr, I.2, R3, R2 R R4 Rs fc) Ra, R5 and R21 correspond to the substitients of compound VI.2 E H p-F H CH.

20

vrr.)

'10

vI-3 vI-4

I{

H
6-Ct

TABLE 4
(Compounds in his Tbl arc com:ouuds of the VII R6 s in dropen.l
Com-

VI-5 \T-6

rt-cl
H
7-lv{e
I

vt-7 vI-8 vI-9


1_s

H H H H H H
H

H
TI

I
H
2-yFI

4-Cl
4-ONie 4-Me

pound Rr
vtI-2 vtf-3
]r'].I-4

m.P-

vI-10

R:
H H H

R3
4-F
H

Rtr

Rs
CHu

R2r

('c.)
1t)?-1t)2.5
20

v[-l1
vI-12 vf-13 vf-14
vI-15

l
6-Ct

II
H H H H
7-OMe

E
H
H 6-Cl 6-Cl H
1- Ve

\'II-5
VII-6

H
I

vil-7
VII-8

H
H
H

H H H 1-F H
4-CI
4-0_\4e

vtl-9
1'II-1

H
I

vtl-l

H H
6-Ct

vIt- t2
VII-_13

t{ t{
FI

4-\4e 2-Cl
4-CF3

vII-14
vII-15 vll-'16
\1t-1 7

II
H
6-OMe H

iI

H
7-OMe

3-Me 3-Me 4-F

H tr H tr H U H H H H H lI +F l{
H
H

C,IL 721-12?

cH3 i-Pr

crIl"

H H

4-CFj
3-Me 3-Me 4-F

CrIL 85,{5.5
CrIa 100.5-101.5

cH3
i-Pr i-Pr i-Pr i-Pr

vI,I6
w:r'7
\rI-19 VI.19

E
ti-

H CH3 H iPr fI cI-I3 H i-Pr H iPr H i-P H i-Pr H i-Pr fI i-Pr H i-P H i-P 4-F iPr
5-Me

149-15:l 130-130.5 ),39-747 163-169


'14().5-t"42.O

15-5.0-157.0 192.0-r 95.0

186.0-188.5

I61.0-r64.0
122.0-t24.O
183_0-186.0
16

t--162.5

Me

H
FI

i-P i-P

137.0-1.i8.0

C,I

10-s.5-106.5
oi.l

c2fls 10r.0-.t02.0

H
6-Cl H

C"It
C,IL
CHs

H H H
H

4-F
4-F

4-F
4--

iP
i-Pr

134.fJ-I3.5 38.0-39.0
108.5-109..s

vl-20 vt-21
25 w-23

H H
FI

C.H, l-Pr
i-P c-Pr i-P i-Pr
Ph

1(i4.0-165.0 141.5-143.5
146.5-14.r.5 t'71.0-17'.tJ

CrHt

vr-22

6-Cl
ri-cl
6-Cl
IT

8-Cl
H

4-OPh 4-F

i.P
i-Pr i-Pr i-P i-Pr CrHs
n-Pr

CrIL :101.0-103.0 Crta 117.-s-119.0

C,IL
C.Hs

oil

5-Me

c?fl
cH.
CzHt

oil
96.0-98.0
1.19.0-139.5
.30

vI-24 v-25 vI-26


vl-2-7

II
H
7-OMe

[I

lt

H H H
FI FI

120-126 i53.0-154.0 9S.5-103


171,.5-172.5

c-Pr
sec-Bu

34.0-6.0
1:t9.0-12:1.0

6-Me

4-F 4-lt
4-F

6'()Me

H H

i-Pr c-Pr

160.0-161.5
11.0-16.1.0

VII-'IS vII-19

tt
6-Ct

H
TT

4-F 4-F 4-F


4-OPh

TI

vil-20
vII-11

vII-22 vlI-2- vI-24


vI1-2-s

6-CI S-c--l -cl Lt 6-CI H HH4-F

H H

H
H

H H
H

iPr
c-P i-Pr

4-F H H

H
H

i.Pr
Ph

l{
IT

c-Pr
5CC-

oil C.Ht 94.5-95.5 cH. 113.5-r16.5 CrHt oil CrHt 96.0-98.0 C=H, 118.8-:t19.5 CH, 97.0-98.5 cH3 oil

In the same manner as in Example 1-c, compouncls V-2 to V-27 wcre preparsd. (1n thble 6, R1, R3, R3, Ra and l5 corresponcl to the substituents of compound of
35

V)

TABI,E

vfI-26

vrt-)7

6-Me lI 4-F 6-OMe 7-OMe 4-F

Bu i-Pr c-Pr

c:lls

ciHu

109.0-11:1.0 153.0-15-1..s

(Compounds in lhis Tirble are conpourds of the lonnula V B,herein Rd is hvdrosen.)

VII-8

40 coorpo*d Rr

R2
H

R3
p-F

R H H ll H ll H H H H II [I H 4-F
5-Me

m.PR5

fc)
.125-1:.S

rI-NMR (in CDCI") ppm: O.92 (t,3L,J:7Ilz\,


; 2. a7 $,3H), 3 .27 (Hep I apet, (q,zH,J :7 Hz), 7.0-7.e3(m, 8H)
(d, 6H,J = 6Hz)
1

l.4l
3. 9 6

f{
v-3
H

CH3

=6

Hz)

v-4
v-5 v-6 v-7 v-8

H
6-Ct

H H
H

VII-14

H-NMR (in CDCI.) ppm: 1.01 (t,3HJ=7H2.), VII-I5

1.42

(d,6H,J=6Hz); 2.38 (s,3H,J=3Hz), 3.'25(Heptapler, lH,J= 6IIz) 4.o4 (q,2flJ=7llz), 6.9 -8.1(m,7*rz) H-NMR(in CDCIJ ir ppm: 0.97(t,3H,I=7Hz),1.43 (d,6H, J=6Hz);2.29 (s,6H) 3.25 (Hcptaptet. lH,J=6Hz) 4.00 (q,2H, I =7Hz), 6.8-3.0(m,7FI)

6-Cl H 7-Me

H
d

H H H H

CII"
i-Pr

143-146

9)43
220-221 140-r40.5 )21.5-114.0 105.1-10!r.2 147.0-147.8
1-5.6- 136.8

CH"
i-P i-P i-Pr i-P i-Pr i-Pr i-Pr i-P i-Pr i-Pr i-Pr C7H. n-P i-Pr c-Pr i-P i-P

t-F
H 4-Cl
4-ON{e

H
H H

v-9

H
H

v-it)
v-11 50 v-12

H
6-Ct

H
I'I

4-Me

119.4-t 20.4
10-s.8-106.9 163."7-tt34.2

v-13
Y-1,1

H H
1

fI
H H
-OMe

2-Cl 4-CF]
.l-Me 3-Me 4-F

v-15

VII.IB
FI-NMR (in CDCI3) ppm: 0.98 (t,3H,J=7Hz), LA2 (t,3H J =7 Hz); 1.6 -a {m,z}l), z.B-3 t (n,zH) a. 03 (q,2 H J=
.

v-]6
v-77 v-18 55 v-19 v-zo y-12 v-23 v-24
v-?5 Y-26 v-'21

fi-OMe H

fl
H
H

t{
6-Ct H

7Hz), .9-8.1(m,BFI)

4-F 4-F 4-F 4-F


4-OPl' 4-F

vU 21 H-NMR (in CDCI.) ppm: 1.03 (t,3H,J=7Hz), I.4I (d,6H,J-6I{z); 3.25(Heptapet,rH,J=6 Hz), a.05 (q,ZH,J = lHz),6.8-8.1(m, 13H)

60

wI-25
H-NMR (in CDC ppm:0.e7 (d,6H,J=6LIz),2.0-2.6 (m,1H); 2.85 (d,2H,J:7Hz), 3.-5 l(s,3H), .s-s. 1 (m,sH) In the same manner as in Example 1-b, compounds VI-2 to Yl-27 were preprecl. (In Table -5, Rr, R2, R3, Ra ancl Rs correspond to tho substiluents in compouncl VI.)

v-27

6-OMe 7-OMe

-cl 8-ct rt-ct H 6-Cl H H4-F 6-Me II

rI

II
f{
4-F 4-F

H H Il I'I H H H HPh H c-P H scc-Brr II i-Pr H c-Pr

16it.1-103.1 120.3-r22.3 164.4-165.2


143.7-144.2

150.2-155.3 164.5-165.3 150.1-15:t.6 106.9-tO7.7


135.0-1--s.7

1'14.3-t75.3 157.5-158.0

r25.0-rt6.5
155.0-157.0 ?00.0-2c0.5

6s

In the sme manner as in Example 1.-d, compouncls IV-2 to IV-6 rvere prepared. (In Table 7, Rl, R2, R3, Ra and Rs
corrcsponcl to the substih-refs

ol compouncl IV)

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 26 of 61

5,856.336

2t
TABLE 7
(Cbmpouncls

))
TABLE 9-continued
(Cornpoun<1s

h tls lble ae compords of the formula lV wheein R is hvdrosen.) Rr


H

)
rn.p. ("C.)

iormua ot
Compound II.1O II-11

i this lble are compourds of [[ wherein Rd is hvdroEen.) R3


4-O\4e 4-OMc 2-CI
4-CF3
R4

the

Conrpound lv-2
IV'-3

R2

R3

R5
cI3

IV-4

t{
6-Ct

tv-5
IV.6

6-Cl

H+FH HHH HTII HI{H HIIH

1i'1,)19

RT
H
6-Cl

R2
I

crI3
i-Pr

CH.
i-Pr

.10 II-12
II.1 3

H
TI

II-14

H H
FI

In the same manne as in Example 1-e, compounds III-2 II.i 6 il,"r'7 to lll-27 were prepared. (In Table 8, Rl, R2, R3, Ra and R5 1-s II-18 correspond to the sutrstinrents of compound IIL)

ff-15

H H
7-Olvfe
FI

3-Me
-1--Me

H l{ fI tI 4-F
5-Me
H
H

6-Or\4e H

4-F
4-F 4-F 4-F

i-Pr i-Pr i-Pr i-Pr i-P i-Pr i-P

C.Ht C.Ht
C=Ht ctzli5

78.O-78.5
75.iJ_7S.0

CrH oil czlrs 73.0-3.0


66.0-71.0

oil
94.A-9i.t}

CrHt 83.0-90.0
oil 11.0-1I3.5
91.0-9.1.0 1'21.O-125.t)

TABLE

(Ccnpounds in lris 'Ible are cornpounds of lhc

II-19 rI-?0 II-21 tr-22 It-23

6-Cl

Ii
FI

H
H

II
H H
H H

t{
H

4-F

6,Cl
6-Ct

8-Cl
TT

4-OPh 4-F

tbrrrqls III rvhegig-S!-!y!9g9.1


m.P.

)n II l4 -" Il-t5
II.26
Lt-21

6-Cl

II
H H
7-OMe

ft
H

4-F 4-F
4-!.-

E
H

GH, Cr,H. n-Pr CrH. i-PL C'II, c-Pr CrHs i-Pr C.H, iP CrH, Ph C,H, c-Pr CrH-, scc- CrH. i-Pr c-Pr
Bu

oil oil
69.e)-11-l)

oil oil oil

ComJoud Rr tfi-')
III.3
ITI-4

R2
H

R.
4,l.'

R4
H H H

R5

("c.)
794-196 17A-171.5 107-10S.5 79?-194 125.5-12? 30.1-A0.2
72.1.1-122.3

6-Me

6-OMc

It

CrH.
CrH_,

H f:I

H
TI

II
H H

CH" CH"
i-P

E
6-Ct 6-Cl H 7-Me

III-s III.6
TTl-7

II
II
H
H
H

II
H
H

2s rr-7
J

CIT
i-Pr i-Pr i-Pr i-P i-Pr i-Pr

I
?-i.

Iil-{r III.9
t[f-10 lII-11 ilr- 12

H
4-CI

H H
t.l 6-Cl

H H
H

+OMe
4-Me 2-Cl

II II
H

[I II

148.0- 149.1 t-17.4-'t40.'I 11 L 6- l1-1. I


3-1.8-4.-i

:o

H-NMR(in CDC13) ppm: 1.21(t,3H,I=THz), 1.32(d,6H. =6*tz); 2.2-2..4(m,"t), 2.5-2.7(n, rH) 3.2s(s,1FI), 3.34 (Heptaplet, lH,J=6Hz) a.0B(q,2H,J=7H z), 4.34.6(n,1.H) 5.28(dd,1[I.J=6IIz,I: l5l[z), 6.-53(dcl,1lI,J:1 .Sltz)= tltz), 6.9-8.t)(m,8H)

iP
-Pr i-Pr

ll-72
H-NMR(in CDC13) ppm: 1.25(t,3H ) =7Hz), 1.33(c{,6H, J=6Hz); 2.2-2.4(m,2H), 2.5-2. B(m, 1 H) ; 3.32(s,2H), 3.38 (Hep ta pl et, LH, I = 6Hz) ; a. (q,2,l =7 Hz), 4 24. 6 (n, tH) ;
7.0-B.0(m,7H)

tIl-14
IIf-15

III- 1 -]

H
FI

+CF
3-Me
-1-

H
FT

+
5-Me
H

126.2-12a.3
124.8-7'2b.+

ivfe

iPr
i-Pr

Iil-16
ffr-

t7

III-13
nI-19

I.]]
I[-21
lI-22

IH fI r,-cl HH HH rt-ct
6-Cl 6-Cl
t1

6-Olv1e

7-OMe

+F

II
H

+F
+F
4-F

H
I

C.Ht
n-Pr

i-P
c-Pr i-Pr i-P
Ph

117.6-120.3 147.8-1 50.9 124.3-728.5 117.S-121.5 1-r5.2-135.9

+F
4-OPh

t{
H H

)41.3-144.1 oil
117-122 142.8-744.3 .t61.0-161.5 78.0-1.0
1-17.0-137.5

8-ct
H

III-]3
ril-24
trf-25

II
i-I

+F

H
I'I

II
H 7-OMe

u
H
H

4-

II.?6

6-Me
6-Olv1e

ltl-2i

+lt
4-t'

c-Pr sec-Bu -Pr


c-PL

Il-15 II-NMR (in CDCI,) ppm: 1.23(t,3llJ=7llz),1.35(d,6ll, t =6Hz); 2.2-2.a(m,2tl), 2.31(s,6H); 2.6-2.8(m,rH), 3.32(s. 40 2H); 3.35(Hcptap lct,lH ) -6Hz), 4. t2(q,2H J :7 Hz) : 4.34.1 (m,1I{), 5.30(cld,rH,J=6Hz,J=16H2); 6.s1(ld,1HJ-1Hz,J=
16Hz), 6.7-8.0(m,7H) {I-r 8
4s

189.5-191.i)

UDCI11) ppm: i.40(d6[I,J:7Hz), 3.44 (FIeptaplel,1 FI, J =7LIz); -5.93(cld, I HJ=8HzJ= 16}lz), 6.8-8. 1

I-22

Fl-NMlt(in

H-NIR (in CDCI3) ppm: 1.00 (r,3H,J=7FIz), 1.26(i, 3ll J =7 l'Iz) ; I. 6-2.3 (m,ztl), 2. 42 (d, 2tl,I =6f Iz) ; 2.6 *3 .2(m, 3 H), 3.3s(s,2H) a. [(q,2HJ= Hz), 4.3-4.7 (m, IH) s.27 (<]c1,
"1

=61",

:1 uHz) 6.46(dct,IH,J

= 1. 5Hz J =

6Hz), 6.9-s.0

(rn,8H)
sa

(m,14H) e.34(d,1HJ=8FIz) In tlre same manner as in Example 1-i', compouncls ll-2 to ll-27 werc pcparcd. (In thblc 9, l{1, R2, R3, l{4 and l{5 corresponcl to the substituents of compound II.)

tr22 H-NMR(in CDCI3) ppm: 1.26(t,3H,I=7Hz), i.33G1,6FI, J =6Hz) : 2.43(d,2H,J =6Hz), 2.6-2.9{m,1H) 3.36(s, 2H), 3.44 (Fleptaplet, I H, I =6H2.) 4. t 3(q.2H,J=7H z.), 4.3-1.7 (m,t H)
5.30(clcl,1H,J=Hz,J=

I6H),
pp m 3.

6.53(dcl,1FIJ=1 .5HzJ

TABLE

(Cbrnporrnds in lhis 'ible irre compourxls o[ the tuffqla of fl wherein R is hvdrosen.) Comm.P.

7.0-7.6(m,6U) 55 II-23 H -NMII(in CDCllj)


I=

=lg1t7,
I(ct,ZH,

1.

23(r,3 H

6Hz)

poutrd Rr
II-2

R2
H
TI

Rj
p-F

R4
H
H

Rs
CH. CH.
i-Pr cI13 i-P i-Pr i-Pr i-Pr

Rr
CrH-t
C:FI5 c2I5

4.13.4(m,1 H) -5.08(c1ct,1FI,J=6Hz,J:1 6H2), .26(dd,tH,J=

=7

Hz),

2.2

2.

4*?.

(m, 111),

25(s,2H)

4 .09

(9,2H,1 =7 FIz),

(.C.) oil
'105-:106

1.5llz,J=l6Hz), 7.0-8.0 (m,i3H)


60 II2-5 H-NMR(in CDC13) ppm: 0.96(d,6H,I=6Hz), t.26(1,3H, I=7Hz), 1.8-2.4(m, 1H), 2.43 (d,2H,J=6H.t), 2.{>-2.9(m,1,H), 2.88(d,2t1,J :7uz), 3.36(s,2II), 4.14\q,2fi )=7llz), 4.34.7 (m,1ll), 5.0-5.5(tr,1H), 6.3-6.7(m,1H), 6.9-8.1(rn,3H) 6s II-26 H-NMR(in C-'DCI3) ppm: 1.25(t,3H,I=7lz), L32(d,6H. s=6Flz), 2.32(s,3H), 2.39(d,2H, J =7Hz), 2.6-3.1(m,rH),

H
I

II.3
TI-4

E
H

H
6-Ct 6-CI

t{
I'I H H
H

lI-5 ti-6
LT-7

[I

rI

tl
2-t'
H 4,Cl

ll
H

38.5-90.5

Cr[L
c:FIs 96-93 c1F15 oil
CzHu

It-8
IT-9

7-\fo
H

H
H

is.5-74.0

CtHt 9r.0-94.0

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 27 of 61

5,856,336
23
6Hz), a. 1 \q,z}{,t =7 Iz), a 34.7 (m,IH} s.0-5. 5(m,1 H), 6.3-6.7 (m,LkI), 6.s-7. e(m, 7H)
3.3 taple t, IH.I =

24
6-3.8(m,1 H), 3.94.2(m, IlH) a.2\q,2tI,J -7 Hz), 4.3-4. 5(m,1 H) 5.2-5.s(m,1 H), 6.5-.8
3.49(Hep taplet, LH,J=

6(s,2H), 3.41(Hep

6Hz)

3.

il-21
H-NMR (in CDCI.) ppm: 0.8-1 .-5(m,aH), t.26(t,3IH"l= 7 Hz), 2.u2.9 (m,4I), 3. 42(s,2H), 3.7 1 (s,3r), a. 00( s,-3FI), 4 .20(q,2H J =7 Hz), 4.4-4.8(m, IH), 5.-3--5.8(m, 1H), 6.4-6. 9 (m,1H), 6.s8(s,1H), 7.0-7.s(m,-sH) In the same manner as in Example 1-g, compcluncls I-1,2
Lo

(m,1H) 7.tI-8.2(m,8H)
I-110

H-NMR (in CDCI.) ppm: 1.29(t,3kI-l=7Hz),1.40(d,6H, J=6H2.\; 1 .-5-1.6(m,2H), 2.3-2.5 (m,2H) 2.8-.1.0(m, 1 H),
3.e-4. 1(m,1

I-\27 rvere preparecl.

