Kowa Company et. al. v. Aurobindo Pharma et. al

I

Anthony J. ViolaJennifer L. DerekaZachary

'W. Silverman

EDWARDS WILDMAN PALMER LLPAttorneys for Plaintiffs

Kowa Company, Ltd.,Kowa Pharmaceuticals America, Inc., andNissan Chemical Industries, Ltd.

750 Lexinglon Ave.New York, NY 10022(2r2) 308-44rt

,i UNITED STATES DISTRICT COSOUTHERN DISTRICT OF NEWâa $È

1n r¡{.11.i.;*

er"'

Kowa Company, Ltd.,Kowa Pharmaceuticals America, Inc., andNissan Chemical Industries, Ltd.,

Civil Action No.

Plaintiffs,

v COMPLAINT

Aurobindo Pharma Limited andAurobindo Pharma USA Inc.,

Defendants.

Plaintiffs, Kowa Company, Ltd. ("KCL"), Kowa Pharmaceuticals America, Inc. ("KpA,'¡

(collectively, "Kowa"), and Nissan Chemical Industries, Ltd. ("NCI") by their undersigned

counsel, for their Complaint against defendants Aurobindo Pharma Limited ("Aurobindo Ltd.',)

and Aurobindo Pharma USA Inc. ("Aurobindo Inc.") (collectively, "Aurobindo"), allege as

follows:

14" CV f;1,ri;ffi? r Y

¡{FÉt r} $; g$t4

Case 1:14-cv-02497-PAC Document 2 Filed 04/09/14 Page 1 of 50

Jurisdiction and Venue

1. This is an action for patent infringement arising under the patent laws of the

United States, Title 35, United States Code and arising under 35 U.S.C. gg 271(e)(2),271(b),

271(c), and281-283. Subject matter jurisdiction is proper under 28 U.S.C. $$ 1331 and 1338(a).

Venue is proper under 28 U.S.C. $$ 1391(b)-(c) and 1400(b). Personal jurisdiction over the

defendants in New York is proper under N.Y. C.P.L.R. $$ 301 and 302(a) and because

defendants are doing business in this jurisdiction.

Parties

2. KCL is a Japanese corporation having its corporate headquarters and principal

place of business in Aichi, Japan. KPA is a wholly owned U.S. subsidiary of KCL. KPA has its

corporate headquarters and principal place of business in Montgomery, Alabama and is

organized. under the laws of Delaware.

3. NCI is a Japanese corporation having its corporate headquarters and principal

place of business in Tokyo, Japan-

4. KCL and NCI are engaged in the business of research, developing,

manufacturing, and marketing of a broad spectrum of innovative pharmaceutical products,

.ômcluomg Llvalo".

5. Upon information and belief, Aurobindo Ltd. is a company organized and existing

under the laws of India, having its principal place of business in Hyderabad, Pradesh, India.

Upon information and belief, ANDA No. 20-6015 was filed under the name of Aurobindo Ltd.

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

a principal place of business in Dayton, New Jersey, and is a wholly owned subsidiary of

2


Aurobindo Ltd. Upon information and belief, Aurobindo Inc. acts as the U.S. agent and

distributor for Aurobindo Ltd.

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

Southern District of New York, at least by making and shipping into this Judicial District, or by

using, offering to sell or selling or by causing others to use, offer to sell or sell, pharmaceutical

products into this Judicial District.

8. Upon information and belief, Aurobindo derives substantial revenue from

interstate and/or international commerce, including substantial revenue from goods used or

consumed or services rendered in the State of New York and the Southern District of New York.

Upon information and belief, Aurobindo Inc. has been registered with the N.Y. State Department

of State, Division of Corporations, to do business as a foreign corporation in New York. By

filing its ANDA, Aurobindo has committed, and unless enjoined, will continue to commit a

tortious act without the state of New York, that Aurobindo expects or should reasonably expect

to have consequences in the State of New York including in this Judicial District.

The New Drus Application

9. KPA sells drug products containing pitavastatin calcium (the 'þitavastatin drug

product") under the trade name Livalo@ in the United States pursuant to the United States Food

and Drug Administration's approval of a New Drug Application ("NDA") held by KCL (NDA

No.22-363).

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

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

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

J


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

on August 3,2009.

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

approved.

The in Suit

13. United States Patent No. 5,856,336 ("the '336 patent"), entitled "Quinoline Type

Mevalonolactones," a true and correct copy of which is appended hereto as Exhibit A, was duly

issued on January 5,1999 to inventors Yoshihiro Fujikawa, Mikio Suzuki, Hiroshi lwasaki,

Mitsuaki Sakashita, and Masaki Kitahara, and assigned to plaintiff NCI. The '336 patent claims,

inter alia, the pitavastatin drug product, and a method for reducing hyperlipidemia,

hyperlipoproteinemia or atherosclerosis, which comprises administering an effective amount of

the pitavastatin drug product.

14. Plaintiff NCI has been and still is the owner through assignment of the '336

patent, which expires on December 25,2020 pursuant to a patent-term extension. KCL is NCI's

licensee for the '336 patent and KPA holds a license from KCL for the '336 patent.

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

Forms of Pitavastatin Calcium," aIrue and correct copy of which is appended hereto as Exhibit

B, was duly issued on October 15,2073 to inventors Paul Adriaan Van Der Schaaf, Fritz Blatter,

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

The '993 patent claims, inter 4þ, crystalline polymorphs or the amorphous form of pitavastatin

or processes for preparing the same.

4


16. Plaintiff NCI has been and still is the owner through assignment of the '993

patent, which expires on February 2,2024. KCL is NCI's licensee for the '993 patentand KpA

holds a license from KCL for the '993 patent.

17. In accordance with its license, KPA sells the pitavastatin drug product under the

trade name Livalo@ in the United States. Sales of Livalo@ are made pursuant to approval by the

FDA of NDA No. 22-363.

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

19. Plaintiffs Kowa and NCI will be substantially and irreparably harmed by

infüngement of either of the '336 or'993 patents (the "Livalo@ patents"). There is no adequate

remedy aÍ.law.

COUNT I

INFRINGEMENT OF THE '336 PATENT UNDER 35 U.S.C. Q 271(el(2llAl

20. Plaintiffs repeat and incorporate herein by reference the allegations contained in

each ofthe foregoing paragraphs.

21- Upon information and belief, defendant Aurobindo filed an Abbreviated New

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

$ 355(i) (ANDA No. 20-6015) seeking approval to market 1 -g, 2 ^g,

and 4 mg tablets

comprising pitavastatin calcium.

22. By this ANDA filing, Aurobindo has indicated that it intends to engage, and that

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

use, offer for sale, andlot sale, or inducement thereof, of Plaintifß' patented pitavastatin drug

product immediately or imminently upon receiving FDA approval to do so. Also by its ANDA

5


filing, Aurobindo has indicated that its drug product is bioequivalent to Plaintifß' pitavastatin

drug product.

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

manufacture, use, import, offer for sale, andlor sell, alleged generic equivalents of Plaintiffs'

Livalo@ pitavastatin drug product prior to the expiration date of the '336 patent.

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

Kowa and NCI that Aurobindo had filed a certification to the FDA, pursuant to 21 U.S.C. $

355CX2XA)(vii)(N). On or about February 24,2014,KP4 received the Notice Letter. On or

about February 25,2014, KCL and NCI received the Notice Letter.

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

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

"invalid, unenforceable, andlor will not be infringed by the manufacture, importation, use or sale

of the drug product described in Aurobindo's ANDA."

26. Aurobindo's filing of ANDA No. 20-6015 for the pu{pose of obtaining FDA

approval to engage in the commercial manufacture, use, importation, offer for sale andlor sale, or

inducement thereof of its proposed pitavastatin drug product before the expiration of the '336

patent is an act of infringement under 35 U.S.C. g 271(e)(2)(A).

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

inducement thereof of its proposed pitavastatin drug product will directly infünge or induce

infüngement of at least one claim of the '336 patent under 35 u.s.c. g 271(e)(2)(A).

28. Upon information and belief, Aurobindo's proposed label for its pitavastatin drug

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

atherosclerosis.

6


29. Unless Aurobindo is enjoined from infringing and inducing the infringement of

the'336 patenl, Plaintiffs will suffer substantial and irreparable injury. Plaintiffs have no

adequate remedy at law.

COUNT II

INF'RING OF THE CLAIM OF THE ' PATENTUNDER 35 U.S.C. 8 271(b)



31. Upon information and belief, approval of ANDA 20-6015 is substantially likely to

result in the commercial manufacture, use, importation, offer for sale, andlot sale, or inducement

thereof, of a pitavastatin drug product which is marketed and sold for use in a method claimed in

one or more claims of the '336 patent, immediately or imminently upon approval of the ANDA,

and prior to the expiration of the '336 patent.