(m,1H) 6.s-6.7(m,1H), 6.9-8.1(m,8H)

3.4-3.6(m,1H) 3.52(Heptaplet.rH,J=6Hz), -r.8S(sJ) H), a.za(q,zR,J =7Hz) 4.34.5 (m,IH), 5.3-5.5

ppm: 1.30(r,3H,J=7Hz),13-r.-5(m. lo H-NMR (in CDCI.) ' " 2H); 1.3 e(d,FI J =6 H z), 2.3-2.. s (m,2H) 2.a3(s,3H), 2.s-.{}

TABLE 10
Rj
l-1
R4

(m,1 H) 3.50(Hcptapict,l HJ: 6Hz), 3. 5 -3.7 (m,IH) 3.9 (m, 1 H), 4.1 9 (q,2H,t =7 Hz) 4.24.5(m,1 H), s.2-s.6(m, I

4.2
H)

OH

1s
lz

t-u2

6.4{.8(m,l H), 6.9-8.2(m,sH)

=H)

OH

FI-NMR (in CDCIr) ppm: 1.30(r,3K,r=7Bz),1.3-1.6(m, 2H); L37 (d,6H,I =6t[z), 2.3-25(m,2H) 2.9-3.2\m,IH), 3.47 (Heptaplet,1H J=6FIz) 3.5-3.8(m,1H), 3.9-4. 1(m,rH) 4. 19 (q,zH,J =7tlz), 4.24.5(m, tH) s.3-5. 7(m, 1H), 6.5-6.S(m, 1H) 7.1-8.1(m,7H)

?0 I-113

N Rr

R5

zs (m,lH) 7.2-8.2(m,8H)
m.p.("c.)

H-NMR(in CDCI") ppm: 1.0-1.3(m,2H), 1.30(r.3HJ= ; L. 4O(ct,6H,I =6Hz), 2.3-2. a@,z}l) 3.3-3. 5 ( m, 1 H), 3.49 (Heptaplet, 1HJ=6Hz) 3.6-3.7(m,1H), 3. 9-a. l(m,1H) a (s,2H J =7Hz), 4.2-4.5(m,1 H) s. 1--5.5(m, 1 H), .s-6.s
7

Hz)

Com-

I-114

pound RI

ass R R
4b-

R4

R5
CH3

R12
ct2il-r

spectum oil 423,292

T-12
I-1.3

H u H

Mle

II
H
6-Cl 6-Cl

II
H H H

764,249

f-11
I-:t5 I-16 f-L7
-.18

H H
H

clts
i-P
CH3

c2II' 92-705
CrHt 97-100 CrHt oil c:Hs oil
C:Hs oil CrHt oil CtH,' 93-104 c2[15 94-94 t--.H. 79-C5

H-NMR (in CDC1.) t\ pprn: 1.2-1.4(m,2H), 1.30(r,3H,J= 1.39(d,6H,l = 6Hz), 2.32(t:s,3H) 2.3-2.S(m,ztl), 3.O-3.3(m,lH) 3.50(Heprapler,rHJ=6HZ), 3.6-3.8(m,1H) -r0 3.8-4. 1(m,1 H), a.Xt(q,2H,J=7Hz) a 3-4.6(m,1H), 5.2-s.6 (m,1 H) 6.-5-6.8(m, I H), 7.0-8.2(m,7H)
7

lz);

I- 115

H
2-F

H
7-\4e

H
H H H H
H

I-:t9
I-110
I-.111

H H
6-Cl

4-Cl 4-OMe

4-\le
2-L:.1

I-112
t-1,1-?

l-1 14 I-1:15

H H
1I

4-CIr
-1-Me

I-116
L- 117

I-118
I-1:19

I-120
f-1 21

r-722
r- 123 r- 124 I-12-5 :J,76

l-117

H [I 4-F HH4-FHn-Pr 6-ClH4-t-Hi-Pr H H 4-F H FI 4-OPb 6-Cl 8-Cl 4-F 6-CI II I'I 6-CIFIHHc-Pr H H 4-F 6-MeH4-FHiPr 6-OMe 7-OMe 4-F

-OMc 7-OMc 4-F

H H

3-Mc

H ]I

5-Mc

H II H H H II H H H +F

i-Pr i-Pr i-Pr i-Pr i-Pr

ts

1Hz); 1.a0@,6H,J=Hz). 2.2-2.5(m,2H) 2.35(s,6H),


2.7

I'I-NMR (in CDCI') ppm; 1.1-1.4(m,2II), 1.30(r,3II,J=

1.1,(m,tH)

3.5

r(Hcpraplcr, 1H,J=6Hz), 3.6a.7

iPr
i-Pr i-Pr i-Pr i-Pr i-Pr C2fI5

3.B-a. 1(m,1 H), 4.2o (q,zH I =THz) 4.2-4.6(m, (m,1 H) .a-6.8(m,1H), 6.8-8.2(m,7H)

rH), s.z-5

@,IH)
.

CrHt oil

I-116

C.I!
C.IL
L--rHt CzH-.

117-128

C.Ht 85-92 CrHt oil CrH. gum


oil

oil

H-NMR (in (CIr) ppm: 1.30(t,3H)=7Hz),l.3lcl,6H, 40 I =6Hz); 1.-5-1.8(m,2H), 2.3-2.5 (m,2H) 2. 9-3.2(m, 1 H), 3.46 (Heptapet,1H,J=6Hz) 3.6-3:8(m,tFI), 3.75(s,3H) 3. 9-4. 1(m,1 I I), 4.0(spr| 4.2tt(q,2ll,I -7 l-rz), 4.24.5 (m, l FI) 5. 1-5.5(rn, 1 H), 6. 4-6.8(m,2H' 7 . 1-7 .5 (m,s]H)

fI H H TI I H

C.Ht 79-32
c-Pr i-P i-Pr
Ph

sec-Bu c-Pr

100-104 c"H. oil CrHt 133-143 c2[Is gum C tHo oil crH. oil CtHt oil C,H. gum

4-s
J

r-117 :7

H-NMR(in CDCI3) ppm: t.30(t,3H,J=7Hz), 1.37(t,3I, Hz); 1..4-1.7 (m,2H), 2.2-2.6(m,2H) 2.s-3.2(m,3H), 3.6-3.9(m,1H) 3.9-4.7(m,4H), s.2-5.7 {m,IH) 6.3-6.7 (m,
1H) 7.0-8.2(m,BH)
B

s0

I-1I

H-NMR (in CDC13) ppm: 1.01(r,3H,J=7Hz),1,.27(t,3kl,


1.4-2.
1

t=1Hz);
I-119
ss

(m,4H), 2.3-2.6(m,2H); 2.8-3.3(m,3rl),

1-17

H-NMR (in CDCI.) t ppm: 1.29(t,3H,I=7Hz),1.40(d,6H, =6Hz) ; 1.4-I.7 (m,zkI), 2.3-2,5(m,2H) 2. 9-3. 2(m, 1H), 3.49(Heptaplet, 1IJ=6IIz) 3.-5-3.8(m.r I I), 3. 9-4.-s(m,2ll)
I

3.6-3.3(m,1H); 3. 9-4. l(rn,l FI), 4. 18(q,2H,J=7Hz): 4.24.5 (m,1If , 5.2-5.6(m,1 FI); 6.4*6.(m,1I I), 7.0-s. l(m,sII);

a.2o(q,2tt,J

=7

Hz), 5.2-5

.7 ( m,LH)

6.5-6. 9(m, 1 F.

7.o{.

(m,BIl)
I-18
7

H-NMI{ (in CDCI.) ppm: 1.2-1.5(m,2H), 1,3r(r,3H,J= ; 1.37 (d,6H -I =7 1t, 2. j-2. 6(m.2H); -3 0-3. a (m, I H), -3.49(Heptaplet,l}J,l:6Hz); 3.6-3.8(m,f H), 3.8-a.2(m,1H); 4.2\q,2H,J =7 Hz), 1.3-4.5 (m,1 H); 5. 2-s.6(m, 1 H), 6.4-6.8
7

Hz)

tlz)

H-NM{ (in CDCIr) ppm: 1.(1.4(m,2H), 1.31(t,3H,J:

(m,1H); 7.0*8.1(m.7H);
60

(m,tH) 6.4-.8(m.IH). 7.0-s.0(m,8H)


l-1

m, 1 FI) 3.48(Heptap1et,1H,Jlz),3.5-3.8(m,1H) 3.8-4. 1(nr, I FI), a.20(q,2H,J =7Iz) 4.24.s (m,t]H), s .2-s . 6 3.
(

r-3.4

1.39 (d,6H,J =

6Hz), 2.3-2. 5 {m,2}J) 2.52(s,3H),

t-1"20

H-NMR (in CDCI3) ppm: 0.8-1.8(m,6H), 1.30(r,3HJ= ; Z. r-2.6(m,3 H), 2. 9-3.3(m, 1 H) ; 3.4-3.7 {m, LH), 3.84.6(m,217); 4.2tt(c1,2H,J=7Hz), 5.4-5.8(m,1H); 6.4-6.3
7

Hz)

J=6IIz); 1.4-1.8(m,2lI), 2.3-2.5(m,2tl) 3.2-3.4(m,1lI),

H-NMR {in CDCI,) pprn: 1.29(t,3I,I=7Hz),1.3S(d,6H,

(m,1FI), 6.8-"3.0(m,8H); r-121 I-I-NMR (in CDCI') ppm: 1.29(t.3H)=7tlz), r.39(d,6H,


I = 6Hz)

4-

I .9

(m,2H),

2.3 -2. 5 (n,2I)

2.7 -3.2(m,t

H).

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 28 of 61

25
3.5l(Heptaplet,TH,J =6Hz); 3.6-3.8(m,1 H),

5,956,336
26

3.94.2(m,1,H); I-I25

6.9-8.2(rn,13H): 1-1'22
(rn,lH);
3.50(Heplapler,rHJ=6Hz)'
(m,-5H);

4.19(q,zH):7LIz), 4.34.6(m,1tf; 5.2-s.(m,1II),

6.4-6.8

H-MNR (in CDC13) ppn:: ,t.-l-1.8(m,2H), 1.3r(r,3HJ=

7Hz); L.4t(d,6H,J:6Hz), 2.1-2.5(m,2H);


1 .7

4.20(q,2H,I-7Hz),5.2-5.6(m,lH); 6.4-6.8 (m,1H),

2.91.4(m,IH), tnc 3.6-3.8(m,1H),3.94.5(m,2Hl r-r_NvrR (in cDCr.) ppm: 1.o_1.6(m,3g), L.?L{.,3H):

(m,rlI),

NMR (in CDCI3) ppm: 0.94(d,6H,J=6Hz), 1.0-1.7(m, 3H), t.zj(t,34,t=iuz),i.s-a.S(m,3H), z.s(d,zgS=tHz), 33-a.4(m,3g), a.I2(q,2H)=7Hz), 5.-5.5(m,IH), 6.24..'l
6.9_S.O(m,S),

7.1-,.-,

(in CDCI') ppm: 0.8-1.9(m,8ll), 1.29(t,3IU: __II-NMR zuz), (m,1H),'7.0-{.2(m,ri; t-124 l-s 2.1-2.6(m,3H), 2.8-3.2(m,1H), 3.72(s,3H), a.OZ{s,3H), H-NMR (in {DCl.) ppm: 0.8-t.8(m,6H), 1.29(I,3FIJ= a.L9(q,2H,I=7Hz), 4.34.6(m,1H), 5.a-5.8(m,1H), 6.4-6.S 7Hz), 2.2-2.6(m,3I{), 2.8-3.2(m,1?t), 3.3-3.7(m,1H), (m,1H), .s6(s,1H);7.u7.4(m,5H) 3.9-4.5(m,2H),4.19(q,2H,I=1Hz), 5.4-5.8(m,1H), 6.5-6.8 In the.same manner a^s in Exmple 2, compouncls I-52 to
3.7-4.3(m,2lt); 4.t7(q,2lt,I=7lzj, S.O-S.r{m,lr-r);

FI-NMR (in crlcl,) ppm: 0.8-1.5 m,2tr), t.ze(t,3lJ= #)' lHz); 2.2-2.4(rn,2H), 2.6-2.9(m,rH); 3.2-3.6(m,1H), =':_'---

r-rz3

2(d,1H,I =6H2.) ;

7Hr.), t.34\d,6l,t=6Hz), 2.34(s,3H), 2.37(a,ZH,J=7IJz),


6

,,., 7.e-]_.l9lH). '" 6'3-6'7(m'1H)'

3.8-4.5(m,2H), a.(q,2HJ=7Hz), s.0-5.5

e-8'(m'7H)'

6.i-6.-5

__

..

(m,1H),

7.1-.0(m,8H),

I-527 w,ere preparecl.

TABLE
Rj
R.

11

ot{

I_-i (Rr = Na)

l2

H)

OH

Rl

N
R

R5

Compound I-52
I-53 I-54 t-55
f-.56

R1
H
I

Rr
H H H H H
TI

m.p.
R3

R4
H
I

R5

Rt2
Na

('c.)
t38-142
(decomposed)

4-F

cHl
cH3
i-Pr
CH-t

H
FI

Na
Na

130-132
(decomposcd) '196-197 (decornposed) 211,:715 (decomposed)

H .ct
6-Cl

H H

N
N
Na

H
2-F
I

H H H
I

i-Pr i-Pr

l9-5-t93
(decornposed)

t-57
I-58 I-59 I-510 I-511
t-5 12

i{
7-Me

193-20'l
(decornposed)

H H
H

iPr
i-Pr

Na
Na

"t70-175
(decomposed)

H H H

4-Cl 4-OMe 4-Me

193-202
(decomposed)

i-Pr H H
i-Pr i-Pr i-Pr i-Pr i-P i-Pr

Na
Na Na

178-193
(decomposed)

H
H

18?-200
(decomposed)

zar2a9
(deconposcd)
(decomposcd)

I-513 I-514 -.i15


(-516

fI
FI

,t-C5

H
4-F

Na Na
Na

H H
6-OMe
TI

3-Me
-l-Me

195-200
(clccomposcd)

i{
7-OMe
I,I

5-Me

'19-t97
(decomposed)

+F
4-F

H H

Na Na
Na

239-245
(decomposed)

I-517 t-518

C.IL
n-Pr

230-237
(decornposed)

fI

+F

19-j-200 (decorq:ored)

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 29 of 61

,n
TABLE ll-continued

5,956,336
28

l-5
R3 R4

(Rr = Na)

OH

OH

Rl

Rs

Conpourd
I-5:19

R1
6-Cl

R
H
H H 8-Ct H

r'P.

Rl
4-F

R4
H H H
H

R5
i-P c-Pr i-P i-Pr
Ph

R12

CC.)

Na

19!198
(decomlnsed) 197:199
(decomposed)

I-520

II
FI

+F
4-OPh 4-F

Na Na Na N
Na Na Na

l-52J
'.-522

6-Cl 6-Cl

180-139 (decomnsed) 1 83-187


(decomposed)

t-523
t-524 I-525
1-526

rI
H

H H
H
FI

190-196
(decomposed)

-cl
FI

H H

c-P sec-Bu i-Pr c-Pr

24-210
(decomposed)

+F
4-F

6-Ms 6-OMe

rI
7-OMe

204-208
(decomposed)

I-527

+F

Na

234.238
(decomposed)

H-NMR (in DMSO-d6) ppm:0.9-1.2{n,2H),1.31G1, 6H,J=7H2.); 1.7-2.2(m,2H), 2.50(s,3H); 33-a.5(m,5F{), 3.-5l(Heptaplet,1H,J=7Hz); 4.04.3(m,tH), 5.3-5.6(m,1H); 6.3-6.(m,1H), 6.8-8.0(m,7FI); -5.2-5.6(m,1H); 6.3-6.(m,1H), 7.1-7.9(m,8H);

8H); I-58

3s H-NMR (in DMSO-d6) ppm: 0.9-1.3(m,2 H), 1.35(d, H-NMR (in DMSO-dd) ppm: o.9-1.2(m,2}l), 1.j7{ct, 6HJ=7Ila)' r.7-2.r(m,2H),23A(d,3H,J=2Hz); 3.0-3.S(m, 6H,I=7Hz); 1.6-2.1(m,2H), 3.48(Heptaplet,IH,J=6Hz); 3H),3.5l(Heptaplt,1HJ=7HZ);3.9-4.-3(m,IH),5.3-5.6(m, 3.7-a3(m,ah\. 5.3-5.6(m,1H); 6.4-6.7(m,IH), 7.r-8.1(m, iH); 6.3-6.6(m,1H), 6.e-8.1(m,7H);
II-s15

I-57

4 H-NMI{ (in DN,ISO-d6) ppm: 1.0-1.2(m,2H), 1.35(d, "" 6H)=7Hz); 1.61.2(m,2H), 2.35(s,6H); 3.G-3.8(m,3H),
I--516

I-_59

H-NMR (in DMSO-d6) ppm: 0.9-1.3(rn,2H), 1.33(d, 6HJ=7Hz); l-6--2.2(m,2H), 3.48(Hepraplet,lH,J=7Hz); 4s

3.s-4.6(m,4H), s.2-5.6(m,2H); 6.3-6.6(m,1H),

8H); r-510 8H); I-511

7.1-8.1(m,

H-NMR (in DMSO-d6) ppm: 0.9-I.3(m,2H), 1.31(cl, 6HJ-7H')' I.7-2.0(m,2H), 3.2-3.7(m,4H); 3.62(s,3H),

3.9-4.2(m,1H); 3.94(s,3H), 5.l-s.5(m,1H); 6.2-6.(m,1H),


7.0-:7.5(m,6H); t-517

H-NMR (in DMSO-cl6) ppm: 1.0-1.3(m,2H), 1.32(d, H-NMR(inDMSO-d6)ppm:0.9-l.-5(m,2H), 1.34(t,3H, 6H,I=7Hz); 1.6*2.2(n,2H), 3.0-3.8(m,4H); 3.86(s,3H), sa I=7Hz); 1.6*2.2(m,2H), 2.7-3.4(m,4H); 3.64.3(m,2H),

4.0-4.3(m,1II); -s.3-5.6(m,1U), 6.3-6.6(m,1I'I);

6.9-8.1(m,

5.2-5.7(m,1tl); 6.1-6.6(n,1H), 6.9-8.1(m,8FI);


I-s1B

H-NMR (in DMSO-d6) ppm: 0.8-1.5(m,6H), 1.7-:2.2 H-NMR (in DMSO-d6) t\ ppm: 0.8-1.3(m,2H), 1.34(cl,6H, (m,2H); 2.32.7(m,l}{), 3.tt-3.9(m,3H); 4.0--a.3(m,1H), l=7]J'); t.6-2.2(m,2H),2.71.9(m,3H); 3.49(Heptaplet,1H, -5.5-5.8(m,1H); 6.4-6.7(m,IH),'7.2-8.0(m,BH); J=7H2,), 3.9-4.3(m,1H); -5.2-5.6(m,1H), 6.3-6.7(m,1H); os f--52l 7.1-8.1(m,8H); H-NMR (in DMSo-d1 ppm: 0.9-1.5(m,2H), 1.36(cl, I-51"4 6kI,I=7lz'); t.71.3(m,2t|),3.e-3.9(m,3fl); 3.50(Ileptaplet,

7.0-B.1(rn,7H); l-513

H-NMI (in DMSO-d) ppm: 0.8-1.3(m,2H), 1.0L(r,3H, H-NMR (in DMSO-d6) ppm: 0.9-1.-3(m,2H), 1.33(c1, I=7Hz); t.6-2,.I(m,a), 2.71.8(m,5H); 3.9-4.3(m,lH), 6H,I=7Hz): r.7-2J{m,2H), 2.41(s,3FI); 3.2-4.3(m,5H), ss 5.2-5.7(m,1H); 6.3-6.(m,1H), 7.1-8.1(rn,8H); 5.3-5.6(m,lH); 6.3-6.6(m,lH),7.0--8.3(m,8H); I--519 I-SLZ I-I-NMR (in DMSO-do) ppm: 0.9-1.3(m,2H). 1.33(d, II-NMR (in DMSO-dd) ppm: 0.9-1.3(m,2II), 1.33(d, 6lt,I:7112);L.6-2.2(m,2tI),2.91.9(m,3rl);3.49(Ileptaplet, 6H,J=7Hz); L6-2.2(m,2H\,3.1*3.8(m,3H); 3.48(Heptaplet, 1IJ=7Hz), 4.O-4.3(m,1H); 5.3-5.6(m,rH), 6.3-6.6(m,1H); I H J =7 Hz),3.9 4.2(m, rFI); 5.3-5. 7(m,1 H), 6.3-6.7 (m,IH) ; so 7 .2-a 3(m,7 H);
l-52A

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 30 of 61

5,856,336

29
tH

30
6.

7.G-8.1(m,u);
I-522

=6Hz), a.04.3(m,1) ; 5 .2-5. 6(m,LH)

4-6.7 (m,li{) ;

TABLE
s
R3 R4

13

H-NMR (in DMSO-d6) ppm: 0.&-1.3(m,2H), L37(d, =7tlz); 1..6-2.2(m,21), 3. 1*3.9(m,3II); 3.51(l Ieptaplet, IH J=7Hz),4.0-4.3(m,IH); s.3-s.(m,1H), 6.3-6.7 (m,Il);
61lJ

ou

t--1

7.1-8.0(m,6II);

(R6: f
10

I-523
(m,2lt);
6.

Rr

1-6.4(m,1H); 7.1-c3.2(m,l3H);

H-NMR (in DMSO-d6) ppm: 0.8-1.4(m,2H), 1.6-2.t 2. 9 -3.t (m,3tr), 3.7 4.1.(m,lLI) ; 5. 1-s.4( m,1 [f ,

R2

\
CompounrJ
I-_-2

R5

1-524

l-i

R l-r

R?
H H H H
IT

R3
4-F H

Rr
I

Rs

(m,2rl); 2.3-21 (m,z}]), 3.e-3.8(m,3H); 3.9-4.3(m,1H),


-5.4--5.8(m,lH): 6.3-6.6(m,1

I'I-NMR (in DMSO-d6) ppm: 0.8*1.5(m,51-l), 1.6-2.2

cIIs
CH.
i-Pr
CHs

I-,33

H), 7.0-c3.0(m,sH):

r-34 I-35
2A

H H -ct
6-Ct

t{
H
H

I-36

H H H H

i-Pr

t-525 H-NMR (in DMSO-<16) ppm: 0.9-1.(m,2H) 0.96(d,6H, =6Hz) ; t.7 -2. 6(m,3H), 2. 89 (.t,2H,J =7 Hz); 3. 0-3.8 (m,3H), 3.9-a.2(m,lH); s.2-s.6(m,1H), 6.2-6.6(m,1FI); 7.1-8. 1(m, FORMULATION EXAMPLE
zs
Tablers 1

8H); l-526

Compound [-5I
Lactose

t.o g

5o

H-NMR (in DMSO-cl6)


L.7

ppm: 1.30(d,6H,J=7Hz),

-2.0(m,2H), 2.3 4(s,3H), 2. 4-2. 6 (m,LLt). 3. 0-3. 3 (m,2H),''' 3.3-3.8(m,3H); 3.9-4.2(m, 1H), 5.2-5.6(m, 1H); 6.3-6. 6(m, 1H), 7.0-8.0(m,7H);
-527

.^

Crystal callulose powder Cqrn starch Hydroxvpropyl cellulose CMC-Ca Magtresium stearate Tolal

g 8.0 g 3.0 g l.o g

20.0 g

35

H-NMR (in DMSO-d6) ppm: 0.7-1.-5(m,-5H), 1.3-2.2 ( m,2rf , 2.2-2.6 (m,ztt), 3. t-3 .3(m,2H), 3. s 9(s,3 H), 3.e 4.2 (m,2FI), 3.9l(sjrf, -5.4-5.7(m,rII), 6.3-6.6(m,1II), 6.52(s,
1H), 7.0-7.4(m,sH);

The above r;omponents were mixed by a usual methocl and thcn tblettecl to prtrduce 100 tablets each containing l0
mg oi tire active ingredienl.
40 Capsules

FORMULAI'ION EXAMPLE 2

In the same manner as in Example 3, compouncls I-22 to I-26 can be prepared.

TABLE 12

Comporrnd [-51
Lactose

1.0 c 3.5

r-2
RJ
R4

45

OII

Crystal cellulose pawder Magnesium stearate Totel

10.0 0.5
1-5.0

=H)
Rr

OH

50

The above components were nrix ecl by a usual method in No. 4 gelatin capsules to obtain 100 capsules each contlining L0 mg of the active ingredient.
and lhen packed F'ORMULAITON EXAMPLE 3

R5

Soft opsules

Com:ound
I-22

R:
H H

RJ

R4
H H I'I

R5

+F
H

CH,

l-24
t-?5

H E -cl
6-Cl

cH"
i-Pr
CFI..

60

E
I

fI
IJ

Comportrd I-51 PEG (polyethylene glycol) 400 Sa[urated ftt-v acid triglyceride Peppsrmirt oil Polysorbate 80 Total

1.00 3.39 15.00 0.01 0.10

g g

g
g g

t-26

fi
H

i-Pr

20.00 g

65

In the same manner as in Example 4, compounds I-32 to

I-36 can be prepared.

The above componenfs were mixed anc{ packed in No- 3 sott gelatin capsules by a usuai melhocl to obtain 100 soll capsules each conlaining 10 mg of the active ingre<Jient.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 31 of 61

5,956,336
31 FORMULAIION EXAMPLE
Oitment Compound I-51
(10.0 c) 1.0 10.0 c (10.0 s) (20.0 d) 20.0 68.4 (se.4 g) 0.1 g (0.1 g)
o.-s

32
4

FORMULAIION EXAMPLE 7
Granules

Componnd l-51
Lactose

Liquid parafin
Cetatrol lMrfue vaselilre Ethylparaben

1.0 c
rt.0 6-5

Cr]5tai cellulqc powdet Corn sialch Ilydroxrypropyl cellulose Magnium staratc


10

5.0 c

Lmenthol
Total

g (0.5 e)

"'
Toal
20.{)

I.0

100.0 g

The above comporents were fixed by a usual method to obtaln a LVo (lO%) ointment.

1_s

'OI,MULAI'ION EXAMPLE 5

Supposi tor

The atrove componerrts were granulated by a usual method and packaged to ohtain 100 packages each containing 200 mg ofthe granules so that each package contains l0 mg of the active ingredient.
We claim: A compouncl of
F

1'

Compound I-51 Witersol II15* Witepsol Vr'35* Polvsorbate 80


Tbrsi

1.0 g 46.9 g 5z,r) g

20

1.

he

formula,
tl

o.i

g 25

100.0 g

*Ttadcmark for triglyceride compound

The above componenls were mel-mixed by


cach containing 10 mg

usual

methocl and poured into suppository containers, followecl by 30 cooling tbr solidification to obtain 100 suppositories of 1

of the active component.


N
35

FOIMULATION EXAMPLE 6
hrjection formulation Componnd I-51 Disliled water for irjeclion formulation

Z=-CH(
1mg

H)-L-I{2-CH(

H)-CHr-CO

O.

t/z

Ca.

5ml

2. A methocl for rcducing hypertipidcmia, hyperlipoproteinemia or atherosclerosis, which comprises administering

an effeclive amount ao defined in claim 1.

of the compound of formuh A


*$.+*.*

as

in

The tbrmulation is prepared by dissolving the compound the distilied water whenever it is required.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 32 of 61

EXHIBIT B

Case 1:14-cv-02760-UA Document 2


I

Filed 04/17/14 Page 33 of 61


us04646547781

ffll ilililll ilt tilt ililt llilt lllll ]ilt 1ilil ]llt
1ro

illlt tililt illl il]

llil

(r,)

Unted States Patent


Muramatsu et al.
STABLE PHARMACEUTICAL COMPOSITION
Inveutors: Toyojiro Muramatsu, Shizuoka (JP); Katsumi Mashita, Fuji (JP); Yasuo Shinoda, Shizuok (JP); Hironori
Sassa, Numazu (JP);

Patent No.: US 6,465 1477 BL Oct.lS,2002 1+s Date of Patent: (s2)


(58)

(54) (75)

U.S.

Cl.

5141277 51.4/306 5141569;

591A
Field of Search
514i256,277, 514/306, 415, 569,97A

Hinryuki

(56)
5,3O2,6U 5.35"896

References Cited U.S. PATENT DOCUMENTS

'lhkeuchi, Fuji (JP)

Yoshio Tanizawa, Okayama (JP); Hidentsu


(.TP);

Kawashima, Fuji

A + 4/1994 Byrne et al. ................ 514/338 A * l0/1994 Kabidi et al. ............... 5t4/256

(73)
(*

Assignees: Kowa Company, Ltd., Aichi-Ken (JP);

Nissan Chemical Industrieg Ltd., Tokyo (JP)

cilecl by exrminer

) Nolice:

Subject to any disclaimer, the term oI this patent is extendcd or adjustcd undcr 35 U.S.C. 1_54(b) by 0 clays.

P ri n ary E xani ne r-&cclcrick Krass Assi s tant Exan ne r--onna Jagoe

Q4) Auorney, Agerz, or Firm-4eter F. Corless; Christine


C. O'Day; Edwarcls & Angell, LLP

(21) Appl. No.: 091436,789 (22) Filcd: Nov. E, 1999


Relaed U.S. Application Data

(57)
3,5-clhydroxy -7
-14'

ABSTRACT -4" -fluorophenyl-2'-cyclopropyl-

Dsciosed is a pharmaceutical compositir:n courprising (E)-

(63)

Aug. 18. 1997, uorv

Continuation-in-part of application No. 08/8f)4"279, l.led


abandoned.

or

quinolin-3'-yl]-6-heptenoic acid, or its saIt. or este of which thc aqueous solution or dispcrsion has pH of from .8 to B. The comirosition has good time-dependent stability and has no change in its <utlvard appearance even alter having been
stored 1ong.

(-5t) Int.

Cl.7

A6

3l I 435 ; A6

lK 3 I I 44 ; AlK 31/19

15

Clairns,2 Drawing Sheets

INK-104I After 2 days at 40"C(pH3)


Data: NK98601.D07 Method: NKSPD.MET Ch=1

mAbs Chrom: NK98601.C07 Atten5


IS NK-'104

OH OH

cooH

NK-104
F

,|

LACTONE
0
0

l0

15

2A

lS: lnlernal Standard

min

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 34 of 61

fJ.S.

Patent

oct.

Ls,2002 Sheer t of Z

us

6,465,477

lNrc104l
After 2 days at 40'C(pH3) Data: NK98601.D07 Method: NKSPD.MET Ch=l mAbs Chrom: NK98601.C07 AttenS 30 rs NK-104
F

OH OH

cooH

20

NK-104
F

OH

o
10

Lactone
0 0

LACTONE

10

15

20 min

lS: lnternal Standard

FIG. 1

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 35 of 61

f.f.S.

Patent

oct."ts,2lo2

Sheer 2 or 2

us 6,465,477 Bl

Data: R980605.D03 Method: Ch=1 mAChrom: R980605.C03 Atten4


'15
5.552

2.879

IFluvastatin]
I

10

5
I
I

.'. 849
I

4.505

0
4.893

10

15

20 min

I
1

After 2 days at 40'C(pH3)

Data: R980601.D16 Method: FLUVADEG.MET Ch=1

mAbs Chrom: NK9B0601.C16 Atten4


ts
F

Fluvastatin

OH OH
Ffuvastatin

't0

?o

40

lS: lnternal Standard

0 min

FIG. 2

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 36 of 61

STABLB

PHARMACBUTICAL COMPOSITION

12

us

6,465,477

Bl

The present application is a continuatic.n-in-part of U.S. application Ser. No. (181894,279 1lecl Aug. L8, 1997, now s esr.er, if tbrmulated in conventional manners, have low' time-dcpcndenl stability, and are protrlematic in that thcir abandoned.

higher, desirabl, pH 9 or higher, but unexpecteclly, it has been 1-ouncl that NI(-104 and its salts and esters are stili unstable even rvithin a high pH range. Theretbe, preprrations comprising NK-104 or its salt or

cyclopropyl-quinon-3'-y1]-6-heptenoic acid, or ts salt

especially (E)-3,-5-clihyclroxy-7-14'-4"-fruorophenyl-2'- to orain stalle pharmaceutical compositions comprising


basis

j,1i,'ii"',:',i": F'ELD oF rHE 'Ihe prescnt invcntion rclates to a pharmacoutical com- prising it is desirecl. oosition with hioh stahlitv ancl- more oreciselv- to a nhar- l0 SUMMARY oF TFIE INVENTION mceutiea tcc,mpisiti rn ..,'-f.iring nn liuc-ca..Ju'.'iui. inhibitor of vi,hich the slability varies depencling on pH, Wc the prcsent invcnt6s have yariously studiecl in orclcr

rNVEN.N

ili*:::i;H-#"ii

ester.

or _, NK-104 nncl, as a result, have founI unexpecre{ly tha ls NI(-1t14 is stable wirhin I reiatively low pII range. n the
of this ncling, we hav completed the present invenhon. Furthermore, we investigated decomposition products of NK-104 ancl fluvastatin in an aqueous solution of pH3. The dcc<-rmposition product of NK-104 lvas founcl in smr11 quantity and consisted oniy of the lactonized trrm of NK-104 (see FIG. .l). On the nther hand, clecomposition products of fluvastatin werc tbund in reiativcly large quantities consisting of more than one lype of proclucts $'hich are believecl to inclutle an optical is<mer and a lactonized fcrrm of fluvastatin (see FIG. 2). These resulls showed that the decomposition pettern and slability of NK-104 ancl fluvastatin were different in the same pIJ. In addilion, we havc furthor founcl that, if a basic substance is aclcled to
a

IIACKGROUND OF TIIE
acicls

INVENTION
,r -"

It s krown that 7-sutrstiuted-3,5-clihydroxy--heptenoc

ol

a general [<rmula:

25

lvherein R represents an organic g;roup, have FIMG-CoA recluctase-inhititing activly and are useful as medicines for hyperlipemia ancl also as medicines for athcrosclerosis (sce

EP-B-304,03).

U.S. Pat. Nos. 4,739,073, 5,0AL25 5, 4,7 5 1,235, 4,804,67 9,


30

proposed. (E)-3,5-dihy droxy -7 -14'-4

Flowever, these 7-substilutecl-3,-5-dihydroxy-6-lreptenoic acicls are ustable at low pH, and require some particular means tbr tbrmulating them inlo preparations. A means of lormulaling lhem al<.rng wilh an alkaline medium, such as calcium carbonate or sodium carbonate, into preparations with pll of B or higher (see U.S. Pat. No. -5,356,896), ancl a means of lbrmulating thcm along with a basic agent, such as magnesium oxide or soclium hydroxide, into preparatiols with pH ot 9 or higher (scc ts1']-ll-336,298) have bccu
"

pharmaceulical composition comprising

NK-104 in such a manner that the aqueous solution or


clispersion of the composition may have pH of from 6.8 to 8, the composition is stable. ,A.n ol-rject of the present inv'ention is to provicle a pharmaccutical composition comprising NK-104, or its salt or ester, of which the aqueous solution or dispersion ha^s pH of from 6.8 to less than 8, preferably has pH of tiom 6.8 to 7.8. The active ingreclient of the composition of the preselt invention is NK-104 to L're represented by the abovementioned structural formula. The conlguratir:n in this substftnce, NK-104 is not specificaily clefned herein. In addition, NK-104 may be in any form of its salts and esters. Thc salts inclu<ie, Ior example, sodium sall., potassium salt ancl calcium salt. Pref'erred is calcium salt of NI<-104,

35

40

-fl

uorophehyl-2

'-cyclopropyi-quinolin-3'-yl]-6-heptenoic acicl (hereinaller this may be refere<l to as NK-104) to be represented by a struchrral tbrmula:
45

BRIEF DESCRIPTON OF DRAWINGS FIG. 1 is a histogram of NK-104 decomposition proclucts anaivzed bv HPLC.