32. Upon information and belief Aurobindo's proposed label for its pitavastatin drug

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

atherosclerosis.

33. Upon information and belief, Aurobindo is aware or reasonably should be aware,

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

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

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

effects of pitavastatin as an adjunctive therapy to diet to reduce elevated total cholesterol, low-

density lipoprotein cholesterol, apolipoprotein B, triglycerides, and to increase HDL-C in adult

patients with primary hyperlipidemia or mixed dyslipidemia would be readily apparent to

7


customers of Aurobindo (ç.g., including, without limitation, physicians, pharmacists, pharmacy

benefìts management companies, health care providers who establish drug formularies for their

insurers andlor patients). Aurobindo will be marketing its pitavastatin drug product with specific

intent to actively induce, aid and abet infüngement of the '336 patent. Aurobindo knows or

reasonably should know that its proposed conduct will induce infringement of the '336 patent.

34. Unless Aurobindo is enjoined from infringing and inducing the infringement of

the '33ó patent, Plaintifß will suffer substantial and irreparable injury. Plaintiffs have no

adequate remedy at law.

COUNT III

INF'RIN oF' METHOD OF THE '336UNDER 35 tI.s.c. ñ 2ttkr

35. Plaintifß repeat and incorporate herein by reference the allegations contained in


36. Upon information and belief, Aurobindo's proposed pitavastatin drug product

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

37. Upon information and belief Aurobindo's proposed pitavastatin drug product will

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

38. Upon information and belief Aurobindo knows that Aurobindo's proposed

pitavastatin drug product will be especially made for use in a manner that is an infringement of

the '336 patent.

39. Upon information and belief sale of Aurobindo's proposed pitavastatin drug

product will result in direct infringement of the .336 patent.

8


40. Upon information and belief, Aurobindo's proposed pitavastatin drug product is

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

use.

41. Upon information and belief Aurobindo knows that Aurobindo's proposed

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

substantial noninfringing use.

42. Upon information and belief, approval of ANDA 20-6015 is substantially likely to

result in the commercial use, manufacture, offer for sale and/or sale (or the inducement thereof

or contribution thereto) of a drug product which is especially made, adapted, marketed, sold, and

approved exclusively for use in a method claimed in the '336 patent, immediately or imminently

upon approval of the ANDA.

43. Plaintiffs will be substantially and irreparably harmed if defendants are not

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

remedy at law.

CO IV

INF'RIN OF THE '993 PA UNDER 35 U.S.C. E 271klQl('¡tl



45. Aurobindo's Notice Letter, purporting to be Aurobindo's Notice of Certification

under 21 U.S.C. $ 355(D(2)(BXiÐ, indicates that Aurobindo intends to manufacture, use, sell, or

offer for sale, its proposed pitavastatin drug product prior to the expiration of the '993 patent.

9


46. The Notice Letter asserts that in Aurobindo's opinion, the'993 patent

purportedly is "invalid, unenforceable, andlor will not be infringed by the manufacture,

importation, use or sale of the drug product described in Aurobindo's ANDA."

47. Aurobindo's filing of ANDA No. 20-6015 for the purpose of obtaining FDA

approval to engage in the commercial manufacture, use, importation, offer for sale andlor sale or

the inducement thereof of its proposed pitavastatin drug product before the expiration of the

'993 patent is an act of infüngement under 35 U.S.C. g 271(e)(2)(A).

48. Aurobindo's manufacture, use, importation, offer for sale, sale, andlor importation

of its proposed pitavastatin drug product will directly infringe or induce infringement of at least

one claim of the '993 patentunder 35 U.S.C. g 271(e)(2)(A).

49. Unless Aurobindo is enjoined from infringing the '993 patett plaintiffs will

suffer substantial and irreparable injury. Plaintiffs have no adequate remedy atlaw.

WHEREFORE, Plaintiffs request the following relief,

(a) a declaratory judgment pursuant to 28 u.s.c. ç 2201d *:that making, using,

selling, offering to sell and/or importing Aurobindo's pitavastatin drug product

for which it seeks FDA approval or any drug product containing pitavastatin will

infringe at least one claim of one or more of the Livalo@ patents;

(b) a declaratory judgment pursuant to 28 u.s.c . ç 2201et seq. that the making,

using, offering for sale, selling and/or importing of Aurobindo's pitavastatin

drug product or any drug product containing pitavastatin, will induce the

infringement at least one claim of one or more of the Livalo@ patents;

10


(c) a declaratory judgment pursuant to 28 U.S.C . ç 2201et !eq. that the making,

using, offering for sale, selling andlor importing of Aurobindo's pitavastatin

drug product or any drug product containing pitavastatin, will contribute to the

infringement of at least one claim of one or more of the Livalo@ patents;

(d) a declaratory judgment pursuant to 28 u.S.c . ç 220r et sçq. and an order

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

FDA approval for Aurobindo to commercially make, use, sell, offer to sell or

import its pitavastatin drug product or any drug product containing pitavastatin

be no earlier than the date following the expiration date of the last to expire of

the Livalo@ patents (as extended, if applicable);

(e) a peÍnanent injunction restraining and enjoining against any infringement by

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

those actingin privity or concert with them, of the Livalo@ patents, through the

commercial manufacture, use, sale, offer for sale or importation into the United

States of Aurobindo's pitavastatin drug product or any drug product containing

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

(Ð Attorneys' fees in this action under 35 U.S.C. g 2g5; and

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

Court may deem just and proper.

11


Dated: New York, New YorkApril 9,2014

Kowa Company Ltd.,Kowa Pharmaceuticals America, Inc., andNissan Chemical Industries, Ltd.

B attorneys

,/eAnthony J.

Jennifer L.Zachary W. SilvermanEDV/ARDS WILDMAN PALMER LLP750 Lexington AvenueNew York, NY 10022(212) 308-441r

David G. Conlin (to be admitted pro hac vice)Kathleen B. Carr (to be admitted pro hac vice)Adam P. SamanskyEDWARDS WILDMAN PALMER LLPlll HuntingtonAvenueBoston, MA02199(617) 23e-0100

t2


EXITIBIT A


I lllll ilil]t ilr ililt ililt llllt l]] ]ilt ]llt illlt ililt ]llil llt ]]l llll

IJnited States Patent ilelFujikawa et al.

us0058-563-36A

Patcnt Numbcr:Date of Patent:

[1 1]

[4s]

5,856,336

Jun. 5,1999

[-54] QUINOT.TNE TypE MI,VAT.ONOI_ACTONES

[75] Inventors: Yoshihiro Fu.iikawa; Mikio Suzuki;Hiroshi lwasaki, all of Funabashi;Vlitsuaki Sakashita; Masaki Kitahara,both olShiraoka-machi, all of Japan

[]31 Assigncc: Nissan Chemical tndrrstrics Ltd.,Tokyo, Japan

[21] Appl No.: 883,398

I/21 lilcd: Nlay 15,1992

Related U.S. Application l)ata

162l Division oI Ser No. 63l,Oc)2, Dec. t9, 1c)Ou.. wbictr ir acoutinuation ol Scr: No. 233.752. Aug. 19, 1988.

[30] l'oreign Application lrriority Data

Prinary Exanùnerl,a:ura I-. StocktonAttorrLey, Agent, or Fírnr4lllon, Spivak, McClelland,lVlaicr & Nousrûdt, P.C.

ls7) ABSTRAC'f

A compouncl of the formula

Japan ....... ......... 62-207224Japan .. ...... 63-15585Japan ...... 63-193606

tAl

N c-P¡

z:-cH(oH)-cH"-cFI( OH)-CHr-CO O.%Cahave IIIVIG-CoA inhibiting eftècts, making them use-ful as inhibitors of choleslerol biosynthesis. The com-pound may be prepared as a phalmaceutical tbr recluc-ing hyperlipidemia, hyperlipoproteinemia oratherosclerosis.

2 Clairns, No Drawings

F

Z

Aug. 2Q, 1987.lan. 26. 1988Aug.3. 1988

IJPIpPlUP]

[s1] Int. Cl.ó ......... A6lK 3'1.147; C07D 275/72ls2l U.S. cl. ..... sl4/3lt; s46tlj3[58] Field of Search . ........... 5461173; 5L4i3tI

[56] References Cited

U.S. PAIENT DOCUMENTS

5,753,675 -5l1998 Wauanasin ..... .... ..... -........... 5t4l31t


5,856.3361

QUINOLINE TYPE ÑIEVALONOT-ACTONES

'Ihis is a division, of application Scr. No. 01i63I,092,f,lcd on Dcc, 19, 1990, which is a continuation of 07t233,752,ñIedAug l9, l988

The present invention relafes to novel mevalonolactoneshaving a quinoline ring, processes fbr their procluction,pharmaceutical cornpositions containing tl¡em ancl theirpharmaceutical uses particularly as anti-hyperlipiclemic,hypolipoproteinemic and anti-a¿herosclerolic agcnts, ancl,..intcrmcdiâtcs uscful t'or their procluction ancl proccsscs for '"thc production ol such intcrmccliatcs.