FIG. 2 show-s histograms of fluvastatin clecomposition


products analyzed by IPLC.

DETAII,,ED DESCRIPTION OF TFIE

:)

INVENTION
as referred to herein indicates the pII vaiue to be delermined in such a manner that unt close of a solid prcpartion comprising NK-104 or its salt or t:stcr is samplecl ancl dissolved or clispersed in lior 1 to 10 nil of pure \ilter. and the pFI ol the resulting aqueous solution or dispersion is measured.

the pII

or its salt or ester is one of HMG-CoA reduclase inhilitors that arc representcd by thc abovc-mentioned general formula, ancl is kncrw"n to be useful as a meclicine for hyperlipemia and also as a medicine for atherosclerosis (see EP-B-304,03). NK-104 is also unstable at low pH, and many clilculties have been enccuntered in formulating il into preparations. It has been reported that these flMG-CoA recluctase inhibitors are formulatecl into preparations with pII tl or

o0

6-s

A basic substrnce may be ad<le<-l to lhe pharmaceutical composilion comprising NK-104 to control the pl-I of the compositioc, which rnay be any of antacicls and pH reguiators including, tbr example, antcids such as magnesium ahrminometasilicate, magnesium aluminosilicate, magnesium alumnum silicatc, magncsium aluminate, dry alumi-

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 37 of 61

34
num hvdroxide, synthetic hy<Jro{.alcite, synthetic

us 6,465,477 Bt
aluminum
disintegrator in an amount ol from 1
Lo 307a

silicate, magnesium cart'ronale, precpitated calcium


sodium hydrogencarbonate; and

by weight,

an<J

,' ilnlJl'$.*J.T,Lt:iji:l?:,"t:hii"li,-,,i.ii: but the " ;, ',' composition may b" tbrmiaied inro tablers, gi^*r;", :tlt:_-l:euticalcompositionofthepresentinvention po.".s, troches, capsulcs, chcwatrles, titrn-"our"a*p..puiu-i :,11^tt:-pt:9:'cl accorcling to any ordinary methods employaltle in,.producing perorai solid pretrraralions' If stirring tions of these, ancl even sgar-cotecl proparation" t#;;;. 36 whec rhe pharmaceurical composition .r,h" p;;;;; f,llj:t',11ii:iill:i;hfTi1jffi,'Jl1"i,:j:i: invention is formulated into such peroral solicl p."pu.nli11:l
vehicles (excipie'ts), binders, disintegrators..and lubricantscanbeaddeclthereto,if desired'Thepreparatio"r. may be tbrmulated frorn the cornposition along with any of ,, "

inciuding aluminum, ancl organic base compoun<ls..For usecl singly. However, [wc] or moro such Lasic substances example, alkaline earth metal means magnesium, calcium, c* b" ,""".t in comtriation. barium, etc. Preferecl is magnesium. Particularly preferred of the present invention can be coated fo , aliialine earth me1a1 silicates inclucling aluminum -,-T""T::lition tablels or sugar-coated tablets' As the "r"'"gnesium aluminometasiticare (IEUSIN rn, *ugn""ioin T:'^:,-1q:"t:l example, usable are celluloses such as aluminosilicate (NEUSILIN A), anct magncsium d;;;; :-".itl:9.l':^T:.,f:r hvdroxvpropvlmcthvl ceilulosc; silicare (vEEcuM F). The pretbnect organic t ns" ;" o'r-g"'5-'lfl::it:t:1^ccllulosc' and also aminoaikyl methacrylate copolvmer E, white sugar, ine. An even more preferred base is L-argiline. rhe pharmaceurical comtr osirion or rhe presenr invenri"" can be formulated into various lorms <.[ preparations. uul"o" nlu..rl. pret'erred are peroral solid preparations. For example,

., ., of the invention in order to makc the :1.1*.,:""Tffition or dispersion of the composition have pH |?::-i:*Tlln u:t, t"than B may be from about 1 to 6 '5vo by :111:i ]"*t nesium-aruminosilicate,lnd l--arginine. fia' #:;'n.;lt,#;t;;i::: Even more preferred ae basic substances that may . be triiti,l r so, if magnesim aluminosilicate (NEUSI1_IX aj is usd, pharmaccutical addecl to the composition comprisng from ab,oui2 to g7o by weight or o, if magnesium alu_ NK-104 to control the pH of the composition ancl that "- miniumsilicare(VgE6firused,orfiomaboutg.3lro maintin lhe outu'ard apperance and stability of said.com- 1s O.I% by *,eigh or so, if i_argini'e is usecl singly. As position. These may be any of alkaline earth metal silicates mcntioncd ab'vc, it is prcferable-tbat thc basic substancc is
.

sodium phosph1e, disocl ium 5 potasotassium dihyclrogenphosphate, disodium cirare, .o".t]',i succinare, ammonium chloride, and sodium u"nt',o*. i rhese, prererrecl are magnesium aluminomerr.si1l"ut",',,g- tr " '"
hydrogenphosphate, soclium clihydrogenphosphate, sium phosphate, dipotassium hydrogenphosphate,

L-arginine,

carbonate, magnesium oxide, aluminum hydroxide, and pI{ regulators such as

thelubricantinanamountof tiom0.5toIOVabyweighr.

If further desirecl, any additionai components, such as sweeteners, flavorings ancl colorants *oylso be aclcled to
thecomp.sitionofihepresentinvenlion. The necessary "-.1 amount of the basic srbstance to be aclclecl

any

of

these,

in any orclinary mnner.

iru"r,,cuetizc with

il;,"g;;ti;;Jrnixecl. Nexr, water is added to the resulring ;i"*;;;;;g;anulated with sti'ing, clicd and drcssed ro F'ur1her, the granules ae mixecr wirh a ;;;;iri;;;;;i;
a pcllctizcr into pcllcts. Aso

rhe vehicres (excipienrs) incrucre, for example,la-ose. corn starch, clenalured corn starch, mannitol, sorbitol, woocl vehicie and disintelrator' are mixecl. Then, an aqueous cellulose, frne crvstallte cellulose cl calcium carbonate, 4 solution.I a bincler is sprayecl o'er the resulting mixrure, which can be usecl either singly or as comlined using a fluidizecl becl gra^nulator, to prepare granules. .Ihese 'I'hc bindcrs inclucle, for example, hyclroxypropyl granules are mixecJ wiih a lubricant, nd theryrelletizecl with cellulose, hydroxypropylmethyl cellulose, polyvinyl a pellerizer inlo pellets. pyrrolidone, polyvinyl alcoh.l, and parlial saponificates of using coating clevices, rhe peilets a.s rocruce<J these, which can be used either singly or as combined +-. u.*iig 'rclinary th"'nOo.r"_menrioned methocls can be coated Especially preferrecl is hy<lroxypropylmethyl celluiose' with a soiution or suspensi.n comprising a coating base ancl The <lisintegralors include, Ior example, low substituted optionally a plasticizer ancl a coloantio girr" fll_coated hydrox;'propyl cellulose, carmellose, sodium carboxystarch, tablets oi s'sar-coated tablets. calciur carmellose, corl starch, partially-alphatized starch, sodium closarmellose and clospovidone, which can be usecl 56 BEST MODES OF CARRYING OUT THE either silgly or as corbined. Especially pretbred is low INVENTION substituted hydroxypropyl cellulosc. rhe lubricanrs incrudes, nrr exampre, magnesium srearare, stearic acid, palmitic acicl, calcium stearate ancl ta1c, which ior ini"""J to iestrict the scope of tlle invention. can be uscd either singly or as combined. 55 'Ihe amounts of ttrc ingrcclicnts constituting the compoExample I sition of the present iuvention are not specifically defined. Decomposition Products of NK-104 ancl or examplc, lhc amount of NK-104 or is satt or ester may Fluvastatine be from 0.01'to 407o by weight preferably from 0.0-5 to t0% by weight, more pretrabl5; from 0.5 to 57o by weight; and oo Decomposition proclucts of NK-104 were analyzecl by the basic substance may lre aclcled to the composilion in such HPI-C at'ler incubation for two days at 4{}o C. in aqueou.s an amclunl that is neccssary for making the aqucous soirLtion solul.ion of pH 3. NK-104 producecl a singie producl, a or dispersion ol the composition have pII of tiom 6.8 to less lactonized tbrm of NK-104 (see FIG. .1). The decomposition than 8. Where the composition is tbrmulated into peorai proclucls r:f fluvastatin were also analyzed for cornparison. solicl preparations, it is desiable thal the vehicle is added o,s Fluvastalin produced many lypes of products, which are thereto in an an'ounl of fror 3A 95% by weight, the beiievecl to inchrcle an optical isomer of fluvastalin and a binder in an amount of trom 1 to 2(l7o by weight, the lactonizcd tbrm of fluvastatin (scc tIG.2).

:ffit:Ji""r"t"r:'*i"itr.i',-i1ffil'i;"i':"*ri1":;

,.jJ:l["",t"'*: j!jffi::t:i1":il:'S, :i:

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 38 of 61

us
5

6,465,477 tsl
6

The conclitions uncler which NK-104 nd Fluvastatine


clecomposil.ion products were anaiyzeci e as fbllows: HI'LC system: 1'ype LC-10 (Shimadz, Japan) Column: D E VtsLOSIL ODS-FIG-5 ( NOIVIUI{A Cf IEM.,
Japan)
Calcium Salr of NK- I04
Lacrosc Lo' Substitrred Hv&oxryropvl Ccllulosc Hvdroxvpropyhnethyl Cellulose 2910

1.0 mg t3.7
12.t) 2.0 0.1
1,.1

Molil Phase: MeOFI,,0.02 mol/L phosphate buft'er (pH 3):7t3

L-argirine
Nlagn$ium Slcarate

Samplc: NK-104 or fluvastatin/pH 314A" C., 2 clays Total (onc tablc) 110_u Detector: SPD-MLOAVB UY 245 mm NK-104 ancl fluvastatin have common cr--clihydroxy-e- 10 ene carboxylic acid chemical structure. However, NK-104 ad fluvastatin diftr in the types and amount of clecompoExample 5 sition products. Namely, NK-1(14 provides a small quantity of one type of clecomposition xocluct while fluvastatin _ _ In the. slme manner as in [xample 2, herein produced provicles tmparativeiy arge quantities of ifferenl rypes of 1-5 w'ere tablets each having the composition rnentioned below. decomposition proclucts (see FIGS. I and 2). Such clifferences show that. stability of each depends no1 oniy on the chemical struclure of a--dihyclroxy--ene carboxylic acid Calcium Salr ol NK- 104 1.0 mg but also on the chemical structrres that are unique to each. Laclose 103.2 20 Low Substituled Hydroxypropyl Cellulose In thc following examplcs, thc low substitutcd hydrox12.0 Hydroxypropvlmethyl Cellulose 2910 2.O ypropyl cellulose was commercialiy availalrie as sold for a Magnesiurn Alurinolnetasilicrre l).6 mcdicinc aclclilivc and contains tom 5-L6Vo of ---OC.HoOH Maglesium Stearate 1.2 group. Hydroxypropylmethyl cellulose 2910 contains (one Total tablet) 120.0 28-3OVc and 7-72o/o Both lorv 25 -OCFI3 -OC3H6-OH. substitutecl hyclro,rypropyl cellulose und' hy,l.oxyp.op yhnethyl cellulose 2910 as used in thc examples are clescribed in 'Ihe Pharmacopoeia of Japan, 12th edition. TEST 1
Example 2 lhe pH of a -57o suspension of tablets producecl in any of produced Herein were tablets each having the composi- 30 Examples 2 to 5 (the suspension ,was prepared by suspen<. tion mentioned below. ing one tablet in 2.4 ml of pure water) was meaiur"d. Aftcr having been stored at 60o C. for 2 rveeks, the percentage retention of calcium sa-lt of NK-i04 in the tablets
Calciurn Salt of NK-104
Lctosc

1.0 nlg
laJ,.4

Lolv Subslituted Ilvdroxvpropl, Cellulose Hydroxypropyln:ethv.l Cellulose 291{) Magnesiturr AluorirotrretasiliGle Maglesiu[ Steat Total (oe tablat)

't2.0
1.O

"

,-_ was measured accorrling to HPLCI. After having lreen storecl at 60o C. fo -l clays, the change in the oiltward appoarnce of lhe tablets \r'as observed. The test resulls ae shown m

2.4
1.2
12D.O

Table

1.

4o
pH of
-59a

TABLE
Example

Example i.'7
97o,to

Exarnple
7.5
)3%

t}tample 5
1.1
924,6.

The components of the above-mentioned composition,


excepl magnesium stearate, wcrc mixed to prcpare a homogenous powclery rixture, ro whicb was aclcled a suitable 4-{ amount of pure water. The resulting mixtre was granulatecl wth stirring, ancl pelletizecl to give pe11ets. Magnesium stcrate was adclcd to and mixed with these pellets, which were then labietted into NK-1O4-containing tablets. Example 3
50

Swpension

7.8
9'7
,4i'

Perceutag

ReteilioI of

Ca NK-104
Change in Outwad Appearance

No chaoge No change No cbange No chalge

tlontrol Examples

1 to 3

In lhe same manner as in Example 2, herein produced


were tablets each having the composition mentionecl trelotv.

5 tablet, the percertage retention of Ca NK-IM,


Calciunr Salt ol NK-_14 Lactose Low Substituted Hvdroxyprol:yl Cellulose

In the same manner as it Example 2, herein procluced wcro control labicls cach having the composition mcntionecl belo'n'. These tablets were tested in the same manner as in 'Iest 1, to determine the pH of the 57a suspension of each
an<1 the

i.0
102.8
12.

mg

change in lhe oulward ppearnce results are shown in Tal'le 2.

of lhe tablets. The

tesl

llvdrcxvpropylmethyl C-ellulore 2910


Dipotassium Hyrlrogenphosphate

z.o
1.0

TABLE 2
6r)

Magesiur Steamte Total (oue tabiet)

t.2

C'ontrol
F-xanrple
Ca NK-104
.1.0 mg 1{J3.8

l?0.0

Clonrol Example
a

C'ontrol Exarnpe
3

1.0

[xample 4
same rnanner as i Example 2, herein procluced wcre lablcls cach having the composition mentionod beloE.

In the

I*close 6-s l.orv Substitued Flyclroxypropyl


Cellulose

rg 98.8 12.0

1.0 rng
98.8

tz,i)

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 39 of 61

us 6,465.477 Br
7
TABLE 2-continued

I
TABLE 4-continued
Bxample ConLrol

Cbntrcl
Hxampie

l2

C'ontol Exanrple

Clo

nlro 3

Exanlple

C--ontrol

F.xanrple -5 Example 6 1.2 111.0 9.3 6.0 Changcd


Lo

Flvdroxv:ropyl Cellulose
291.4

'z.a
1.2

2.0
5.0

?.0

Maglesirun Stearale Total (ole tablet) pH ol 5Vo Srspension

1,.2

120.0 7.-i
93..1

1.? 120.0

9.8

Sodium Ascorbale Ascorbic Acid Magncsiunr Slearatc Total (one tablet) pH ol 5% Suspension Percantage Retenlion ol Ca NK-104, alle stored a! 60'C. lbr 2 rveeks Change in OuMard Appearance, ater stocd at 60" C. fo 3 datr

5_D

pa.o 6.6 83%

120.0 ri..t 7'7.h

10
120.0

i.3
38,b

}IK-104 renaining () alter ? week$ at 60' C. Changc in Outu'ard Appcarance, aftcr I rveeks at 60" C. Clrarge in Oulward Appearalce. ater slore<1 t 60'' C. tbr 3 days

No
change

brown
CJranged

No change No change lfo change


15

to pale velowish
green

\rere t&bles each traving the cornposition mentionecl belo\4'. suspension of the composition having pH of 7 or higher is high, after having been stored aa 60o C. for 2 weeks, while 20 These tablets were tested in the same milnner as in Test 1, to determine the pH of the 57o suspenson of eacb tablet, ancl the same n the 57o suspension thereof having pll of lower the changc in thc outward appcarance ofthc tablets.'Ihc tcst than 6.6 trecomes lorver with the decrerse in the pFI value results are shown in TaLle 5. thercof. Example 6 and Control Example 4
25

As in Talrles 1 ancl 2 showing ihe lest results, il is obvious thal the percentage reLcntion oI Ca NK-104 in the 5lc

Example 8 and Control Example 7 In the same manner ,s in Example 2, hereirr

produced

'lAft_E

.5

In the same manner as in Example 2, heren producecl werc tablets each having the composition mentioned below. These tablets rvere tested in the same manner as in Test 1, to ca NK-104 determine the pH of the 5% suspension of each tat"rlet, ancl 30 Lacrose l os' Substtuled Hydroxqrrop_vl the change in thc oufward appe aranco of thc tabie ts. 'I'he tcst Hyrhoxyllrop_vlnlethyl Cellulose esults are shown in Table 3. Sodim Hydrogcnqrbonatc
.IA-BLE
3
Fxample Ca NK-.104
LacLose

Hxanrple

Control Example 7 1.0 mg


93.9

1.0 rg
101.8 Celluose 291t)
12_0

2.4
2.O

t2.o ?il
9.9

fi

3j
Control Exalnple 4
1.0 Eg
9-1.9

Magilesinl Slearate Toral (otre tablet) pH of 5% Sus:ension Change in OuLwad Appeiraoce, alter stoed at 60''' C. t'or -3 davs

1.2 1?0.0 7.3.

t.2
:120.0
9.J

No

chalge

1.0 trlg
101.4 12.0 2.t)

Changed l0 drk nYy bluc

Low Subslihted H,vdroxy:roprl


Cellulose Hydroxypropylmethyl Celulose 2910 Magnesiurn AlumiIornetasiicatc Magnesirrn Sterate Tolal (one tablet) pH ol 5c,'c Suspensiou Change il Outwrd ifle sored at 60- C. tbr ^ppearance, 3 days

12.O

?.4 9.9
1.2

40

Exampie 9 and (lontrol Examplc 8

120.0 7.8 No changc

12.t)
8.-

Changecl Lo pale

yellowish b.own

In the same manner as in Example 2, herein producecl were tablets each lraving the composilion mentioned belo\,. These fabiets \/ee tested in the same manner as in Test 1, to determine the pFI of the 57o suspension ol each tablet, ancl 45 the change in the outwarcl appearance of the tablets. The test -Iabie results are showt iu 6.

Example 7 and Control Examples 5 and 6

'lAgl-g
-5{)

Exanple

In the same maner as in Example 2, herein produce6l were tblets each having lhe composition mentionecl below. These tablets',vere tested in the same manner as in Tst I, to determine thc pH of the 5% suspelsion of cach tat)lct, nd the change in the outward appearance of the tablets. The test results are shorvn in Table 4.
TABLE 4
Exaorple

Contol Example 3 1.0 rng


9-_?_9

(la NK-104
l,aclose

1.0 mg
102_3 12-t)

Low substituted Hydroxlpropvl Cellirlose


55

Ixample Ca NK--104 Lactosc Low Substituted flydroxypropvl Cellulose lfydroxypropymcthyl Cellulose TC-5R
l-.

Control Cotrtrol 5 Example o


1.0 mg
95.8 12.0 1.0 nrg 93-{)
'12.0

6(l

Hydroxy,propylncthyl CclIlosc 291{-) Dipotassirun Ilydrogenphosphate Magnesium Sterate Toral (one tablet) ptl ol 5% Suspension Change io Outs?rd Appeam[ce, afer stoed at 60'C. for 3 days

t-{l
1.0
120.1)

12.O 2-t)

9.9

r.?
120.0
'1.7

3.4
Changecl

No change

lo olargc

1-0 mg 13.7

li.0
).t)
(). I

,A,s

is obvious liom the tqst results in Tables 3 to 6,

ncr

2911)

1.r)

argirine

2.0 3.0

9.9

change in the outrvard appearance of the tablets was tbuncl w'her tlle 57a suspensions of the tablets had pH of I or lower, 6-s even atler having been stored at 60" C. tbr 3 days, bul the oulw-rd appearance of the tablets change(l lvhen the 5% suspensions of thc tablcts had pH of higher than .9.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 40 of 61

I
Example
1O

us

6,465,477

Br
10

of the 57a suspension of each tablet, but the percentage retention of Ca NK-104 ancl the change in outrvard appearance oflhe tablets were observed one month after storing at 0" C. Thc test resuifs arc shown in Table 7.
cletermine the pFI

The tabiets were testcd in the same manner as in Test 1 to determine the pll of. the 57a suspension of each tablet, but Ma gnesium luminometasilicate the percentage retentior of Ca NK-104 and the change iu produced In the same mnner as in Example 2, herein outwarcl appearance of the tablets were observecl one monlh werc tablcts eaclr having the composition mentioncd below. The tablets were tesled in the same manner as in Test 1 to r ater storing at 60o C. The test results are shown in Tabie 9.

]ABLE
2

9
3 4

)
1.0 mg
43.S 12.0 2.A 60.0

1o ca K-to+

1.0 mg
100.2 12.0 2.t) 3.6

1.0

TABI-E 7
-f Ca l.{K-104 Lctosc Low substitted 4 1.0 mg
5-1.8 5

Lalose

Low strbstituted Hvdroxrropyl Cellulose Hvdroxlpropvlmetbyl


Cellulose ?910

nrg 1.0 mg 1.0 rng 99.4 97.8 91.8 n.a 1:.0 1?.t)

1.0 mg
10.t.4 12,'J
'2.4

1.0 mg
1110.8

1-0 rrg

2.O 2.
4.1 1.1 120.0 8.2 98.8
6.0
1.2,

91.8

1.0 mg

2.4
12.
'1.2

15 Malesium Alunitrum
Silicate

12.t)

1:.0
2.0
i 2.{)

12.0

t2.i)
2.0
103.3

Hydroxypropvl Cellulose Hydroxyprop\4nethyl Cellulose 29 10


\4agnesiunr

2.0

t.0
50.0

Magtresiufi Steaat Total (one lablet)


pH of 57o Suspension

r.2
120.O

r.2
1,20_t)

i20.0
8.7
98.1

3.0
1,2
7_8

NK-104 rcnaining rate

Alumirometasilicale Magnesiunr Starate Total (one tablet) pH of 5o,' Suspension NK-104 reRiflirg rate (q. tl-er 'i nror[h t

120.0 120. :120.0

97.4

r.z 1.? t.2 1.2 r20.o 8.1 8.4 9.0 9.3 96.5 92.2 S4.5 69.1
No
change

2q

(Vc) after

I notth

7-5 97.1

130.0 9.1 92.5

9.7 84.3

at

60'c.
Change in Outward ppearatrce, atr stored at 60" C. for 1 month

No ilo Pale chalge change yeliow

Pale
gray

Gray

60' C. Change in Outward


Appearalcc, aftcr storcd at tiO' C. tbr 1 month

No Pale Pae Pale chauge l'cllos' -vcllow ycllow

25

INDUSTRIAL APPLICABILITY OF THE INVENTION


The pharmaceutical composition of the present invention with having no change in the outrvard apperancc thereof cvcn aftcr having been stored long. Therefbre, the cornposit.ior is good in medical usc, espccilly in thc lbrm of pcrorl solid preparations. The pharmaceutical compositions of the present invention that contains NK-104 or sah or ester thereof are especiaily useful for lreating a patient, particularly a human" thal is su[ering from or susceptible to hyperlemia or atherosclcrosis by administering the pharmaceutical composilion ro such patient. Particularly preferrcd unit closages have been described in the examples above. It will lre appreciatecl the specifically prefe{recl dosage amounts of a pharmaceutical composition ofthe invention used in a given therapy will vary accorcling 1o various known factors such as lhe particular compositions
has gcrod time-clepenclent stabilil.y,

Example

11

-ro

Magnesium Aluminosilicate

In the same manner as in Example 2, herein produced were ablets each having the composition mentioned belor,. The tatrlets were leslecl in the sme manner as in Test 1 to determine the pFI of the -5la suspension of each tablet, but the percentage retention of Ca NK-1O4 was otrservecl at both 2 weeks and one month atler storing at 60" C. and the change in oulward appearance ol thc tablets was observcd one month after sbring t 60" C. The tesl resulls are shown in Table 8.
TAI}LE 8
2

35

40

31
.1.0 mg .1.0

Ca NK-104
Laclose

1.0

l.ow subslil.qled Hvdroxlropyl Cclhrlosc


Hvdroxvpropvlmcthl'l Cellulose 2910 Magnesium Aiuminosilicale Magnesium SLearate Total (one labet) pH of 5c,b Suspension NK-104 renrainirg rate (9) ater two week at

rg 1.0 nrg 103.2 I2.6 12.O t2.0

mg

1.0 trg
9.8 12.0
2.O

101.3 12.(i
1.O 2.O

98.8

l2.o

2.0
.6
r.2
t10.
6.8

2.O

2.O
5.0
'1.2

1.)

7.0
1.2

50

\.2
120.0 98.5

7.2
12{).()

120.0
8_4

t20.0
3.7 86.8

97.3

8.1 91.7

41.4

f,

60'c.
NK-104 retrairting rare e"l afier I nrotl at 60" c.
Chaugc in

9'7.5 93.5
fio
chalge
No

51.2
No

i0.7

79.1,

Outward

io

No
60

Appearalce, after stored at 60" C. fo. 1 ronth

change change change chauge

Exampie 12
Magnesium Aluminum XSilicate

s wherein
proclucccl

formulated, the specific compound ufilized, the mode cf application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be reaclily ascertainecl by those skilled in the at using convetional dosage determination tests conclucted with regarcl to Lhe foregoing guiclelines. 'I'hc invention has bcen dcscritred in clctil with reforcnc to preferred embodiments thereof. How-ever, it will be apprecited that those skilled in the art, upon consideration of ttlis ciisciosure, may make modifications and improvements within the spirit and scope of the invention as set tbrth in the tbllowing claims. Wbat is claimed is: L. A pharmaceutical composition cornprising (E)-3,5clihyclrox'-7-[4'-4"-lurophenyl-2'-cyclopropyl-qu inolin-3'y1]--heptenoic acicl, or its sa.lt or esler, and a pharmaceutically acceplable carrier, ol which an aqueous solution cr dispersion tif the pharmaceutical composition has pH of from .8 to 7.8. 2. The pharmaceutical composition as claimed in clairn l,

In [he same manner as in Example 2, heretn

the salt of (E)-3,5-dihydroxy-7-14'-4"-

wefr: tablclq each having thc composition mentionccl bclon.

flu orophen y l-2'-cyclopropyl-qu inolin-3'-yl]-6 -hep tenoic acid is a calcium salt of thc acid.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 41 of 61

us

6,465,477 Br
12 selectecl from the group consisting

11 3. The pharmaceulical composition cf claim l wherein the composition further comprises a basic substance.

of

vehicles,

4. The pharmaceutical compos.ition of claim 3 wherein the basic substance is an organic base compound. 5. The pharnraceutical composilion of claim 3 wherein the s tion. 12. "fhe pharmaceutical composition of claim 3 wherein basic substancc is an alkline carth metal silicate. the composition firrther comprises a lactose vehicle. 6. The pharmaceulical composition of claim 5 wherein the 13. The pharmaceutical composition of claim 3 where.in basic substance is an aluminum compound. the composition further comprises hydroxypropvl cellulose 7. The pharmaceutical composition of claim 5 wherein the wilh a low degree of substitution. alkaline earth metal silicate is a magnesium salf . l0 14. The pharmaceutical composition of claim 3 wherein 8. The pharmaceutical composition olclaim 3 wherein the the composition further comprises a binder of hyclrory lasic sutrstance is one or more selected frr:m magnesiunr propylmethyl cellulose. aluminometasilicate, magnesium aluminosilicate and mag15. The pharmaceutical composition of claim L wherein nesium aluminum silicate. the composition further comprises at lcast one material 9. 'lhe pharmaceutical composition of claim 3 wherei the r-s selected from the group consisting vehicles, basic substance is I--arginie. clisintegrators, binclers and lutrricants. 10. The pharmaceutical composilion of claim 3 wherein *a+** the composition further comprises at least one material

clisintegrators, binders and lubricants. 11. 'fhc pharmaccutical composilion of claim 3 whcrein the composition further comprises a peroral solid prepara-

of

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 42 of 61

EXHIBIT C

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 43 of 61 r il1il ililllll ilr ililr ilil il|l llllt |l1il llllt ilil lllll ffi ffi ill ir
us00855799382

r'rr
(54)
(7

United States Patent


Van der Schaaf et al.
CRYSTALLINE F'ORMS OF PITAVAST?ITTN
CAT,C'IUM
Nissn Chcmical Industries,

(ro) Patent No.:


1+s

Date of Patent:

I"IS 8,557,993 B2 Oct. 15,2013

FOREIGN P,{TENT DOCUMENTS


!lP
EP EP NP EP EP JP JP JP JP JP
JP .IP

t) Appiicant:

Ltd,

Too
(72)

(JP)

Inventors: Paul Adriaan Van der Schaaf, Hagenthal-le-Haut (FR); Fritz Bltter,
Reinach (CH); Martin Szelagiewicz, Muenchenslein (CH); Kai-Uwe Schoening, Oberwil (CH)

(73) i\ssignee:
(*

Nissan (lhemical lndustrics f,td.,

Too

(JP)

) Notice:

Subjeot to any disclaimer, the term of ilris patcnt is cxtendcd or acljustcd under 35 II.S.C. 154(b) by 0 days.
131664.498

'wt)

JP

wo wo wo wo

(2t) Appl. No.:


(22) (65)

wt)

Filed:

063 2,',1989 406 l2it992 I 099 694 5;2001 I 472 227 tL'2044 I 472228 ll:20{J4 9t2006 I 697 326 6t-17U64 8,'1986 05-t48237 5i t99i 6-92910 4t994 8-1?6',74 li t9q6 2005-500382 1,'2005 2005-516064 6i2A05 2005-5208i4 7:2045 2007-516952 62007 03/0l6it7 ^2.'2003 031064382 812003 wo 03i064392 8i2003 wo a3i0'707t7 812003 031087091 10,'2003 wo 2004i072040 8i2004
0 304

0 520

Oct. 31.2012 Prior Publication Data

OTFIER PUBLIC,\TIONS
Jan. 21, 2010 Subrnission of Refernces in .rP 2006-501997 (JP counte.part to present application) with English rrmslation. t\l. 3. 2010 Suhmission of References in JP 2006-501997 (.lP counterpilt to present application) u'ith English trmslation. Mar. 26, 2010 Submission of Relences in .rP 2006-501997 (JP counterparf to prsent application) with English translation.

US 2013/0053413

AI

Feb. 28,2013

Related U.S. Application Data

(63)

Continuation of application No. 13,280..131, filed on


Oct. 25, 20 1 I , norv abandoued. which is a contiluation ofapplication No. l21331,086. filed on Dec. 9, 2008,

No.
(30) Feb. (s1) (s2) (58)

now abandonecl which is a continuation olapplication

10!544,752.

PCT/8P2004/050066
abandoned.

filcd as application No. on Feb. 2, 2004, now

Foreign Application Priorir* Data

12.2003

(EP)

03405080

Int, Cl.
c07D 215/38 u.s. Ct.
USPC

(2006.01)
546111:t1,

F'ield of Classification Search 546l{\t USP(] Scre application file fi'rr complete search history Rcfcrcnces Cited

(56)

U.S. PATENT DOCLIMENTS


3,175,944
5,0 I 1,930

3'1965 Hoekserna

Ju. 29, ?010 Office Action i JP 2006-501997 (JP counterpart to presenf application) with English translrtion. Aug. 23. 2010 Subrnission ofReferences i JP 2006-501997 (JP counteparl to plesent application) with English t&mslalion. Dec. 27,20i0 Subrnission of Refeences in JP 2006-501997 (.IP countepart to present application) rvith English tuanslaton. .Ian. 21, 2010 Subrnission of References in JP 2006-520594 (JP counterprt to lelated U.S. Appl. N-o. 13,'487,289) with English transltion. Mr'. 3, 2010 Subm.ission of Rctbences in JP 2006-520594 (JP couaterptrt to related L.S. Appl. No. i3i4ti7,289) with English tlanslation. Mar. 26. 2010 Subrnission of References in JP 2006-520594 (JP cotmterprt to rcl:rtetl Li.S. Ap1. No. 13i487,289) with English transltionApr 12, 201 Ollce Action in JP 2006-520594 (JP counterpart to rclatcd L;.S. Appl. N. 13/487,289) rvith English tr:mslation. Alciba et al., "Six-Month Reprted C)ral Toxicilv Study of NK-i04 ir Rats." The.lournal o1'Toxicological Sciences, vol. 23. Supplement!', i t3-'720. t998. Aug. 26, 2004 Iternationl Search Reporl in EP 2004-7Qi237 (EP counterpart to present application). Mm. 14, 2006 Offce Action inEP 204-707232 (EP counterpil{ to plesent application). Dec. 14, 2006 Thir<l Party Submission in IP 2004-707232 (IP corurterprt 1o present application).

4,'1991 Fuiikawaet al. .............

546i

5,284,953 A { rl? o?o 5,473,075 A


5.5 14,804

l0l
Prmary Examrer

1994 Ohara et

(Continued)

1.

5,856,336

5,872,t3t
5,939,552 6,335,449 6.528.661 6,815.8:8 7,37 r.865 2002!0099224 2003,'0 I 05159 2004'006i96.t
200510130978

4i t995 Tkahashi et al 12,i1995 Ohaa ct al. 5'1996 Ohua et al. v 1.999 Ftjikawa et l ............. -s l4l3 I t 2i 1999 Ftjikawa et al .............514t311
811999 Ikeda et
1.

(74) .4narnv;,-.

-D M or Firm Agen,
Seaman

McClelland, Maier

& Neustadt. L.L.P. -Oblon.


.,{BSTR|CT

Spivatri,

A
B1

(57)

tsz B2 A1

ti 2002 Ohara et al, 3i2003 Nidcla.rn et al. 12i2004 Clen et al.


512008

Acernoglu et al.

;\1

2003i 02i3001 A1

7i2402 Niddan et al. 6i2003 Van Der Schaafet al. t2!2003 Storz
4t'2004 Van Der Schaf'et al. 6i2005 Yul et l912012 Ohara et al.

The prcscnt invcntion is dircctecl to nera.' crystallite fonns of Pitavastatin hemicalcium salt, refned to hereinafter as polymorphic ForrnsA, B, C, D, E and F. s well as the amorphons fonn. Furtlrermore, the present inventior is directecl to processes ftir lhe preparation of these crystalline lorms and the

AI
A1

anorphous ltrrm md pharmacenticai compositions comprising these clvstalline fr:nns or the arnorphor.rs loms.
39 Clairns, 9

20120245204

AI

Drawing Sheets

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 44 of 61

us
(s6) References Cited

8,557,993 B2
Page 2

OTHER PUBL]CATIONS Aug. 11. 2008 Tld Party Submssion tn EP 2004-i01232 (EP
counterprt to present application). Feb. 17, 20 l0 O1ce Action in EP 2004J0"1212 (EP coulterpat to prcsent application). Sep. 29, 20 l0 Third Party Submission in EP 2004-707232 (EP counterprt to present application). Ja. 25, 2011 Office Acton inEP 2004-707232 (EP counterptut to present application). .Iul. I 5. 2005 International Search Report in EP 2004-8C7807 {EP counterpart to related U.S. Arrl. No. 13i48'1.289). Sorbera et a1.. "NK-104: llypolipidemic iIMG-CoA Reductase lnlibtor," Drugs ofthe Future 1998.23(8). pp. 847-859. rov. 14. 20C15 Intemtional Prelirninary Rerqd Patentability in

Ogta, How to Ope.te Chemicl Experirnent, vol. 1. 1963, pp. 154-155. 185- 199 (Feb 5, 2013 Office .A,ction n JP 201 l -260984). Dec. 10, 2012 Subrission of References in JP 2006-501997 (JP counterprt to prcsent application) wth English tlanslation. i'r-ov. 6.2012 Subrnission ofRetrences in JP 2006-520594 (JP coLrrterpat to elated U.S. Appl. No. l387,289), with English hanslation. "-\{edical Supplies lntervieu. Fbnn: HMG-CoA reductse inlibitor designated dmgs LIVALO Tblet 1 mg and LMLO Tablet 2 rng," Japanese Society ofHospitl Pharmacists. Sep. 2003. with English
tanslati on.