Some fermentation metabolic proclucts such ascompactine, CS-514, Mevinolin or semi-syntbetic dc.riva-tives ol frrllv synthetic deriv¿rtives thereof are known to L¡e

inhibitors against HMG-CoÂ rechrctase which is a rare 1-s

limiting anzyme tbr cholesterol biosynthcsis. (4. Endo J.Med Chem., 28(4) 401 (1985))

CS-514 and Mev.ioolin have been clinicall.v provecl to bepotentiall;r useful anti-hyperlipoproteinemic agents, anclthey are consiclerecl to l¡e elfective for curìng crr preventing 20

diseases of coronary artery sclerosis or atheroscle¡osis.(IXlh Int Syup. Drugs Affect Lipid Metab., 1986, p30,p3l, p66)

Horvever, with respect to tìrlly synthetic clerivatives,particularly hetero arom¿ìtic clcriv¿tivcs of inhiLritors againsr 25

HMG-CoAreductase, limitecl int'ormation is clisclosed in thefollowing literaLures:

wPI ACC NO. 84-l-58675, E6-O28274,86-098816,3 6 -33207 0, 87 -1245 19, 87 -220981, 8.q-0778 1, 88 -008460,88-091798 and 8B-11-2505. 30

Ttre present inventors have t'ouncl that mev¿rlonolactoneclerivatives baving a quinoline ring, the corresponding dihy-droxv carboxyLic acids and salts and esters the¡eof have highinhibitory activitics againsr cholcstcroÌ [riosynlhcsis rn'hcreinFIMG-CoA recluctase acts as a rate limitin-e enzvme. The 35

present invention has been tccomplishecl on tbe b¿sis o[ tbisdiscovery'.

The uovel mevalonolacto¡e derivatives of tbe presentinvention are represented by rhe tbllowing formula I:

RJ R{

(rvhcrcin Q is -Cl(O)-, -C(Oiì13)2-

or -CH(OH)-;w is

-C(O)-, -C(oR13)2- or

-C(RuXoH)-r R'1 is

hyclrogen or Cr_. alkyl; Rt2 is hydroge n or R14 (wherein Rl'ris physiologically hvdrolvzable alkyl or M (wherein M isNH.*, soclium, potassiurn, % calcium or a h;rclrate of lorveraikvlamine,two R13 areor two I{r3and lì18 archyclrogen, Cr-u alkyl, Cr_. alkenyl, Cr_u cycloalkyl,

2

R

lì tt

o o

o o

RuoY CO]RL2R18

o

(r)

(rvbcrcin I{e ìs hydrogcn, C,-,, alþI, C,-., altrioxy, fluoro,chloro, bromo or lrifluoromethyl), phenyl-(CH.),,,(wherer'n m is l, 2 or 3), --{CHr),,CH(CHr)lhenyl orphenyl-(CFI"),,CH(CH3)- (rvherein n is 0, t or 2).

Various subsliluents in tfie t'ormula I will be describecl indet¿il rvith reference to speoific examples. Flowever, itshoulcl be unclerstctocl that the prescnt invcntion is by nomcans rùstricted by such specifie exlmples.

Or_u alkyl tbr l{r, Iì2, R3, l{4, Iì6 and l{e incluclos, tbrcxamplc, mcthyl, cthyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-bu1yl and rbutyl. C,_, alkoxy tbr Rr, R:, R3, R4 and R6

o,, includes, for exam¡le, methoxy, ethoxy, n-propoxy ancl' l-propoxy.Cr-. alkyl tbr Rll inclucles, for example, methyl, etl-ryl,

n-propyl ancl ipropvl.Cr-, alkvl lcrr Rr3 inclucles, lbr example, methyt, ethyl,

n-propyl anct i-propyl.4-\ Alkyl ibr ll1a includes, tbr cxamplc, mcthyl, cth.rrl,

i-propyl, n-butyl and i-butyl.a melal capable of forming a pharmaceutically

R n-propyl,Mis

Rr

wherein R1, R2, R3, Ru and Ró are indepenclently hyclrogen,Cr_u a1kyl, C._,, cvcloalkyl, Cr_. alkoxy, n-butoxy, i-butox¡5sç-þutoxy, RR"N- (wherein R7 ancl RS are inclepencleutlv .;5

hyclrogen or Cr_- alkyl), trifluoromethyl, trifluoromethoxy,difluoromethoxy, fluoro. chloro, bromo, phenyl, phem-rxy,bcnzyloxy, hydroxy, trimethylsilyloxy, cliphcny'1-t-bu tylsilyloxy, hyclroxymetbyl or

-O(CFI=)rORre (rvhereiu

Rlo is hvdrogen or C-r-, alkvl, ancl I is 7,2 or 3); or whenlocatecl at the c¡rtho posirion to each other, Rr ancl R2. o¡ R'and Ra together tbrm -{IFI:CFI CH:CH ; or whenItrcated at the ortho ¡tosition to each other, Iì1 ancl Rrtogetlrer tbrm

-OC(R I i)(R t")O- -(where in R' 5 rncl R1' arc

independently hydrogen or C,_. alkyl); Y is -CIIr-.-C]H?CH^-, -CËl:CFl-. -CIJ2-CFI:CH- or

-CH:CH-(]FI--; and Z is -Q-CH.W'CFIr-CO¿Iì 1?,

acceptable salt, and it inclur-les, lbr example, scldium antlpotassium.

-i0 COTIVI inclucles, tor exaurple, -CO2NÉI4

and -CO"FI.(primary to tortiary lowcr alkylaminc such as

trimethylanine)Cr-o altriyl fbr ll' inchrclcs, for examplc, mcrhvl, cthyl,

nlropyl, i-propyl, n-butyl, i-[rutyl, sec-trutyl, t-butyl,n-pentyl ¿rnc{ n-hexyl.

C:-c cvcloalkyl t'or R5 include.s, tbr example, cyclopropyl,cyclobut)¡l, cyclopentyl a¡d cycl¡hcx)rl

C-_, alkenyl tõr R' inclucles, tor example, vinvl ancli-propenyl.

tto Phcnyt-(CFI.).,,- for [ì5 incluclcs, tbr examplc. bcnzyl,13-phenylethyl ancl y-phenylpropyl.

Phenyl-(CH.),,UH(CFI¡)- itrr R' inclutles, tbr example,trlhenylethyl and c-trenrylethyl.

C, . alkyl tbr R7 ancl RB includes, lor example, mcthvl,6-5 ethyl, n-propyI and i-lxol>yl.

Further, these courpounclsm¿rv have at least onc ol twoasymmetric carbon atoms ancl may have at least trvo to t'our

N

v-7.


5,856.33634

crptical isomcrs- The compounds oI the [<¡rmula I incÌucle all dimethyl, 6.8-cJimethvl, 6,7-<ìimethoxy, 6,7-dietbctxy, 6,7-of these optical iscrmers ¿nd all of the mixtures rbereol. clilrromô o¡ ó,g-cjibrom<_¡.

Whcn l{1, lì2 ancl l(6 arc not bydrogcn, thcy togcthcrreprcseot 5,7-dimothoxy-8-hyclroxy, -5,8-dichloro-6-

5 hyclroxy, 6,7,8-trimethoxy, 6,7,S-rrimethyl, 6,7,8-trichloro,-5-tluoro-6,B -dibromo or 5 -ch loro-6,8-dibromo_

Now, prelèrrecl substiluents oI the compouncls o[ theprcseDt invcntion will bc described

In thc following prcferrccl, morc prcfcrccl srill furlhcrAs prefèred examples t'or Y,

-CHr-CH.- and (E)--CFI:CFI-mav lre mentionecl. As more preferrecl

._ examples Eor Z, ¡ha above pretèrred examples for Z may be: mentionecl.

20

25

As pref'errecl examples for R-t aocl Ra, when Ra is ishyclrogeo,Raishyclrogen,4'-ch1oroor4,-fluoro,orR3andhytlrogen, R3 is bydrogen, 3'-fluoro, 3'-cblorr¡, 3'-methyl, t{'t iogcthcr ."pr"r"ãt 3'-mcthyl-4'-fluoro.4'-metbyl,4'-chloro and 4'-fluoro. Still further pret'erred exrmples t'or R5 inclucle erhyl,

other preferred combinations of R3 ancl R+ inchrcle 30 n-propyl, ipropyl ancl cyclopropyl.3'-mcthyl-4'-chloro, 3',-5'-dichloro, 3',5'-difluoro, 3,,5'- Still furrher pre tèrrecl exim1ilés for y inclucle (El_dimethyl ancl 3'-methyl-4'-fluoro CFI:CH-.

Prelerred examples for R5 inclucle primary ancl seconclaryCr_u alkvl and Co_u cycloalkyl.

Prclèrred examples for Y incÌude -CH2-CH.- ancl 35

-CII:CII-.Preferre(l examples f'or Z inchLde

,4s still further preferred examples tbr Z, the a[rove-mcntioned prelerrecJ example ïor Z mtty be mçnticuecl.

Norv, thc most prcftrrcd substitucnts tbr thc compoundsof the present inveotioo lvill l¡e clescribed.

As thc most prctbrrccl cxamplcs tbr lì.r, l{2 and lì6, whcnLroth R: and Rd are hvclrogen, Rtis hyclrogen,6-methyl or6-chlorc.HO o

o4tr When only R6 ìs hydrogen, Rt and Rtr together represent,

lbr example, 6,7-climelhoxy.,4s the mosr pretèned examples t'or. R3 ancl R't, R3 is

hydrogeo and R'Ì is bycìrogen, 4'-chloro or 4,-fluoro.

-cr(or-r)cr2crr:(orr)crr:co,R1¿, -cr-r(o*r)cn,c(o) ., "rlli.ï;itåît:'ï,'j"","iî.t:::":i:T;îÏtJi:j iîii.'ü:cH2corRr::Lnrl -cH(oH)cHrc(oR'r)-cHrco-Rî.. ¡É;_' [,¡r:,.r,_.

Now, more prefèrrecl sul-r,stituen¡s of the compouncls of the As the most preterred examples for Z, the above-present invention will Lre clescribed. mentionecl preferrècl examples foi Z ma,y be mentìoned.

-,AtT::"preferredexamplestbrRt,R2andlló,rvhenboth Now, paiticularly prefeirect specr'fic compounds ol theR' ancl Ro are hvdrogen, Rt is hyclrogen, 5-flrroro, 6-lìuoro,

. -50 prcsent invcnLion wilì be presentecl. 'Ihe lbllowing .9m-7-fluoro, S-lìuoro' 5-chloro, 6-chloro, 7-chloro, S-chloro, pouncls (a) ro (z) are shown in the torm of carboxylið acicls..5-bromo, 6-bromo, 7-bromt¡, 8-bromo, .5-methvl, 6-methyl, ilow-ever, rhe piesent ioventioo inclucle uot onl.v the com_

pounds in the tbrm of carboxylic acicls lrut also ihe corre-sponcling lactones lormecl by the cclnclensation ol the car-

5 boxyfic acic]s with byclroxy âr tbc s-posirion, and socliumsalts ancl lower alkyl esters (such as methyÌ, ethyl, i-¡rropylan<J n-propyl esters) oI Lhe carboxylic acicls, which can be

when R6 is hycrr.gen, R, ancr R2 rogetrrer represenr ttäi'Ëti:å]l1.llii:ilJõitÌ.ll?-:l',?l;.Llirîîiij,

r,6-chloro-.3-methy[,6-bromo-7-merhox.v, 6-methyl-7-chloro, 60 ms,thylethyl)-quinoiin-:,_1,t]_trepr_O_enoic acid6-chloro-B-hyclroxy, 5-rnethyl-2-hydroxy, 6-methoxy-7- (trj (eÍ-j,j-¿ilyar""y-i-[.i,-(4"-fluor¡phenyl)-2,-(1 '-chkrro,6-chk¡ro-7-methoxy, ó-hyclroxy-7-chloro,6-chloro- *"ìn,vtctty¡-0,_chlãro_quinolin_-3;_yl]_hcpt_å_euoic acicl7-hydroxy, 6-chloro-8-bromo, -5-chloro-6-hyclroxy, icj 1e¡-a,:-alhydroxy-7-[4'-(í"-iuor..pbe'yl)-z -(1 '-6-Lrromo-.s-chloro' 6-bromo-8-bydnrxy, 5-me thyl-S-chloro, mcìnvt"úyl)-o'-r"itryt-qíioolin-ì'-yl]-hcpt-'6-cnoic acicì7-hyclroxy-8-chloro, ó-bromcr-.9-byclroxn 6-metboxy-7- o-s t¿i tei-:,-s-crihidr;x),-7-[+ -1i"-nuo.ophenyl)-2'_methvl,6-cbloro-8-b¡6¡1¡,6-r-.erhyl-S-L-rr.mo,6,7-crifhroro, (L';methyleth¡il)-6',7,-dim;th.--ry-qu.inolin-3,lvr]-ú"ót-o-6,8-ctifluoro, ó,7-mcthylcncdioxv, 6,8-dichloro, -5,8- enoicacícl


5,856,3365

(e,) (E) -3,-s -cli hydrox y-7-[4'-( 4 " - fl ucr rop he oy t) -2, -cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid

(f) ( E) -3,-s -di tr ydroxy -7 -[4'-(4 " -fl rLo roptren yl) -2' -cyclopropyl-6'-chloro-quinolin-3,-yl]-hept-6-enoic acid

(g) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophelyl)-2'- scyclopropvl-ó'-me thyl-quinolin-3'-yl]-hcpt-ó-enoic acicl

(b) (E)--1,5-clih5,droxy-7-[4'-(4"-fluorophenyl)-2,-cyciopropyl-6',7'-d imetb oxy-quino lin-3'-¡rl]- hep t-ó -enoicacid

(i) (E)-3,5-dihyclroxy-7-[4'-(4',-chlorophenyl)-2'-(1"- romethyte thyl)-quinoli n-3'-y1l- hep r-6-enoìc acicl

0) (E)-3,-s-dih¡rclroxy-7-[4'-(4"-chlorophenyt)-!, -( t,, -me thylethyl)-6'-chloro-quinolin-3'-yll-hepr-6-enoic acid

(k) (E)-3,-5 -dih yclroxy -7-[4'-(4" -chtorop l.ren yl)-z, -(1,, -mcthyiethyl)-ó'-mcth/-quinolm-3'-yl]-hcpr-ó-cnoicacicl 1_s

(t) (E)-3,-5-dihyctroxy-7-[4'-(4"-chlorophenyl)-2'-( 1,,-methylethyl)-6',7'-climeth<,rxy-quinolìn-3'-yl]-hepr-6-enoicacid

(m) (E) -3,-5-dìh ydroxy-7-[4'-(4" -chlo roph eny t) -2' -cyclopropyl-quinolin-3'-yl]-hepr-ó-enoic acicl zo

(n) (E)-3,5-clihydroxy-7-[4'-(4', -cfilorophenyl)-2'-cycloprop-vl-ó'-chloro-quinolin-3'-yl]-hcpt-ó-enoic acid

( o ) (E) --r,5 - cl ihy c1 r oxy - 7 -14' - (4 " -chlo r.op he n yl) - 2'-cyclop ropyl-6'-mcthyl-quinolin-3'-yl]- hcp t-6-cnoic acicl

( p ) (E)--r,5 -cl ihyclroxy-7-[4'-(4', -chloroph e oyl) -2' - zsc yclop rop yl-6'7'-clime t ho xy-qu ino lin-3'-yl]-b ep t-6-enoicacid

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

(r) (E)--1,5-dihydroxy-7-[4'-pbeoyt-2,-(t''-merhytethyl)- :o6'-chloro-quinolin-3'-yt]-hcpt-6-cnoic acid

(s) (E)-3,5-dihyclroxv-7-[4'-phenyl-2'-(t"-methylerhyl)-6'-me thyl-quinolin-3'-yll-hep t-6-eaoic acid

(t) (E)-3,-5 -clih ydloxy-7-[4'-ph enyl-2' -( 1,' - me r b ylerh.rrl)-ó',7'-dimethoxy-quinolin-3'-yl]-hept-6-enoic acid 35

(u) ( E)-3,-5-dihyclroxy-7-[4'-phenyl-2'-cycloirropyl-quinolin-3'-yl]-hept-6-cnoic acid

(v) (E)-3,5-clihydroxy-7-[4'-phenyl-2'-cvclopropyl-6'-chloro-quinolin-3'-y1]-hept-6-enoic acicl

(w) (E)-3,-5-clihydroxy-7-[4'-phenyt-2'-cyclopropyl-6'- +omethyl-quinolìn-3'-yl]-[-rep t-6-enoic acicl

(x) (E)-3,5-dih¡'clroxy-7-[4'-phcnyl-2'-cyclopropyl-6',1' -clim ethoxy-quinotìn-3'-yl]-hep t-6-enoic ¿cicl

(y) (E)-3,5-dihyctroxy-7-[4'-(4"-tluorophenyl)-2, -(1,,, -methylethyl)-6'-methoxy-quinolin-3'-yll-hept-6-enoìc acicl 4_5