EP 2004-80'7807 (EP counterpart to related Li.S. Apl. No.


l:i487,289).
Jzn. 19,2007 Oilce Action in EP 2004-t07807 (EP counterpart to elted U.S. AFpl. lio. 13!487,289J. Apr.4. 2008 011ce Action in EP 2004-S07807 (EP counterpart to related U.S. Appl. No. 13i487,289). Aug. 2. 2010 ()fce Action in EP 2004-80?807 (EP counterpart to related U.S. ;\ppl. ),Io. 13,'487.289 l. Sep. 29, 2010 Thinl Pally Subrnission i EP 2004-80780? (EP corurterpa:f to related Li.S. Appl. \o. 13i487.289). Feb. 8.2011 Office Action in EP 2004-807807 (EP counterpart to rclated U.S. Arpl. \o. 13.'487,289). Apr. I 1. 201 I Third Party Submssion in EP 2004-807807 (EP cornter?rt to elted lLS. Appl. ).Io. 13,487.289). Bym et al,, Solid Staie Chenistry ofDrugs, 2d ed,. SS(il. Inc., 1998, pp. 59-64. The United Sttes Pharmacopeia20 l i. The National Folnulary, USP 34 NF29. vol. 1. Brittair. Polymorphism in Phamaceutical Solids, 2c1 ed., Informa Healtlrcare US;\, 1999 , 2009. Berge et al., "Phannaceutical Salts," Journal ofPhannaceutical Sciences, vol. 66, No. I, Jn. 1977 . pp. I to 18. Takhashi et al., "Synthesis of an Adifrcil HMG-CoA Reductse idlibitor NK-104 vi a Hytlrosilylatior-Cross-floupling Reaction," Bull. Chcrn. Soc. Jpn.. 68, 2649-2656 (1995). Miyachi et al., ";\ Novel Synthetic Method of FIMG-Co Rednctase Inhibitor NK-I04 Via a Hy<lroboration-Cross Couplng Sequence." Tetrahcdron Lctters, vol. 34. i-o. 51, pp. 8267-8270, 1993. Bhattacharya, et 1., "Thennoirnalytical and Crystallographic N,fethods." Polyrnorphisrn in Pharmceutical Solicls, Brittai H. ed..2ded., lnform Helticare USA. Inc..2009. pp. 318-315. Ivanisevic, ei a[., "Uses o[X-Ray Powder Di11iction in the Phumaceutical Industry," Pham. Form. Qual., 2011, pp, 30-33. Evaluation Reports fbr Approval fi:r Prcscription Dmg: Pitavastrtin Calcium, LIV'ALO tablet I mg. LI\ALO tablet 2 mg, http:llwww. info.prnda.go.jpi. made public Sep. 10, 2003, wiih pa:tial English tlarsltion. Feb. 5, 2013 Ollce Actio in JP 20i1-260984 (JP counterpzut to relatetl LI.S. Appl. No. 13i487,289). with pafial English translation.

Aug. 19, 2010 Subrnission of Refeences in .IP 2006-501997 (JP corrnterpart to present application) with partial English trmslation. Nlu. 8. 2011 Office Action i JP 2006-501997 (JP counterpart to plesent application) lvith English trmslation. 26,20ll Subrnission of Retrences in JP 2006-50199? (JP counterpalt to present application). Sep. 30. 2010 Submission of Reliences in JP 2006-520594 (JP counterpilt to lelatetl il.S. Appl. No. 131487,289), with pmtial English tla.nslation. Introrctory Chemistry Colrse 2. Physical Chemistry, pp. 321-341, ALrg. 28, 1997 (Sep. 30, 20 t I Subrnission ofRetrences in JP 2006-

\pl

52tJ594).

Apr. 26. 2011 Submission of Relences n JP 2006-520-594 (JP counterpart to relatetl U.S. Appl. No. 131487.289), rvith partial
English translation. Japarese Phalmacopoeia, Foudeenth Edition, pp. 49-51 v1ar. 30. 201 1 (,\pr: 26. 201 1 Submission of Relences in JP 2006-520594). Mar. 27. 2012 Ofce Action in JP 2006--520594 (JP cornterpart to rclatetl Li.S. Appl. No. 131487,289). with English taslation. Information O11r Form dispatched Apr. 6. 20 l0 in Japanese Patent Applcation No. 2006-5001997 (with English-language translaton). Iformatio ()r Forrn dispatchcd Fcb. 23. 2010 in Japesc Ptcnt ,\pplication No. 2006 -50 1997 (rvith English-language translation). Infonnation Ofi'el Foln <lispatched Apr. 2i .20fi in Japarese Ptent Appfication {o. 2006-501997 (rvith EngtishJanguge translation). Official ction dispatched Jun. 29. 20 l0 in Japanese Patent,,\pplication No. 2006-50i997 (u'ith English-language tra.nslaliol). Nl. Suzrki et al. First Systetntic Chiral Syntheses ofTwo Pairs of Enantiornes witl 3,S-Dihydroxyheptenoic Acid Chi, Associated r,vith Potent Synthetic Statin NK-104. Borgonc ,k Metlicinal Ch e m isrrl.' Lettet's, 9. (1 999), 29ii -298). Tlird Palty Obseryation Sublnitted on Aug. 21, 2010 in JP 2006501977 (including excerpt tioin.IP-A-2005-520814). English Languagc Transltion ofAug. 21. 2010 Thiid Partv Observarion submitted in JP 2006-501977 (includig excerpr fiom wo 0-/064932, which is a counterpart to .fP-A-2005-520814). Suzuki. Mikio. Development Wolk fol' HMG-CoA Reductase Inhibitor NK- 104, (200 t ), (partial English translation attached). Certificte tirr Libraty }laterial stored in the National Diet Librar-r, Devcloprnent Work for HI\4G-CoA Reduciase Inhibitor NK-104. Published (2001) lblume Heisei-13, Chief Librr'iar of Kmsai-kan ofNational Diet Library, KazuytlkiYamaguchi (partial English tlanslation attached).

cited by examier

Case 1:14-cv-02760-UA Document 2

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(IRYS:4LI,INXI FORMS Ot' Pl

l2

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9,557,993 82
polymorphism. Polymorphism is commonly delined as the abiiity of any substance to have two or more diflrent crystal

CAL{:IUM

I:'{VAS'|,{l'tN

cRossREFERENCEST'RELATED,*i!i;,"?:ijffitrJ.*:3:1iffi.j,:::
APPLIC.{TIONS
-s referred to as pseudopolynorphs. It is also possible that the
amorphous form

li"r" can appreciably i'flueuce phmiace'tical prt-rperties I,) suchasclissoiitionrzifearbioa'ailabilitv. filectonDec.9.2008.nowabandoned;whichisacontinuation ... ltisalsoec.nomi_ paterrt of U.S. application Ser. No. 1o/544.752, filed onAug;;;i;,h;;h;;r"d;;l;;i"i" r". 8' 2005' u.w aband.ned; rvhich was a 371 of nter'ati.tral ""llt ".,r"Jp";;, ihe ft,r specialized storage concritions. It PatentApplicationNo.PCT1EP2004n5OA66.filcdonFeb.2.,_-_; . "'".'. 'eea "irr-";itd;, " to evaluate pollmorpbism of dmg subparent 2004, and claims priority to European application. stances ::l::::ti.:jfl-*nt Frrthemore.thediscoveryofnew-crystalli.nepoly034050B0.7,filedonFeL. 12.2a3.altofwhichareinco.'' - r-t rnorphic fbrms of a dmg enlarge the repertoire of materals raled herein by refrence in their entiretie.. The preseni invention is directed to new crystalline itrms that a fomtllation scierist has with rvhich to design a phar'vith a largeted relese anci the amorplrous f'orm of Pitavastatin calcirun, processes maceutical dtrsl8e. lbnn of a dru-9 for the prepartion thereofand phamtacctical compositions profilc^or other desired characteristics. Wt now liave surpris29 ngly found novel crystalline forms of Pitavastatin c.lcirun. compriiing these f'orms. TLrepreJentinenlionrelatestonewcrystallinel-onnsad herein.designateds fomr A, B, C, D, E aud F, and tlre anorphons fomr,of Pitavastali calciurn. the amrphous 1mr of pitavastatin calcium. pitavastatin js also kruwln by the names NK-104, Itavastatin and Nisvasta- Accordingly', the-presed inventiou is dires-ted to the pol,vtin. Pitavastaih calcium is knorvn by the chemical arne: nt-orPhic Folms .{.. P, C, D, E ald F, and the arnorphous fonu 2-5 ofPitavasTatin clcium salt (2:1)' (3R.5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoli'-3-y'll3,S-ait,aro*y--O1j-hepienoic acid tremiclcim salt. piiav- -^9ry:!j::, of the invention is a crystalline polyrnorph of (3R,5s)-7-[2-cyclopropyl-4-(4-flr.rorophen'1) quinolin-3astatin calcium has the following fonula: yll-3,5-clihydroxy-6(E)Jreptenoic acid henicalciun salt. herein designafed as Form A, which exhbits a characteristic 36 X-ray powder <fiflraction pattern with ciraracteristic peaks expressed in d-values (,{) arrd in 20 as given in Table 1 (vs:very strong intensit),. s=strong intensity. m:rneclium irtensity', rv:weak intensity, vry:very weak intensity).
continuation of U.S. patent applicatiou Ser. No. 12/331,086,
f

Tris application is a continuation of U.S. patent applica- pseuopolymorphs or the arnorphous form differ in teir tion Scr. No. 13i280.431, filcd oct. 25,2011, which is a pnyri"ot jr.rp"iri.r such as rneting point. solubiliry erc.

is

clcountered. Differcnt polyrnorphs,

35

TA.BI,F,

d-ccins<.n.1 , nslqs l'or Form A. d-spacirg [] 40


17.6
t-1.0

Angle

[20]

Rel. Irtensitv
s

-J_0

9.7 8.8

6.8 9.1 Ir,l.0 10.5

s
s Ill

Pitavasfatin calcium has recently been developed as a nelv

8.4
8.1

chemically synthesized and powertrl statin by Kowa Company Ltd. Japan. On the basis ofreported data, the potency of Pitavastatin is dose-dependent ald appears to be equivalent to that ofAtorvastatin. This ncw statin is safc and well toleraied in the treatment ofpatietts with hypercholesterolaemia. Sigliflcan interactions with a nuluber of otlrer commonly used

11.0
13.3

It
s

+s

6.7 6.5
6.-3

13;l
1.1.0

6.0
5.5
t-

14.7

15.9
16.9

5.2,i

drugs can be considered to be extremely so Processes ltrr the preparation ofPitavastatin are described in EP-A-0304063 and EP-A-1099694 ancl in tliepublications by N. Miyachi et al. in Tetahedror Letters (1993) vol. 34, pages 8267-8270 and by K. Takahashi et al. in Bull. Chem.

low.

5.i7
4.82

4.64 4.27
4.20 4.1

t7.1 18.4 19.r 20.8

I1.1
21.6
?2-t)

3.74 23.7 trt 68,2649-2656. Tlese publications ss 3.6' s describe the synthesis ofPitavastatin in great detail but do not ,.) 1 25.2 clescribe the hemicalciurn salt of Pitavasratin. The publica...39 2'7.1 lu tiors b;, L.A. Sorbera et al. in Dnrgs of the Future (1998) voli.02 29.6 2.95 3i.2 23. pages 847-859 and by M. Suzuki et al. in Bioorganic & 2.63 34-Cl Medicinal Clrenistry Letters (i999) vol.9, pages 2977-2982 60 describe Pitavastatir calcium, however. a precise procedure for its prepamtion is not given. A hrll sytthetic procedure nother object of the inventiou is a cryslalline polyrnorph tire preparation ofPitavastatin calciurn is describecl in of (3R,5S)-7-i2-cyclopropyl-4-(4-luorphenyl)quinolin-i0520406.In the process described in t1s patent Pitavastatin yll-3,5-dihydroxy-6(E)-heptenoic acid iremicalium salr, calcium is obtailed byprecipitation &ornanaqr:eous solution os herein designated as Form B, which exfiibits a cfiaracteristic asaw'hitect-vstallinematerialwithameltingpointof 190-192 X-ray pow'der clifraction patteru with cluracteristic peaks C. It is krown that pharmaceutical substances can expressed in d-values () aud in 20 as given in Table J.

Soc. Jpn. (1995)

vol.

m tl

lor EP-A-

exhibit

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 55 of 61

us
3 .IABLE2
d-suirgs ard ?0

8,557,993 82
4
l AIlt
.Fr 4

uels

fb Fom B.
Rel. Intensity
_s

d-spiles
d-specng
17.-s

ad

20 areles for

Fort

D.

d-spcjg Il
19.0 16.6
14.2 l 1.5

Axgle

[20]

[]

.tuigle

[20]

Rel. Itrtersiry

4.6
5.3 6.2 7.7

5.
6..t

Itl
m
s

t-3.5

13.0
s

6.8 8.7
10.{)
1{,r.2

9.6 9.2
8._s

9-2
9.6

n
m 10

r0.l
8.8 8.6 8.2 6.8 6.,i5 6-2i) 5.78 5.52 5.28

m
D

1rl.i
1

w
m

t
m

1.4 7.6
7.1)

1.3

10.8 13.1 13.5 14.3 15.3 16.1

1t.1
12.6
13.()

m
s

6.8 6.4
6,O

5.94 5.
,s.43

13.9 14.7 14.9


15_

1-5

i6.8
18.2 18.5

4.8i
u1

I 6.3

5.22
5.f-r

t7.o
11.4 18.0 I 8.7

4.92 4.74 4.59

20 nt m
s
III

4.80 4.66 4.46 4.34


4.23
4.()()

m
tn l1 s

19.
19.9

2.5

2r.0

t9.3
2t-)-0

2t.7
22.3

20.5 4.26 4.19

2.8
21.2 21.5 23.2 23.6

shoulds nl
m
s

25

3.99 3.80 3.70


3.4'7 3.4t.t

4.ti
3.9i
3.83 3.73 3.64 3.53

23.4 24.0 25.6


26.2

tn

nl
lod

24.4
?5.2 26.0 26.4

30

i.42 3.3i
l. l9
3.09

2't.o
2-.9 28.9

^ 35

.Another object of tle invention is a crystalline poiymorpl (3 R,5 S)-7-[2-cyclopropyl-4-(4-fluorophenyl)crinolin-3 yll-3,5-dihydroxy-6(E)-heptenoic acid hemcalcium salt, herein desipnate<l as Form E, whch exhibits a characteristic X-ray powder diffraction patteru with characteristic peaks expressed in d-values () an<l in 20 as given in'l'ahte 5.

of

Another object of the invention is a crystalline polymorph

'ti\Br,H
d-spaciugs

of' (3R,5S)-7-[2-cycloprcpyl-4-(4-lluorophenyl)quiuolin-3yll-3,5-diltydroxy-6(E)-heptenoic

acid hemicalciun

salt,
40

ud

20 arsles fo For E.

herein desiguated as Forn C, which exhibits a chaacteristic X-ray powdcr diffraction paftern with characterisTic peaks cxprcsscd iu d-vahrcs () and in 20 as givcl in Tablc 3.

d-spuchg [,{] 20.0

Argle

l20l

Rel. Intensily

t].7

4.4 5.0
6- 6.8 8.9
1f1.0

s s s s

TABLE 3
d-mruiuss d-spaciry []

13.4
13.1

ud

20

urel* lbr Fcrnr (',

45

Argle

[20]

Rel. Inlensity

2t.6
1_s.9

4.I
5.6 7.8 8.3

m m m
m

10.0 8.8 8.6 8.2 6.6 6.5

m
s

t0.:
1r).8 13.6 14.0
1.5.2

tl
s

m
S

1t.4
t0-
8.6 7.7 5.06 4.95 4.14
4.5_5 1
1

6.i
50
5.84 5.56
5.-39

l0.l
1.6

1i.9
16.4

7.5

16.9

t8-7
19.5 2.6
21._5

ft
s

4.99 4.84 4.69


4.39

17.8 18.3 18.9

ll
vs

4.31 4.13
4.t16

m
m

4.34
4.3()

20.2 20.4
2(t--! 2t)-9

2t.9
23.t
24.Q
2.4.&

i.84
3.58

m
60

4.24
4.12

m
\rs

2l.l
21.6
21.7 22.3

4.08
3.99 3.77
f .7,7

m n m

(3R,55)-7-[2-cyclopropyi-4-(4-luorophenyl)quinolin-3yll-3.5-drydroxy-6(E)-heptenoic acid hemicalcium salt. herein designated as Fc-nn D, u'hich ex.hibits a characteristic X-ray powder diJfraction patten with characteristic peaks (pressed in d-values (.4.) and in 20 as given in able 4.

of

Anothe object of the iuvention is a crystalline polymorph

i.69
3.60

23.5 13.8 )4.1 25.4 26.6

It
m

os

.i.,i0
3.35

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 56 of 61

us
f
]:A.fll,f-l 5-coutinned
d-spcies

8,557,993 B2
6
h'urthermore, the presenl invention is directed to prlcesses f'or tlre preraration of Fonn A, B, C, D, E and E and the