(z ) ( E)-3,5 -di h yclrc-rx y -7-[4' -(4" - Iluo ro p h c ny l)-2, -cyclopropyl-6'-mc thoxy-quinolj¡-lr-y1]- bcp r- 6-cnoic acicl

The mevalonolactones of the formula I can L-e prepared lrythc t'ollor,ving rrractioú schcmc. Thc cnal III can also bepreparecl by processes K, L, ancl N,f . -i(J

RJ R4

RL

Rt

Rl

Rt

Rt

R:

RJ

RJ

6-continucclRr

CH¿OFI

N' Ri

Rr

-õ->

-D->

-r-->

Co¿Ììrz

-E->

vl

CTIO

t\¡

Ri Rr

R5

oEr

OFI

OII

N

IVR Rr

cHo

N

üIR3 R o

Rr

-\ì

6.1

-F->CO¿R]L

-ã-> N lÈ

R IIN

VII

Rs


5,856,3367

-continucdR{

IRi R3

-continuedRlOH

OH

OH

OH

o

CO¿R12

5

-E>

-->

\K-

N Rs

N R-5

N R5

IIT

R

CO¿R¿2

CH¿OÉI

CHO

-->Rl

R2

Rl

R2

Rl

Rr

RL

10

35

6rl

R2

Rr

R2

R3

R3

R5

N Rs

I-2 ßr2= H)I-5 (Rt3 = Na)

R: R{

R5

N

I-1R1

R4VTII

R

OH

CosRtz 1-5

1¡ T>=->

LXR425

30

o

RtN

OHRJ

R3 OH

OII

otr

CO,Rrz

CO"Rl¿

ñ>

t-.3

R4

CFIO

o o

40

45

50

-t)

N RrRs

N

I-1

R5

Rs

R1RRl

RJ

I-4

R{

R

N

RtI-6

N

Rt

R5

65

In the above reaction scheme, Rl, R2, R3, Ra, R-, R6 anclRttr are as defìned ahove with respect to tbe formula I, and


5,856.336910

Rrr and R22 indepenclentlv represent C-r,u lower altriyl sucb c¿ubon in a so-tvent such as meth¿rnol, eLhan6l, l.elrahyclro-as methyl, etbyl, n-propyl, i-propyl or n-butyl. furan or acetonitrile at a remperarure of äom ó" to Sd" C.,

step A represents a recluction reactioa of the ester to a prefer.ably from 10o to 25. i.primary alcohol, Such ¡ecluction reaction can be conducted Step K represenls a ¡eaction for lhe synthesis of anby using various metal hydrides, preferably cliisol¡utvlalu- 5 o,l3_ri.rtu.i!Jca.toxyli. acicl ester,whereby a traos_f.ormminium hydride, in a solvcnt such as tctrahydrofuran. or ct,jì-unsaturatccì carboxylic acid estcr can lrc obrainecl by aloluene al a temper¿ìture of liom -20' to 20. C., preferably ,nl"ott"J Uo."".-W;u;g reaction by using an alkox¡rcar.l.:o-tiom -10'to 10" C.

Srep B represenrs an oxicrarion reacrion or the primary :J.iitiliå:::'::i:iî"Ihïïiï:î,ïì"'::ti:';*t#i1Ïalcohol to an aldehycle, which can be conclucted bv usrng 10 tetrahJ¡clrofuran at a temperature of fiom _åõ;' ì; ó: ä--various oxicliz.ing asenrs. pretèraLrly, rhe re¿rcrion ian oi ;;;ffiì;'f."* -zo" ,o -15" c.

of the a,p-a1cohol. 'l'hìs

l-s various metalricle, in a sol-a temperatureStep C represents t synthesis of a 3-ethoxy-1-hy<Jroxv- of tiom _10" to 10" C., preferatrly frorn _10. to 0o C.2-pro1>ene derivative, lvhich can be prepared by reactrng a Õ,

compõund V to lithium compound ihi"t hn, uá"n p..t-iåi- ^,^l-t*, .Y I"l_teseots art oxidation reaction of the allyl

nariliy formed by treating cis-ì-edroxy-2-(rri-n-Uur'l"tunilril , |]::.T] j"..1n enal' This oxiclarion ¡eaction can Lre conclnctecl

etbyiene witb trutyl litl¡"iurn in tetrah-ycl¡ofura.. by using valiclus oxiclizing agcnts, particularly activc man-,As thc rc¡ction rcmpcrarure, it is prcfcrrcd ro cmploy ^ l:::_i.

oîîilo^:l t" a solvent such as tetrabydrofuran,low temperalure at a låvel of from -60. tr¡ -7Bo C. acctLìno' ctbyl cthcr or eth)4 acctatc al 0 lemperatrue of from

Stcp D rcprcscotsasynthcsisof ancnalbyacidichyclroly- 0"fo l0o' c', preferably tìom 1-5" to -50" c.sis..As the icid catalysi, it i-s pretèrrecl to employ p-íolr"å. zs

^SLep N repr€senls a reaction fcrr the synthesis o[ an

sulfonic acicJ, hycìrothtoric acicl or sultìricâcitl, an<1 rhe cr,l3-unsaturated ketone by the selective oxidarion of thereaction may be tonducted in a solvent mixture ofwaier ancl dihyclroxy carboxylic acid ester'. This reaction can be con-telrahyclrofuran or ethanol at a temperùture of lrom 10o to duc,ted [rv. using activatecl mangâoese clioxide in a solvent25" C. The 3-ethoxy-l-hydroxy-2-propene derivarive such as eth;rl ether, tetrahydrofuran, lrenzene or toluene at aobtainecl inStepCcantreuseãiostepDwiihourpurification i0 tcmpcraturc of tiom 20o to 80" C., pretèrably tiom 40'toi.c. by simply rcmoving tctra-n-buiyl rin t'ormôd simuftr- 80" C.

neorLsly. In aclciition to the compounds disclosecl in Examples givenStep E represents a clouble anion concleusation reactìon lrereinafter, comporLnds of the formulas I-2 ancl I--5 given in

between the enal III and an ecetoacetate Such conclens¿tion 'lhblc 1 can bc prcparr:d by thc proccss of thc prcsentreaction is prelèrablv conductecl by using sodium hyclricl" 35 invention. In Table 1, i- means iso, sec- means seconclaryancl n-butyl lithium as the base in tetrahydrofur¡ìn at a and c- means cyclo Likewisc, Mc mcans methyl, Et mcanstcmperalure t¡f fr<¡m -80" to 0" C., prcferably liom -30" lq ethvl, Pr means propyl, Ru means butyl, Pent means pentyl,-10' C. Hex meaos hexyl and Pb means phenyl.

Step F represenls a recluction reaction of lhe carbonylgroup, which can bc conudctcd by using a mcral hydridc, +o TARI_E Ipreferablv sodium borohyclride in ethanc¡l at a temperatureoI lrom -10" to 25" Lì., pretèrably lìom -10" to -5o C.

Further, the reductic¡n reaction may be conducted by usingzinc borohyclride in tlry elhyl ether or clry telrahvclrolur¿rn ata temper¿ture of -100" to 25" C., pretèrably tiom -80" to ¿_s

-50" c.Stcp G is a stcp for hydrolyzing the cstcr.'I'he hydrolysis

c¿rn tre cooducted by using an equimolar amount of a Lrase,prctcrably potassium hydroxidc or sodium hydroxidc, in asolvent nixtu¡e of rvater ancl methanol or ethanol at a 5l)lcmperaturc of tÌom 10" to 25' C. lhc ticc acicl hcrcbyolrtained mav be convertecl to a salt with a suitable base.

Step H is a step l'or lbrmiug a mevalonolactone by thedehydration reaoion of the iiee hvclroxy acicl I-2. Theclehydration reaction can be conclucted in Lrenzene or toluene s¡under reflux rvhile removing thc resulting watcr or by addinga suitable dehydrating agent such ¿s molecular sieve.

Further, thc clehydration reaclion may be conductecl in drymethylene chlo¡ide by using a lactone-forming agent such ascarbodiimide, preferably' a lvater soluble carbodiimicle such

Ri R

N R5

OHI-2 (Rt? = H)t-5 (tìt2: \a)

Rd ot{R

R1

R1 R2 R4 R5 R6

6-OlVleô-OMe6-Br6-Me7-OMc

HHHS-Me3-OMcTI

i-Pri-Pri-Pri-Pri-P¡i-P¡

H4-F4-t4-F4-F2-F

4-F

HHHtJFI

H

H

IILIHHHH

FIas N-cyclohexyl-N'-[2'-(merhylmorpholinium)erhyl]carbodümicle p-toluene sulfonatc a( a tempcralurc o[ lromt0" to 35 ' (ì., pretèrably tiom 20" ro 25' C.

Step J represents a reaction I'or hydrogenating the doublelactone moicty rncl the quino- o-s

re¿ction can be conclucted byalladium-cartron or rhocl ium-

.... 6-B¡OU

6.'1 i-Pr


5,856.33611

TABLE l-continued

l2

R3 R4 otI

OH

R] R5

I-2 (Rr2- FI)I-5 (Rtz = Na'

They may be lormulalecl into v¿Lrious suitable formula-lions clepending upon rhc manner of tbe administration. The

prcscnt invcntioo may bc administcrcd inacicls or in rhe form of physiologicallv

5 acceptable esters or lactones, or pharma-ble salts.

. The plrarmaceutical com¡rosition of tl]e present inventìonis pretèrably adminìstered orally il rhe lorm of the com-poun<J of tbe presenl invention per se or in the form of

1o powders, granules, tablets or capsuÌes t'ormulated by mixingthe compouncl of the present invenlion with a suitabiepharmaceutically acceptable canier including a binder suchas hydroxypropyl celhrlose, syrup, gum arabic, gelatin,sorbitoi, tragacenth gum, polyvinyl pynoiiclone or CMC-Ca,

,- an excipienl such as lactose, sìigar, corn starch, calciumphcrspbate, sorbirol. gly.cine or crystal cellulose powcler, alubricant such ¿s magnesium stearate, talk, polycthyleneglycol or silica, an<l a rlisintegrator such as potato starch.

20

by using oily basc material such as cacao buttcr, polycthyl-ene glycol, lanolin or latty acid triglyceride, a trans<lermal

,- lherapeut liquic{ paralhn, whirevaseline, ointment, hyclrophilicointrnent an injection formula-tion tbrmulated by using one or more materials selectedfrom the group consistiug of polyethylene glycol, hyclro-gel

,o basc matcrial, disrillcd watcr, tlistillcd rvatcr lor injcclionancl excipient sucb as lactose or corn starch, or a t'onnulationtbr a(lministration tbrough mucous memtrranes such as anocularmucous mentbrane, a nasal mucous membrane and a¡oral mucous memb¡anc.

35 Fuûher, the cornpouncls of the present invention may becrrml¡inecl with Lrasic ion-exchange resins wt.icb are capalrleof binding bile acids aud yet not lreing absorbed in gas-trointestinal tract.

'l-he daily dosc of the compound of thc formula I is tiom4. 0 05 to -500 mg, preferably fron 0.5 to 50 mg f'or an adult.

Ir is administered from <¡noe lo lhree times per clay. The closemay of course he varied clepending upon the age, the weightor the condilion oI illness o[ the patient-

The compouncls of the ttrrmuias II ro VII tre novel, ancl

4-. they are important iutelnediates t'or the preparation of tbecompounds of the tbrmrLla I Accorclingly, the present inven-tion relates also to the compounds of the fomrulas II to VIIand thc processcs tbr thcir procluction.

Now,, the present invention will be clescribecl in further-n cletail with reference to Test Examples tbr the pharmaco-

logical activiries of tbe compouncls of the presenr invention,tbeir Preparation Examples and Formulation Examples,Ilowever, it should be understclod thal the preseot inventionis by oo meaos rest¡iclecl by such specilìc Eramples.

55 PFIAIIMACOT,OC;ICAL 'I'L,S'I' I,XAMPLþ,STest Â: Inhibitio¡ of cholesterol biosynthesis t¡or¡ ace ta te inv i Lrc.¡

Enzvme solution was prepared fiom ljver of male Wistarrat billìal.v cannulalecl zncl clischargecl bile for over 24 bours

6(l Liver was cut out at micl-clark and microsome trncl superna-tant fraction rvhich was precipitable rÀ/ith 40-8020 of satu-ration of ammonium sultìtc (.sup traction) wcrc prcparedfrom liver honogenate according to the moclifled metlrocl ofKnauss ct. aI.; I(urocla, M., ct. al., Biochim. Biophys. Acta,

0-: 489, l]-q (1977). For assay of cholesterol biosynthesis,microsome (0,f mg protein) aocl sup liaction (1.0 rngprotein) were incubated lor 2 hours at -17" C. in 200,r¿l o[. the

Rô

Rr

N

R1 RT

H 4-F H H

HÉTHÉI6-CI II6.CL FI6-OCH2P I ËI

HHHH6-Cl H6-Mc,N H6-Me II6-iPr H7-Mc H6-OMe ÉI

6-Bt E6-i-PL H6-Ct 8-CÌ5-F 6-8r6-Oùle 7-olvle6-Me 7-Me6-Cì 7-ClHIITI TI6-OMe 7-OÌvfe6-OMe 7-Olvle6-OMe 7-Olvte6-OMe 7-OMe&OMe 7'ONfe6-Mc tl6-Me II6-Me H6-Me H6-Me Hrt-cl H6-CI H6-C] II6-CI TIri-ct HHHut{HFITI TÌTI II

4-PhCH,4-Ph H i-Pr

H i-PrII c-PrH sec-BuH i-PLH i-tst¡H c-PentH c-PctrtH i-PrFI c-P¡H i-PrH c-PrH cPrH c-PrH c-PrII c-PrËI i-PrH i-P¡H i-PrH i-PrFI c-BüH c-I-IexH i-PrH i-P¡H c-PrH c-PrFI cP¡H i-PrtI i.PrH c-PrFI c-P¡H c-Prt{ i-PrÊI i-PrfI c-PrII c-P¡H c-PrH ì-P¡H i-PrH c-P¡tI c-PrII c-Pr

HHIIHHHHHÉI

[IIIÈt

HHTIIIB-B¡

4-F.1-F

4-F4-I-4-F4-È-4-F4-F4-F4-t4-F4-F4-F4-F4-F4-t+-F4-F4F4- trTT

4-CtH4-Ct4-FH4-ClH4-Crt4-1.H4-CttI4-Ct4-FH4-ClH4-L14-F

8-OMc.3-Mes-clFI

ÉI

HHFI

HHHIITI

HHIJHFI

IIFI

HÉI

FT

IIfi

capable oI suppressiug or retlucing the ¿mo unt oI choleste rolthe compound.s of the present

agen ls agaírrst hyperlipidemia,eroscleosis.


5,856,33613

rcaction mixture containiog AT?; I mM, GluLaLhione; ó mM.Glucose-l-phosphate; l0 mM, NAD;0.2-í mM, NADP; 0.25mM, CoA; 0.04 mM and 0.2 mlVI [2-]'1C]sodium acetate (0.24Ci) with 4¿1 of test compound solurion dis.solvecl in wareror tlimethyl sulfoxicle. To stop react-ion ancl saponify, 1 ml o[ 5

15% EIOH-KOFI lvas adcled to the ¡eactions and heated al7-5' C. t'or 1 bour. Nonsaponiflable li¡rids were extrauerl withpctroleum cther ancl incorporatccl laCì radioactivity lvascounted. Inhibitory activity of compouncls was indrcateclwith IC-50. 10

Test B: Inhibition of cholesterol biosynrhesis in culturc ccllsHep G2 cells at over 5th passage were seedecl to 12 rvell

plates ancl incubatecl witf¡ Dulbecco's nrodifled Eagle(DME) medium containing IOdh of letal bovine serunì 1,s

(FBS) at 37" C.,57o CO. until cells were contluenr tbr aboul7 rlays. Cells were exposed to the DME medium containing-í% of lipoprotein clelìcient serum (I-pDS) prepared byultraccntrifugation mcthod tbr over 24 hours. Medium waschanged to 0.5 ml of f¡esh 5% LpDS containing DME before ?0

assay ancl 10 ¡d of tcst compound solution dissolvccl in wareror DMSO were aclded. 0.2 pCi of l2-1'rC]sodium acetare (204l) was addecl at O hr(B-f) or 4 hrs(B-2) ¿Iter ¿ddirion ofcompouocls. Afler 4 hrs further incubarion wirb [2-1'rC]sodium acetate, mediuut was removecl and qel1s were 25

washcd with phospbate buftbred satinc(PBS) chillcd at 4" C.Celis were scraped with rubl¡er policeman ancl collectecl totutres with PBS and cligestccl wirb 0.2 ml of 0.-5N KOFI ar

-37" C. Aliquot of digeslion was usecl for protein analysis andremaining was saponifred r¡,ith 1 ml of 157¿ EIOH-KOFI at 30

75' C. for I hour. Nonsaponifiable lipids tvere extracted rvithpetroleum ether and raC r¿rdioactivity wa,s counLecl. Countswere revised by cell protein ancl indica¡ecl with DPMlmgprotein. Iohibitory aclivity of compouncls was inclicatecl withIC50. 35