amorphous l:rm of Pitavastatin calciruu. Form A can be generall,v prepared from Ptavastatil d-spachg [.4.] Rel. Intensity .\le [20] sodiuru upor reaction lvith CaCl, in an aqueous reaction mediun. Altematively, Form A of the invention may also be 2.96 -1i).2 2-64 34.1) obtained ir siru f'rornthe free acid ((3R.5S)-7-[2-cyclopropyl4-(4-fl uorophenyl)qui nol in-3 -5,11 -3.5 -dihydrox,'-6(Elheptenoic acid) or the correspotding lactone with Ca(OH)r, Another object of the inventitn is crystalline polyrrlorph advanlageously also an aqueous reactiou mediitrlt. The t0 (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-]of aqueous rcaction nedirun usually coutaits at least 80% b.w. yll-3,5-dihy<lroxy-6(E)heptenoic cid hemicalcium sa1t. of .*'ater; preferably it is water or \rater containing rninor hereiu clesignated as Fomr F, which exiribits a characteristic amounts of soivents andlor ectants from previous steps. X-ruy pow<ler dill-raction patteru with characteristic peaks Fbrm A may contain up to 1570 rvater. prelerably abonl 3 to 1270. more preferably 9 to I l7o olrvater. expressed in d-vahres (,&) and iu 20 as given irr Table 6. I Form B can be generally prepared by suspending fomA in ethanol containing water as a co solvenf . The amouli oflvater T,A.BLE 6 is preferably about 1 to 50%. d-mcins rnri 2e nsle.s lr Fom Fonn C can be generally prepared b' suspending formA in isopropanol contailting water s a co solveut. The amount of d-spacing ll Argle [20] Rel, lntensity 20 water is preferably about 1 to 50%. especially I to 209 and more prefembly about 5%. Fonn C can also be prepared fiom 11.2 .5.1 n 15.8 5.6 a mixture of isopropanol and a ketone solveut. contairritlg 12.6 7 -t) s \r'ater as a co solvent. Preferably, the ketone solveut is t0.0 trt 8.8 acetone, nd the amtunt ofketone solvent are bont 1 to 30%, 9.2 9.6 s 2.5 lnore preferably about i0?. The amount of water is prefr8.7 1t).2 8.1 10.9 ably about I to 20Vo, more preferably about 59'o. 7.8 1 1.3 Form D can be gener:lly prepared by suspending fonnA in 7.4 1 t.9 m absolute ethanol. 7.1 12.5 [1 Form E can be generlly preparecl b;r suspending firmrA in 6.8 s l_.0 6.5 13.7 30 i,4-clioxne containing water as a co solvent. The arnount of s 6.2 t4.4 water is prelerably about I to 50%o. 8.04 14.7 Il Form F car be genemlly prepared by suspending f'orm A in 5.79 i 5.3 methanol coltaining water as a co solvent. The amorurt of 5.70 l 5.5 5.28 6.8 m water is prelrably about I to 507o. 5.0:l 17.6 In{he above aentioned processes srnll amonts ofseed4.85 1 8..1 m ing crystals of the desired crystalline lirrm may be added to 4.61 ltl 19.3 the reaction mixture. Preferably small amounts are about I to 4.51 19.7 t 20.6 trt 20 weiglrt 7, more preferably ab 5 weiglrt %. Seeding vs 4.18 21.2 crystals nlay be added belore or, where appropriate, aller the 4.08 2 1.8 s 40 step initiating the crystallization (e. g. cool'ing, acldition of 3.90 22.8 s notl-solvcnT etc. as dcscribcd abovc). Aclditiou beforc ilitiat3.84 shoulder 3.74 23.8 ing the crystallization is ofspecific technicl interest. 3.69 24.t 5 The amorpirous form can be generally prepared by addition s 24.8 -3..s9 01 a tlon-so1velrt te a corcentrated solution of Pitavastatir 3.46 25.7 m +s calciun in an organic solvent. As non-solvent may be taken 3.40 26.2 3..i5 26-6 m lbr example heplne or nethyl tert-butyl ether, whereas 26.9 exzunples for the orgulic solvcnt re 1,4-dioxmc, tetmhydro3.14 28.4 rrau and etlryl metl ketore. I1 is preferable that the ron3.02 29.5 solvent arrd solvent are miscible. The arnorphous t'rrn cur 3.00 29.8 2.89 3.9 m 50 lso be prepared by lyophilization ofan aqueous solution of Pitavastatin calcium. Preparations of polyrnorphic 1'om1s A. B, C, D. E. F as well Small changes in the experirnentl details can cause small as the amorphr)us fbnn are usually done in substantially pure deviation inthe d-vaues and 20 ofcharacteristic peaks in the reaction syslems. essentially coruisting ofthe educt specified, X-ray porvder diftiaction pattems. 5j preferably iu substantially crystalline form. and solvents and./ Another object of the invention is the amorphous form of or utn-solvents as given above. (3R, 5S) -7- [2-cyclopropyl-4-(4-fl uorophenyl)quinolin-3 -yl],Anoflrer object ofthe present inverrton are processes lbr 3,5 -dihydrox.v-6(E)-heptenoic aci<1 heruicalcium slt vl'hich the preparation of crystalline forms of Pitavastatin calcium cxhibits charactcistic X-ray powder diffraction pattems as essentially free ofresidual orgadc solvent. depicted in 60 Particularly. the present invention is related to processes Powder X-ray dilTraction is perlirmred on a Philips l7l0 for the preparation of crystallile fonus of Pitavastatin calpowder X-ray diractometer using Cu k (c1) radiation ciutn essenlially l-ree olresiclual organic solveut by exposing (1.54060 ;: 20 angles are recorded with an experurental the crystalline fbnn ofPitavastatin calciuur to an atmosphere rvith a delined reltive air humidiry. More particularly'. the error of :0. 1-0.2". A discussitn ofthe theory of X-ray powder difTraction pattems can be found in "X-ray difliaction proce- os present invention is directed lo a process I'or thepreparationo f dures"by H. P. Klug and L. E.Alexande.1. Wile.v, NewYcrrk any crystalline fonl or arrotphous f'om of Pitavastatin cal(1e74). cirun which is essentially fee of residual organi solvent.
20 meles f'or Fomr E.

ud

il

35

FIG.7.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 57 of 61

novel ftrnns k) prepre such solutious is cousidereci to be within the coemplatit-rn of the invenliol. Capsule dosages, of course. will contain the solid conpositionwilhinacapsulewhichmaybemadeol'gelatinorother conventional encapsulatilg rrlaterial. Tablets and powders may be coated. Tablets and powdens may be coaled with an 807o, is used. enteric coating. The enteric coated powder fonus may have Antlther obiect o I the present inveution are phannaceutical coatings cornprising phlhalic acid cellulose acetate, hy<lroxcompositions comprising an effective amount of crystalline . ypropylmethr1-cellulose phthalate, polyvinyl alcohol phtha^ polyrnorphic lornr , Fl, C, l), , or F or the amorphous fonn tu late. carboxymethylettrylcellulose, a copolymer ol styrene of Pitavastatin calcium, and a phannaceuticai acceptable car- and maleic acid a copolymer of rnethacrylic acid and urethyl

'lesecan, tbrexample,bepreparedbyexposingthecryslallinei-onnoramo4)hous formtoanatmospherewitha relative air hunidity of 5 to 100%. Preferably, these are preparecl by exposure to an inert gas stren with a defied relative air hundiry- to exchange residual orgarc solveut witir w'ater. In -s gencral, a rclativc ai humidity of 5 to i00%, espccially 40 to

78

us

8,557,993 B2

rier.

These polylrorphic fomrs may be used as single nent or as rnixtures with other crysta.lline fonns or the

phous As to the novel polyrnorphic forms and amorphous fonn Pitavrstalitr caloitm is prelrre<l lhat these 25-l0yo by rveigfrt, especially 50-100% by rveight. of least onc ol the novel llrms, based on the total allounf of Pita\,astatin calciurn. Preferably', such an amount of the pt'rlymorplc fortns or arnorphous folu of Pitavastatin cium is 75-i009zo by rveight. especially 9}-l00yo by

fbm.

conrpoamor- , ,

it

of contain at

least one of the novel f'or:ms. In addition, the compositions that are contemplated by the present invelrtion mar ilclude dilueuts. such as cellulose-derived naterials like cellulose. rnethyl celhrlose. ethvl cellulose, hydroxyethyl
Iose. carboxymetI, cellulose salts and other substituted uns*bsr.irrrre<1 cell.loses; slarch: pregelatnir"a *ror"tr,

nolel cal- al.ly, the combited weight olthe weight. Pitavastatin calcium ltrrms ofa unit dosagcare from 2.5 mg HighJyprefrredisanamountof 95-100%byweiglrt. ro80rng, fcrrexarnple 5, l0,20or40rng. The compositions ofthe iuvention include pow-ders, gfamr- 2-i The i'ollwing Examples illstrate th invetion in ruore lates. aggregates and olher soiid compositiols comprising at detail. Terlperat'res are given i' degrees Celsi.s. rrther celL{NIpLE I
Preparation ofForm

methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coatecl t:rblet may have a coating on the surlce of the tablet or may be a tablet comprising a porvder or granules wilh an enteric-coating. Prelerredunitdosagesofthephamraceuticalcornpositions ofthis invention pically contain from 0.5 to 100 rug ofthe zo novel Pitavastalin calcium lrrms or mixtures thereof with each other or other forms of Pitavasatiu calcium. IVIore usu-

powdered cellulose, incrocrystalline cellulose. microfne o

and .-.,,.-^;,_-, _.,- ; acid tert-buryl i,i, :"lt-]..1]l:l'5-dihydroxy-6(E)-hepteuoic ester) was suspendecl in 52 ml oi ga-uic dil.e'rs like calciun carb.nre and catcium aiffi- :i - :Ylll1i1t]:lTlrert-butvl phareandotherdiluentsknowntothepharmaceuti"oliirJur11"i**ofmethyltett-butyletlrerandmethanol(10:3)'To this nlixtLrcrvcrc addcd 2 lT rnl ofa 4M aqueous solutir:n of try. yet other suitable cliluents inclue w.axes, ,ugur* ooa NaoFI' and.theresr-rlting 1'ellox'ish sohtion was stirred for2.5 srigar alcohols like mamitol and sor.bitol. acrylate pioty-"i, hours at 50' (1. '['he reaction nrixture rvas cooled to room an copoly'rers. as well s pectin. dextrin aud gelaln.
Furtieiexcipienrsthatarrvithinrhecontemflationolrhe 40 te]nleralirre followed by the addition of 50 ml water aod
preselt inventit inclucle binclcrs, such as acaci gum, latinized starch, sodiuur algrate, glncose and other binders used wet ancl dry granulatou alrd direct complession tableting processes. Excipients that also mery be preselt in so.lid cornpositioru further include disirrtegrarts like sodium +i starch glycolat. crospoviclone, low-sitbstituted hydroxypropyl cellulose ald others. In aciclition, excipicts may tableting lubricants like magnesium and calciutu stearate soditlrn slearvl fumarate; flavoringsl sweetenersi preselyativesl pharmaceutically acceptable dyes anclglidants such as 50 silicon dioxide.

lulose,hvdroxypropylcellulose,hydroxypropyknedrylcellu- 4.15 gr of (3R,5s)-7_[2-cycloprop.1-4-(4-fl'orophe'yl) -

prcgcfhe

ir

include ancl

Theclosagesincludedosagessuitableltrroral,buccal,rectal, parenteral (including subcutaneous, intrzrnuscular,

intravenous), inhalant and ophthalmic admjnistration. ,AJthougir the rnost suitable ronte in any g.iven case will ss depend on the nature and swerity of the conditiou being treted. the most prefrred route ofthe present invention is oral. The dosages may be conveniently preseted in unit
dosage form and prepared by any of the ruellrods in the art of I)osage t'omrs include solid dosage frnns, like powderu. capsules. srtppositories, sachels, troches an<l

and

stirring for an additional hour The aqueous phase was sepratecl and ouce extracted,uvith 20 ml ofmethyl tert-butyl ether. To this aqueous solution were added a solution of 0.58 gr CaCl, in 80 ml of w-atcr ovcr a periocl of I hoLr. Thc resu.lting suspension was stirred for about 16 hous at rooru temperanue. The suspension was filteed and the obtahed solid was died at 40'C. and 50 mbar 1-or abont 16 hors. The obtained prodrict is crystal F orm ,,\ which is characteriz-e<l by an X-ray potvder diffraction pattem as shorvn in FIG. l. Further chaiacterizatio of the obtained Fonn A by thennogravimetry coupled with FT-IR spectroscopy revealed a r.vater content of about 107o. Differential scanning calorimetry revealed a

reltigpointof95"C.
EXAIV{PLE 2 Preparation ofForm B

phamracy.

wel.l-larown the also

ges as well as liquid suspensions arxl elixirs. While description is not intended to be liruiting. the invention is

100 mg Pitavastatin calciuur FormA was suspeuded in 2 ml 60 rvaterandstirredatrt-orn temperaturefor-3Oruin, lollowedby tablets, the addition of 2 n'r.l of ethanol and additional stinilg for lB krsen- hours.'[he suspension lvas tiltered and <lried in a'ir, vielding

36 mg of Fomr B. The obtained crystal Form B is character, ized by an X-ray porvder diffraction pattem as showu in FIG.

notirtendedtopertaintotnesolutionsol'Pitavastatincall- e:2.FurtherchaacterizationoftheobtainedFormBbythercinm rvhereupon the properties that distinguish tlre solid nogravirnetry coupled with FT-IR spectroscopy revealed a fomrsoTPitavastatincalcirunarelost.However,theuseofthe lvatercontentofabout 10olo.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 58 of 61

us
9
;XAMPI,F):]
Preparation of Fomr C

8,557,993 82

l0
solitldried in air.'lheobtainedcrystal Fbnn F is characterized b' an X-ray powder diffraction pattem as showr in FIG. 6.
EXAIVIPLE 8

62 rng Pitavastatin calciurn Fom A was suspended in 2 m1 isopropanol contailing 59lo water. This suspension lvas heated to 60o C., which led to almost cornplete dissolution oT Ftirm,,\, and again cooled to K)oln lemperture. At this temperature t1 suspension rvas stirred for 66 hous. The esulting suspensiur rvas ['iltere<i, once washed with some isopro-

Preparation of the Amorphous Form


62 mg of Pitavasfatin calcium FonnA was dissolved in 0.3 ml I,4-dir-rxane. To this stirred solution ras slowly added 2.3 ro rl n-heptane at roorn temperature, aud stired for an additional 16 hours. The resulting suspersiou was filtered and

panol contailing SYo water. and dried in air. The obtained crystal Fom C is chaacterized by an X-ray powder diftraction pattern as shown in FIG. 3. Further characterization of the obtailed Fonu C by thermograviruetry coupled with FTIR spectroscopy revealed that tlre sarnple contains about 6.37o isopropanol and a snall arnount ofwater.

driecl in air. 'Ihe obtained solid lvas amorphous as is shorvn by fhe X-ray diffraction pattem givcu in FIG. 7 (top).

r-s

,XAIVIPL; t)

Preparation of the,{morph,rus Fonn

EXAMPLE

preparation of Fo,'r

'
a r.vith firr

60 mg of Pitavastatin calcium

FornA as dissolved in i.5

i'1":'']i:iliffJ5'.li;l'.'*:i,ift';'i:f::'";j
resulting snspensiou was stirred at rt'lom ternperarure f'or

65 rng Pitavastatin calcium Form A was suspendecl in a about 1 6 hours. The suspension was ltered and the obtained mixtureofO.9mlisopropanol,0.lmlacetoneald4Oplwater. solid rvas dried in air. Arr X-mv difliaction study on the Stirring this suspension fo about I hour 1ed to uearly com- 2-s product slowed it to be aruorphous, see FIG. 7 (bottom). plete dissolution. Seecling with 4 mg of Form C (from l'urlhercharacterizatitrof theobtainedpnrductbythernoex:unplc 3) and stirring for 2 lrours lcd to thc fomration of concentrated snspension. This snspension was diluted the same amount of solvert lnixfure as above and stirred an additioual 40 hours. The suspelsion r,vas lltered and the 30 btained solid rvas rlriecl a1 40u C. ftrr about 10 min. by X-ray powder diffraction indicates the producr to be crystal Form c as shown i FIG'

glavimctry coupled with FT-IR specoscopy revealcd that the sarnple contained about 5.5% methyl tert-butyl etherDifferential scarning calorirney sholved the sample to have a glass transition tenperattre of about 68o C. BRIEF DtrSClp.l.ION OF TIIE DRAWINGS

Analysis

FlG. I is a charcteristic x-ray powder diffraction pattern 35 ibr Form A' FIG. 2 is a characteristic X-ray powder cliffa*iou pattern for Fon ' preparaion ofForm D FIGS. 3A and 3B are two characteristic X-ray powder clifl"action nafterns for Form C. 60 rng of Pitavastatil calcium FormA was suspended in 1 on F'l(i.4 is a chuacteristic X-ray pow-iler dilraction pattem lr]l absolute ethanol and stirred at rLrot temperature f'or 20 fbr Fon' D. horus. The resulting suspensiol rvas llrered and dried in air. FlG. 5 is a chaacteristic X-ray powder difhaction pattem 'lhe obtained crystal Form l) is characleriz.etl by an X-ray for Form E. powder dilfraction pattem as showl in FIG. 4. FIG. 6 is a characteristic X-ray powder diiTracfion patteru

3'

IlxAMpl,r,l

IXAMPLE
Preparation

4t

T,q ,,', ztJ are rwo ctraracrerisric X-ray pow<ter cliffraction patterns for tlrc arnorphous form.

'i-T'iff

olForm E

The inr,'ention claimed s: 1. A crystalline poly-rnorph A, B. C, D, E, F, or the amorruixture of i,4-dioxane and water (l:1), and stirred fo 18 phous f'onn, (3R,5S)-7-[2-cyclopropyl-4-(4-fluohorrs at room tempemtue. The resulting suspension was ropherrye)quinolin-3-ytl -3. 5-dihydroxy-6(E)-lreptenoic acid lltered and dried in air. The obtained crystal Fonn E is charhemicalcirun salt wherein acterized by an X-ray pow<ier dilliacliou patlem as sholvn in A) polymorph A exhibits a characteristic X-ray powder FIG. 5i diflraction pattem with characteristic peaks expressed in 20at5.0(s), 6.8(s), 9.1 (s), 10.0(w), l0.s (m). 11.0(n), EXAMPI,F, T 13.3 (l'w"), 13.7 (s). 14.0 (w). 14.7 (w). 15.9 (vw), 16.9 (w), 17.1 (vw). i8.4 (ru). 19.1 (w), 20.8 (vs).21.1 (m), Preparation ofForm F 21.6 (m). 22.9 (.m).23.7 (m),24.2(s),25.2 (n),27.1 (rn), 60 29.6 (vw). 30.2 (w).34.0 (w); 0 mg of Pitavasttin calcium FonnA wls suspended il 3 B) polymorpir B exhibits a chaacteristic X-ray powder rnl melhanol containing 207o lvater. and stirred at 40" (1. lor I <li llraction pattenl w'ith characteristic peaks expressed iu hour. The resulting suspension was slowly coolecl to roon 20 at 4.6 (w), 5.3 (vs), 6.2 (s),7,7 (s), 9.2 (m). 9.6 (m), temperane and stirring vu'as cottir.ted for 4 hours. The sus10.3 (w), 11.3 (m). li.7 (w). 12.6 (vw), 13.0 (w). 13.9 persion was heated again to 40o C., stirred for 30 min, slowly o: (m). 14.7 (r'w). 14.9 (w), 15.6 (w). 16.3 (ru). 17.0 (vw), cooled to roon temperatule ancl stirred ftrr an additionally 15 17.4 (vrv), 18.0 (w), 18.7 (m), 19.3 (n),20.0 (s),20.5 horus. The suspension was filtered and the obtained w'hite (w), 20.8 (m).21.2 (rv, shoulder). 21.5 (m), 22.4 (nt),
60 mg of Pitavasttirr calcium Form A was suspended in