Test C: Inhibitioo of cholesterol biosynthesis in vivoMale Sprague-Dawley rats weighing atrout. 1-50 g were tèd

normal Purina chow cliet ¿rnd lvatcr ad libitum, and cxposeclto 12 hours lightll2 hours clark lighting partern (2:00 ,,.PIVI-2:00 AM clark) prior to use ttrr in vivo inhibirion test of *"

cholesterol biosynthesis. Animals were separated gnrupsconsisting <¡f fìve raLs ¿l,s tr-¡ be average mean bocly weight ineach groups. Test compouncls at dosage of 0.02-{.2 mg/kgbody weight (0.4 rn|100 g body weight), rvere dissolved in ,.\tater or suspended or in O.5Vo methyl cellulose and orllly ''administered at 2-3 bours befo¡e mid-clark (8:00 PM), whilecholestcrol biosynthcsis rcacbcs ro maximum in rats. Ascontrol, rats rÃ,ere orallv acìminislered only water or vehicle.At 90 minutcs after sample aclministration, rats wcre _^

injected intraperitonealty wittr t0 ¡rCi of ¡2-ttclsodirrm ''']

acetate at volume of 0.2 ml per one. 2 Hours later, Lrloodsamples were obtainecl ¿rnd selum were separated immecli-ately Total lipicls were extr¿rctecl accordiog to tlle methocl ofFolch et al. aocl saponified with EIOFI-KOÈI. Nonsaponilì- __

able lipids ne¡e extractecl with petroleum etber anci radio -"activity incorporated inlo nonsapouifla[rle lipicls wascountecl.

Inhibitory âctivi¿y was inclìcatecl as percent decrease ofcounls in tesling groups (DPM/2 ml serum/2 hours) fronr u.¡that in control group.

With respect to the compouncls o[ Lhe prcsenL invention,tbe inhibitory activities against the cholesterol bkrsynthesisin which HMG-CoA reductase sewes as a rate lin.itiogenzyme, were measurecl by the above Test A and B The o_s

results a¡e shown in Tables, 2, 2-2,3 ¿r.:rcl 3-2. Further, theresults of the mcasurcmcots lry 1'cst C arc also prcscnlccl.

[rhibiLorv activities bv'lèst A

t., (nrolar conccntlrtion)

l4-Tê.BLE

2

Compound

(C'oor¡:ounds of tbepresonL rnventtonj

t-13r-51

I--sj(Relerence conrpounrJs.)

ìVlev inoLin

cs-sl4

125 x lù '.1 0x l0 s

7I x l.ù-8).9 x ID 1

14 x l(l e

90x 10-ç

In'Iable 2-2, ¡he relative activities tre sholvn based on theactivitics of CS-514 bcing cvaluatcd ro bc 1.

TABLE 2-2

Reiatil'e activities bv Test A

Corrrpouod Relative ac¡ivilies

(Compourds of thepresenl i[\€u!ion)

t-_l 6

I- 116l-111t-120t-522

Structures of relerence compouncls:

(1) Mevinotin

1.7-S

2.25o313 21,076

o otr

orr

o

o tI

oËI

CÉL

tLC

(2) c--s-_514

o

H,CH

o

CH¡


Inlibitorv autivilies bv'lþst ts-I

t--o (ntolar conccntratio¡)

5,856^336

16Example l-b

4-(4'-fluorophenyl) -3 - hyclroxyme t hy l-2 -( l'-me tbyle thyl)-clLrioolitre (compound VI-I)

5.4 g(0.016 mol) of compounct VII-1 was dissolved in (lry5 toluene uncler a oitrogen atmosphere ¿nd coolecl in ice lrath

lo 0" Cl. 'lb this solution, 40 ml of a 16 wt 7c dirsobutyla-luminium hyclricle{oluene solution rvas clroprvise aclclecl, andthe mixture r¡'as stirrecl at 0" C. for two hou¡s. Afterconfirming the coml)lete clisappearance of compouncl Vll-l

10 by thin liLycr ohromatography, a saturatecl ammonium chlo-ride solution rvas added thereto at 0o C to terminate there¿rction. Ethyl ether rvas acldecl to the reaction mixture, ândthe organic layer tvas separatecl. A gelled product wasclissolved b;r an acldition of an aqueous sodium hvc'lroxicle

t-s soÌution and extractccl anew with ethyl ethcr.'l'he erhyi ethcrextracts we¡e put toeether, clriecl over anhydrous magnesiunrsull¿rte and ûlterecl. The solvent was distilled ofL. Theresiclual oil unclerwent crystallization when left to stand Itwas recrystullizecl frcrm ethyl acelate-n-hexane Lc.¡ obtain 3.3

uo g of wbite crvstals Yielcl: 70%. Melting point: 136"-137" C,

l5

TABL.L 3

Corrrpound

(Coorpound cf the

PlgscúL LrverlronjI--51(Refcrcncc conrpor:nd)cs-514

I x 1l)-'

3 5 x l0 I

In f'al¡le 3-2, tlle ¡elative activilies are shown basecl on tlreactivities of CS-514 Lreing evaluatect ro be 1

T BLE 3-2

Relative activities by Test B- t

(-'ompound lìelâLive acLivities

I-116 19 +t-_î20 20 0II-)0 20 o'

I{csults of the rlcasurcment of the inhibitory activities byTest C

The percent decrease of counts atter the oral administr-a-¿ion of 0 (l-5 mg/kg of compouLrcl I-520 was 55Va rcla,Live totbe mcasured valuc of thc control group. I'he pcrcontdecrease o[ counts atier the oral administration of l0 mgftgof CS-514 was 557o uncle¡ the same condition. The ccrm-pounds of the pre.sent invention exhiltited activities superiorto the relèrence compouncl such as CS-514 o¡ Mevinolin inTest A, and exhibitecl activities superior ro CS-514 in TestsB and C.Test D: Acute toxicity

AO.57o CMC suspension of a test compouncl was orallyaclministered to ICR male mice (group of three mice). Theacule toxicity was determinecl based on the mortality afterseven ilavs. With compounrl I-57, I-58, I-59, 1-5\1, I-512,I-5 13, I--51:1, I-.51.5, I-.517 and I--523 of the presenr inventìon,Lhe rlortali[v was 09la even rvhen they were onLìly aclminis-lered in ûn amount of 1000 mgikg.

Example 1-c4-(4'- üuorophe nyl)-2-( t'- me thyte th yl) -q uin o lin-3-yl-carhoxyalclehyde (compouod V- I )

2.0 g (9 3 mrnol) of p¡rricliniurn chlorochromate zrncl 0.4 gof anhydrous sodium acetate was suspencled in 10 ml of clryclicbloromethane To this suspension, a solution obtained byclissolving I g (3.4 mmol) of compouncl VI-1 in 10 ml of drydictrloromethane, rvas immecliately aclcled at room temera-ture. The míxture wâs stirrecl tbr one hour. Then, 100 ml ofetbvl etber rvas acfded thereto, ancl the mixture was throughlymixed. The rcaction mixlure was lìltered unclcr sucl.ionthrough a silica gel layer. The flltrate was driecl unclerrecluced pressure. The rcsiclue was dissolved in the isopropyiether, ancl insoluble subst¡ìnces we re fìltered off. The filtratewas again d¡ied under reduced pressure, and ttre resìdue wasreclystallizcd from diisoprop]¡l ether to obtain 0.7 g (Yield:70%) ol slightly yelkrw prism crystals. Melting point:124"-126" C.

[xample l-d3 (3'-elhoxy-l'-hydrox¡r-2'-propenyl)-4-(4'-fluorop heny'l)-2-(1'-methylethyl)-quinoline (compound IV-1)

I 13 g (3.13 mmol) of cis-1-e1hox5,-2-(td-o-but.vlstannyl)ethylene was dissolvecl ir: 8 ml of dry tetralryclrofulan, accl

the solution was coolecl to -78" C. in a nitrogen stream. Tothis solrrtion, 2 nl (3.2 mmol) of a 15 rvt % n-butyllithium-n-hcxane solutíon was dropwisc adclccl. 'lhc mixture wasstirred f<lr 4-5 minutes. Then, a solution prepared by clissolv-ing 0 76 g (2.ti mmol) o[ compound V-1 in l0 ml of dlirterrahydrofurao was clropwise aclcled thereto. The reaclionmixtule was stined at -78o C. fo¡ two bours. Then, 2 ml ofâ saturated ammonium chloride solulion was adcled therelofo tÈrminate the reaction The organic layer wa-s extractedwith dicthy.l cthcr, ancl thc dicthy'1 clhcr cxtract was v/ashcdwith a saturaled soclium chloricle aqueous solution aucl clriecl

over anhy(lfous m¿rgnesium sulfate, The solvent was dis-tilled off uncler reduced pressure. The resiclue was separatedwith ¡-hexane and acetonitrile. Thc solvent was rlistillecl oll'under reclucecl pressure tìom the acetonitrile layer, ancl anoily substaoce thereby obtaiuecl was purifled by siìica gelcolumn chromatography (eluent: 2.5c/a meLha.¡o|-cbloroform) to obtaio 0.91 g of the clesi¡ecl comporrncl in a

¡rurilìed oily tbrm.tI-lvlNR (CDCI-) ò ppm: LI(t,311,7ÍIz) 1.37(ct,6lIJ:

7 H z) 3.1 (n,lI1); 3.1 (q,2rI,t =71-Iz) 4 7 5(t, ttt,THz) 5 1 (n,1FI) 5.9s(m,1H) 7.0s-8.2(m,8H)

25

30

35

4t)

Examplc IEthyl (E)-3,5-clihyclroxy-7-[4'-(4"-lìuorophenyl)-2'-1 t "-

a-s

me thyÌethyl)-quinolin-3'-y1]-hept-6-enorte (compound I- 1 1)(prepared by steps of Example [-a through Example I-q)

Example 1-a 50

Ethyl 4-(4'-fluorophenyl)-2-( L'-rnethylethvl)-quinolin-3-yt-c¿ìrboxylate (compound VII-1)

The synlhesis rvas conclucted in trccorclance witb themethod disclosed in J. Org. Chem., 2899 (1966).