59

of

5.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 59 of 61

(s),23.ti (m). 24.4 (vw),25.2 (w. broa<l), 26.0 (w), 7. A process tor preparing the cryslalline polymgrph or 26.4 (vw),27.A @),27.9 (vw),28.9 (w); anorphous fonn according to clairn I, whereii: C) polymorph C' exhibits a characteristic X-ray powder the crvstalline polymorph or amorphous form being prediffraciionpattemi.vithcharacteristicpeaksexpressedirr paed is the crystallinepolymorphC; and 20at4.1(n).5.6(s).7.8(m).8.3(m), 10.3tn), 11.6(w), 5 the process comprises suspending the crystalline poly17.5 (w). 17.9 (w),18.7 (m), 19.5 (s),20.6 Qn).21.5 morphAinamixlrucofisopropzurolanclakerouesol(wv)'21 .9 (m)'23.i (m).24.a(rv),24.8(w); vent.containingwarerasacosolveut. D) polymorph I) exhibits a chaacteristic X-ray polvder 8.'Ihe process according to claim ?, lvherein the ketne
2'"1.2

tl

us

9,557,993 82

l2

25.6 (w). 26.2 n); ,,. cium salr. E) polymorph E exhibits a characterisiic X-ray powcler 10. The process accorcling to claim 7, whereir re water is dilTraction pattern wilh characteristic peaks expressed in present ir an amount of I to 20o by volume ofdre snspensiou 26 at 4.4 (vw), 5.0 (s). 6.6 (s), .fl (s), {1.9 (s), 10.0 (rn). ol (3R,5s)-7-[2-cyclopnrpyl-4-(4-liuorophenyl)quinoli-310.3 (s)' 10.8 (m)' 13.3 (s), 13.6 (m), 14.0 (s), 15.2 (vw), yll-3,5-di.ydroxy-6(E)-heptenoic acid hemicalcirun salt. 15.9 (w), 16.4 v), 16.9 (vw), l7.tt (r'w), 1f.3 (m), lll.9 2e 11. A process tbr preparing the crystalline polyrnorph or {tv),24.2 (r's), 20.4 (n),20.1 (rn), 20.9 (ru), 21.1 (vs), arnorphous fom according to clairn I, wherein: 21'6 (m)' 21.7 (n).22.3 (ru). 23.5 (m), 23.8 (n), 24.1 the cr-vstalline polymoph or amorphous lbrm being pre(u')' 24.7 (vw), 25.1 (vw), 26.6 Qu). 30.2 (w).34.0 (r'w): pared is the cr"vstalline polynrorph D: and and the process comprises suspending the crys&rlliue polyF) polymorph F exlbits a characteristic X-ray powder z,s ruorphAitabsoluteetlnnol. dilTractionpattemwithcharacteristicpeaksexpressedin 12. A process l-or preparing the crystalline polymorph or 20 at 5.1 (m), 5.6 (w). 7.0 (s), 8.8 @). 9.6 (s), 10.2 (w), amorplrous f'onu according to claim l, wherein: 10.9(m), 11'3(w), 11.9(rr), 12.5(rr), 13.0(s). 13.7Q:t). thecrystallinepolyrnorphorarnorphousfonnbeingpre11.4 (s), 1.4.7 (n't). 15.3 (vw). 15.5 (w), 16.8 (tr), 17.6 pared is the crystaliine pol,vmorph E; ald (w), 18.3 (m). 19.3 (m). 19,7 (m).20.6 (n),21.2 (vs). :o the process cornprises suspending The crysTalline poly21.8 (s), 22.8 (s.),23.1 (w), 23.8 (w, shoulder). 24.1 (s), morphAil 1,4-dioxanecontainilgwateras acosolvent. 2zl.B (s), 25.7 (iri), 26.2 (vw),26.6 (n, 26.9 (w),28.4 13.Theprocessaccordingtoclaim12.whereinthewreris (rv). 29.5 (w). 29.8 (wv). 30.9 (m); w'herein, 1r each of present in tlre arnount of I to 50% by volune of tire suspensaitl polymorphs, (vs) stands for very st(rng sion of (3R,5s)-7-[2-cyclopropyl-4-(4-fiuorophenyl)quinointenst-; (s) stards firr strong intensity; (rn) stantls f'or :s lin-3-y1l-3,5-dihydroxy-6(E)-heprenoic acid [emicaicium medjum intensity; (w) stands I'or irrensity; (vw) salt. stands for very weak intensitf "veak 14. A process for perparing the crystalline pol'morph or 2. A process ibr preparing the crystalline polyrnorph or amorphous fonn according to claim L rvherein: amorphons l'orm according to claim l, wherein: the cr,vstallile polymorph or amorphous form being pre, the cryslalline polyrnorph or amorplxrus lorm being pre- 40 parecl is the crystalline polymorph : am1 paredisthccrystallhepolyrnorphA;and the proccss cornprises suspending thc crystalline polydre process comprises reacting (3R,5s)-7-[2-cyclopropyl- morph A iu methanol containing water ai a cosolv-ei, 4-(4-lluorophenyl)quiuolin-3-yll -3.5-cliltydroxy-6(E)- 15. Tlre process according to claim l4, wherei the w'ater is hepteloic acid soditun salt vith CaCI2 il ar aqueous presentinanamountof 1 to 50% byvolumeoftlresnspe.nsi reactiou medium. +: of (3R.5S)-7-[2-cyclopropyl-4-(4-fluorophe[yl)quinolin-33. A process t-or prepzring lhe crystalline polymorph or yll-3,5-clihydroxy-6(E)-heptetoic acid heiicalcium salt. aurorphous fonn according to claim l, wherein: l. Thc process according to clailr 2, whcrein (3R,5S)-7the crystalline polymorph or amorphous form being pre- [2-cyciopropyl-4-(4-fluorophenyl)quinolin-3-y1]-3.5-dihypared is the crystalline polymorph B: and clroxy-6(E)-heptenoic acid lremicaicium salt'is isoiated by the process coiuprises suspending the crystalline pol,v- so fiitratiolranddriedinairorvacnum. motphr\ in ethanol containing wTer as a cosolvent. 17. The process accorcling to clajm 2, wherein seeding is 4. The process accorcling to claim 3, wherein the waTer is carriecl r.'rt with crystals of tire desired crystalline polymorph. preseut in an amounl of 1 to 509/o by volume of the suspension 18.4 process preparhg rhe crystalline polymorphor amor-

diffractionpattemwithcharacteristicpeaksexpessedin solvent is acetone. 2flal 5.0(m),6.5(m),6.3(s),8.7(rn). 10.0{m). 10.2(*), t0 9. -lhe process accor<ling to claim 7, wherein the kefone 10.8 (m)' 13.i (w), 13.5 (m), 14.3 (s), 15.3 (v*'), 16.1 solventispreseltinanamotntof 1to30%byvolumeofrhe Qu). 16.8 (w), 18.2 (w). 18,5 (n), 19.0 (w), 19.9 (m), suspersion of (3R.5S)-7-[2-crvclopropyl-4-(4-fluoropheuyl) 20.5(m),21.0(vs),21.7(s),22.3(w1.23.4(m).2a.0@), cluinolin-3-yll-3,5-dihydroxy-6(E)-heptenoic acid henical-

yl]-3'5-dihydroxy-6(E)-hepteroic acicl hemicalcium salt. 55 the crystalline polylrorph or amorphous foru being pre5. A process for preparing the crystallile polvmorpir or pared is the amorphous forml aud amorphous frrut according to claim l, whereil: the prcrcess crurprises adding a nor-solvenT to a solulion of the crystalline polyrnorph or amorphous forru being pre(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quiolipared is the crvsTalline polymorph Ct and 3-yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium the process courprises suspending the crystalline poly- ao salt iu an organic solvent. ruorph A the process comprises suspend.iug the cr,vstal- t9. The process according fo ciaim 18, wherein the nonline polyrnorph in isopropanol containing \i,ter as a solveut s selected l'rom heplane and methyl tert-br-rtyl etfier.
20. The process accordin to clain 18, wirerein the organic solvent is seiecterC fiom l,4-dioxane. tetrahydrofuran aud os ethyl nethyl ketone. (3R,5S)-7-[2-cyciopropyl-4-(4-fluorophenyl)quitolin-3- 21. A prccess tbr preparing the crlstalline polyrnorph or yll-3.5-dihydroxy-6(E)Jteptenoic acid hencalcirun aruorprons fomr according claim l. w[eei:

of

(3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyi)qnolin-3-

phous f'onu according claiin 1, rvherein:

cosolveu.

6. The process according to clairn 5, wherein dte water present in an amotut of I to 5fflo by voltrne ol the suspension

is

ol

salt.

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 60 of 61

13

us

9,557,993 B2

the crystalline polyrnorph or amorplxrus lorm being pared is the amorphous f'orm; the process comprises drying an aqueous solutiol of

intensity. (m) stands lrr medium intensty, (w) stancls trr and rveak iltetsity, anci (l'w) stancls f'or very weak intensily. (3R, 29. A cr5rstalline polymorph C of (3R.5S)-7[2-cyclopro5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- pyl-4-(4-fluorophenyl)quinolin-3-yl] -3,5-dilrydroxy-6(E)yi]-3,5-dihydroxy-6(E)-heptenoic acid hemicalciun s heptenoic acid heinicalcium salt. haviug an X-ray pow'der salt by lyophilization. dilfraction pattern substanlially as depicte<l in tr(iS. 3 an<l

pre-

t4

22. A phamtaceutical composition comprising

nlotutt of the crystallinc polrmorph or zunorphous

23. A crystallitte pol,vmotphA. B, C, D, E, F. or the amorphtins form. ot(3 R,5 S)-7-[2-cyckrpmpyl-4-(4-luorophe- peaksexpressedin20at5.0(m).fr.5(m).6.8(s),8.7(m), 10.0 nyl)quinoliu-3 -y1l-3,5-dihydroxy-6(E)-heptcnoic acid (ru). 10.2 (m), 10.S (m). 13.1 (w), 13.5 (m), 14.3 (s), 15.3 hetuicalcium salt of claim 1, wherein polymorph A has an (vw), 16.1 (n), 16.S (w), 1S.2 (wJ, 18.5 (Ir1), 19.0 (rv). 19.9 X-raypowclerdiftractionpatternsubstalliallyasdepictediu r,s (m),20.5(m).21.0(vs),21.7(s).22.3(w),23.a@),2a.AQrr,, FIG. 1, polymorpli B has an X-ray powder diifraction Fattern 25.6 (w), and 26.2 (rn). wherein (vs) stands 1br very strong substatiallyasdepictedinFl(i.2.polynohChasalX-ray intensity, (s) stards lbr stn-rng iltensity, (n) stands foi pow'cler difliaction patteru substantially as depicted in FIGS. rnedirm ittensity, (w) stands f'o weak intensity, and (r'w) 3A and 38, polymorph D has an X-ray powclel diffraction staucls for very weak intcnsitlr. patlem substantially as depicted iri lIG. 4. polymorph E has zo 31. A cr,vstalline poly'morph D of (3R,5s)-7[2-cycloproan X-ray pow'derdiflractiou patten substantially as depicted pyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6@)irr FIG. 5, polyrnorph F has an X-ray porvder diliaction heptenoic acid lrernicalciun sa.lt. havirg an X-ray porvrler pattern substanrially as depicted in FIG. 6. and dilliaction pattern substantially as depicted in FIG. 4. the amorphons fonn has an X-rzy powder diffraction pat32. A crystalline poyrlrorph E of (3R,5s)-?[2-cycloprotem substantially as depictecl in FIGS. ?A ald 78. zs pyl-4-(4-fluorophenyl)quinolin-3-y1l -3.5-dihydroxy-6(E)24. A crystalline polymorph A of (3R,5S)-7[2-cyclopro- heptenoic acid hemicalciun salt. wlich exhibirs a characterp"v1-4-(4-fluorophenyl)quinolin-3-y1l-3,5-clihydroxy-6(E)- istic X-ray powder diffraction pattern wirh characteristic heptenoic acid hencalciurn salt. wirich exhibits a character- peatris expressed in 20 at 4.4 (vw:,5.0 (s), 6.6 (s), 6.S (s), istic X-ray powcler difl'racTion paltern with characteristic 8.9(s), 10.0(m),i0.3(s), l0.S(rn). 13.3(s). 13.6(ur), 14.0(s), peaksexpressedin20at5.0(s),6.8(s),9.1 (s), 10.0(w), 10.5 o 15.2(vw), 15.9(w). 16.4(w),16.9(vrv), 17.8(vw). 1S.3(n). (n, I1.0 Gu), 13.3 (vw). 13.7 (s), 14.0 (fl, )a.7 (w). 1s.9 18.9 (w), 20.2 (vs), 20.4 (m). 20.7 0,20.9 (m), 21.1 (r.. (vv'), 16.9 (w). 17.1 (vw). i8.;r (m). 19.i (rv), 20.8 (vs), 21.1 21.6 (m), 21.7 (m),22.3 (m),23.s {m).23.s (m).24.r (w), Qtt), 21.6 (nr).22.9 (m),23.7 (n),24.2 {s),2s.2(w), 27.1 (n. 24J (vw). 25.4 (vw). 26.6 (m), 30.2 (w). and 34.0 (vw). 29.6(vw),30.2(w),and34.{)(w),wherein(r,s)stands ftrrvery rvherein (r,s) stan<ls lor very strong intensitv. (s) stancls lirr strong intensty, (s) stands f'or strong intensity, (m) stands l'or 35 strong iutensity, (m) stands ftr medium iutensity, (rv) sta<ls medium intensity. (w) stands for weak iutensity, and (vw) :r w'eak intensity, and (vw) stauds ltrr very weak intensity. stancls for very weak inlensity. 33. A crystalline polymorph I of (3R.5s)-7-[2-cyclopro25. A crystalline polymorph A of (3R,55)-7[2-cyclopro- pyl-4-(4-fluorophenyl)quinoiin-3-yl]-3,5-dihydroxy-6(pyl-4-(4-fluorophen5rl)quinolin-3-y1l-3,5-dihydroxy-6(E)- heptenoic acid hemicalcium salt. having an X-ray powder heptenoic acid hemicalciutn salt, having an X-ray powder o dilfraction patlern substant'ially as <iepictetl in FIG.5. diffraction patteru strbstantially as clepictcd in FIG. 1. 34.AcrystaliinepolymorpirF of (3R.5S)-7[2-cyclopropyl26. A crystalline polynorph B of (3R,-sS)-7-[2-c,\'s.']tr.- 4-(4-fluorophenyl)ciuinolin-3-yll-3,5-dihydroxy-6(E)-1p-

rier.

according to claim 1, and a pharrnacentically

fonn acceptable car-

al

eftctive

38.
30. A crystalline polyrorph D of (3R,5s)-7[2-cyclopro-

py1-4-(4-1uorophenyl)quinolir:-3-yll-3,5-dihydrox,v-61p 10 heptenoic acid hernicalcirun salt, which exhibits a characteristic X-ray powder diffractitt pafrem with characteristic

salt, which exhibits a characteristic pr:wder diffraction pattern with characteristic peaks istic X-ray powder difTraction pattem with characteristic +s expressed in 20 at 5.1 Qn), 5.6 (w).7.0 (s). 8.8 (n, 9.6 G), peaks expressed 2Q aI 4.6 (w), 5.3 (vs). 6.2 (s).7.7 10.2 (w). 10.9(m), it.3 (w'), 11.9(m), 12.5 (m). 13.0(s). 13.7 (m).9.6(m),10.3(w), 11.3 (m),11.7(*),12.6(vw),13.0(w), (m). 14.4 (s). 14.7 (m), ls.3 (rrw.), 15.s (w), 16.8 (m), t7.6

pyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dilrydroxy-6(E)- tenoic acid hemicalcium


heptenoic acid heruica.lcium salt. w'hicr exhibits a

character- X-ray

(s),9.2

13.9(n), 14.7(r'w), 14.9(w), 15.6(w). 16.3(u).

22.8 (s),23.1 (w).23.8(w, shoulder),24.1 (s),24.s{s).25.7 20.8Qn).21.2(w,slroulder),21.5(n),22.4(ttr),23.2(s).23.8 so Qn). 26.2(vw-}26.6 (m),26.9 (w).2s.4 (w). 29.5 (w),29.8 (n),24.4 (vw).25.2 (rv, broad), 26.0 (w), 26.4 (vw), 27.0 (vvr'). and 30.9 (m), wherein (vs) starids l'or very srrong inren27.9 {vw-), antl 28.!) (w), wherein (vs) stands lbr very sity, (s) stnnds lix srrong intensity. (m) stands ltrr meclium intensity, (s) stands for strong intensity, (rn) stalds intensity. (w) stands for 'eak intensity, and (vw) stads l'or mediuru intensiry (w) stands lor weak intensit-v. and very weak intensity. stands tbr very weak 35.AcrystaliinepolymorphF of (3R.5s)-7[2-cyclopropyl27. A crystalline polymorph B of{3R,55)-7-[2-cyclopro- 4-(4-fluoropherryl)quinolin-3-yl]-3,5-dilp,droxy-6(E)-[eppyl-4-(4-fluorophenyl)quinolin-3-yll-3.5-dihyclroxy-6(E)- teuoic acid hemicalcium salt, lmving an X-ray powder dif'heptenoic acid hemicalcium sall, having an X-ray porvder liaction pttern substantially as depicted in FIG. 6. diffiaction pattern substantially as depicted in FIG. 36.Thearnorphousformol(3R,5S!7[2-cyclopropyl-4-(428. A crystalline polyrnorph C of (3R,5s)-7[2-cyclopro- oo fluorophenyl)quiuolin-3-yl]-3.5-dihydroxy-6(E)-hepreuoic pyl-4-(4-fluorophenyl)quiuolin-3-yll -3.5-diirydroxy-6(E)- acid hemicalcium salt. treptenoic acid hemicalc:iLrur salt, lr,hich exhitrits a 37.'['heamorphous lorm of (3R.5S)-7[2-cyclopropyl-4-(4istic X-ray pow'cler diii"action paltern with characteristic fluorophenyl)quinolin-3-yll-3,5-cthyclroxy-6(E;-hepienoic peaks expressed in20 at 4.1(m), 5.6 (s), 7.8 (l, 8.3 (rn), i acid hemicalcium salt, having an X-ray powder diftraction

17.4 (vw), 18.0 (w), 18.7 (m),

i9.3 Qn),20.0 (s).20.5

17.0(i.w). (w-),

(w). 18.3(m), 19.3(n). 19.7(m),20.6(m).21.2(r,s).21.8(s),

intensity.

(w). strong for (r'r.v) ij

2.

character0.-j

(m)'11.6(w), 17.5(w), 17.9(w), 18.7(m), 19.5(s),20.6(m). ,i patternsr"rbstantiallyasdepictedinFlGs.TAand?8. 21 .5 (vrv), 21.9 (rn). 23.1 (rn), 24.0 (w-), and 24.8 (w). whereil 38. A process l'or prepaling the crystalline polymorph or (vs) stauds fc r,ery stroug intensitv. (s) stands fbr strong amorphons ftrrur according to clairn l, wherein:

Case 1:14-cv-02760-UA Document 2

Filed 04/17/14 Page 61 of 61

us

8,557,993 B2

l5
the crystalline polyrnorph or amorphons lbrm being prepred is the crystalline polymorph F; and the process cornprises suspending the crystalline polymorphA in nrethanol containing water as a cosolvent. 39. The process according to clairn 38, whereil the water present in an amount of 1 to 50Vo by volume ol the su.spension (3 R,5S)-7[2-cyclopropyl-4-(4-fl uorophenyl)qui nolin-3 yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium sa1t.

t6

is

of

:lr**tj