6.45 g (0.0-l mol) of 2-amino-4'-fluorobe(lzoptìeoone, -sí5.53 g (0.035 mol) o[ cthyl isobutyrylecctalc ancl 0.1 ml ofconc. sulfuric acicl were clissoh'ed in -30 ml of glacial aceticacicl, ancl thc mixlure was hcatc(l at 100" C. tbr about t0hours. After conflrming the substantial clisappearance of2-amino-4'-fluorobenzophenone by thin leyer oo

cltromatography, the reactioo solution was cooled to roomlempecaLurc, ancl a mixLure o[ 4-5 ml of conc. ¿ìqueousrmmonia ancl 120 mi of lr.ater cooled with ice, rvas gr.aduallyadclecl thereto- A sepalated oily srLbstance rl.as soliclificclwhen letì to stao(l overnight in a retrígerator. f'his solicl was 6.5

recrystallizecl [ror¡ a small amount of ethanol to obti¡in 6.47g (55çb) of whitc powclcr. Mclting poinr: ó8'-70.5' C


5,856.336l7 18

Example l-e aqucous sc¡lution was dropwise added Lhereto. The mixLure(E)-3-[4'-(4"-iluorophenyl)-2'-(1"-meth¡ lethyl)-quinolin-3'- wis stined at room tempãrature tor further one hour, anclyl]propcnaldchyclc (compound lll-1) elbanol w¿,s clistillecl off rìnder reclucecl pressure. Then, 5 ml

0.91 g of compound lV-l rvas dissolved in 20 ml oI o[r¡,ater lvas adclecl thereto, ancl rhe mixnrre was extractedtetrahydrofuran, and -5 ml of water s with ettryi ether. The aqueous layer was freeze-clriecl top- obtain 40 mg (67tì'/o) of hygroscopic whitc powder. lVlcltingstiso point:207o-209" C. (decomposed).

ex cl soclium chloriclc Example 3âqueoüs solutiou ancl driecl over anhvclrous masnesium l0 (E)-3,5-dihycÚoxy-7-14'-(4"-fluorophen¡'l)-2'-(1'-sulfatc. Thcn, thc solvcnt wasdistiilect off. Thc rcsiclue was ^"

methvlethyl)-quinolin-3,-1rl]-hepr6-enoic-acid-(compounclpuriflecl by silica gel cohrmo chlomatography (eluent: I-21)chlorol'orm) io t-¡btain the tlesirecl product as rvhile prism 110mg(0244mmol)of compouncl I-.L1 wasclissolvedincrystals. 0.4 g (SOC/o). Melting point: 127"-t28" C. l0 ml of ethanol lhen, O.j9 mlof a 0.5Nsoc.lium hydroxicle

Example I-f 1-i aqucous solution wa

Erh),1 (E)-7-[4'-(4''-fluorophenyl)-2'-(1"-meihylethyl)- was stirred 1l ::]o-

quinolin-3'-yl]--5-hyclrox.v-3-åxohðpfo-6-enoat" 1.å-puitía cthanol was distiiled

II-1) ' of water was addeci

-5ô mg oÊ rí07a socliunl hydride wa The aquetrus lt¡,er ',vas weakly aciclilìed

perroleum elhe:r an<,I clried uucier a nitrgg lute hydrochÌoric aqueous solution and

iuspeoded in 5 ml of clry retrahyclrofui es with ethyl ether. Tbc etbyi ether layers

was coolccl to -l5o C'. inl nirrogen atm and dricil ovcr anhvtlrous magocsium

mg (0.92 mmol) of erhyl aoetoacetate solvent was clistilled off under reclucecl

thèreto, ancl the mixtul.; rvas stirrecl tbr 90 mg of slightl.v ycllow oily substancc.

0.ó mt (0.92 mmol) ol a 15 ivt 9zc n-bur .) ò ppm: 1 36(d,6HJ=7Hz) 2.4(m,2Fl)solutiori was rtropiise aclclecl thereto, a 'IH); 3.8-a'6(m'2H) 5.40(dd,lH,J1=stirrecl tbr 30 minutes. Then, a solurion p 5 (d,1H,J=l9Hz'l 7 tI-8.3(m,8FI)

ing 160 mg (0..5 mmol) of compound III- t in clrvtetrahvclr.lur¿n, lvas clropwise adclecl th

tr rtr Y Examplc 4

ture was stirre(l fbr one hour.'ri¡ the rea ophenyl)-2'-(ì"-methvlethyl)-quinolin-]'-

of a satrratecl amnronium chloricle aqrL :xy-3'4' 5'6-tetrtthyclro-2H-p¡'r¿¡-)-en"

atlcled at -15" C. Then, the mixrure rvas cwlh dierr,),I erher. rhe crietrryr erher so

",ïåii"i::#J.ätîî'.:l #",rL,"[12witb a saturatccl sodium chloriclc âquoous E a Dean Slark apparat*s.over anhvdrous magnesium sultite The s ,tillccl off uncle I ròàucccl prcssurc, and thcrate(l to clryness uncler reducecl pressure. The residue was L-esiclual solicl was recrystallizecl from clüsopropyl elher torecrystallized tìom diisopropyl etber ¡o obtain 1:!l

^m^g obtain 40 mg of coloilcss prism crystals. Mciiing poi't:(yiekJ: 59otL) <.¡f white crystals. Melting point: 99" l0l" C. lS2._1S4 . ð.

l,xample 1-g Bv siliea gel thin chromalographv, the prodtLcl gave LwoEtbyl (E)-3,5-dihyclrox_v-7-[4'-(4"-fluoropbenyl)-2'-(-t ''- ''' absoqrtion spots close lo each other attributable to themcth-vlcthyl)-quinolin-3 '-yl]-hcpt-ó-cnoatc (compouncl diastereomers. (Developpiog solvert: 3c/o netha,ool-I-11) chloroform)

110 mg (0.245 mmol) of compound II-1 lv¿s rlissolvecl in These clìasterorners wore separated aod isolated by silica-5 ml ol ethanol irr a nitrogen atmosphere, ancl the solution ,. gcl thin laycr chromatogr¿ìphy, [Developping solvcnt:was cocrle<ì i)" C. Ihen, l() mg (0.263 mmol) ol sorlium "-' t-BuOlVleihexane,'/acetone=7i2i I (vlv), Rf=0.6 ancl 0.7borohvclride 'was added, ancl the mixturer r.vas stirrecl f.or one (olrtainecl weight ratio: 1/2)lhou¡. Therr, I ml of t't l0o1o hydrochloric ¿cicl aqueous Rtt().7; trans lactoLresoiution was adclecl therer6. ¡nd the mixture rvas extracted H-NMR (CDC13) ò ppm: 1.40(cl,6HJ=7Hz) L6(n,2H)three times wilh elhvl erher.'l'he ethyl ether sohrtion *0. --,. 1.6.5(m,2FI) 3.48(m,1H); a.20(m,tH) 5. l-5(m,1H) -5.37(cld,washod i¡'irh a saturatc(l soclium chloridc aqucous solution ''' lH,Jr=13¡1r,Iz='lqz) 6.68(cl,1H, I=L9kIz.) 7.1 S.2(m,8H)ancl dried over anhyclrous magnesium sulfate. Then, the Rf=0.6: cis lact nesolution was evaporatecl to ctryness u¡der recfucecl pressure. H-NIVIR (CDCI3) ò ppm: 1.40(d,6HJ:1Hz) 1.6(m,2i-I)The ¡csìclual oil was purified bv silica gel column chroma- 265(m,211) 3 4.3(m,1FI); 4.20(m,1H) a.ó5(m,1FI) -5,40(dd,tography (eluent: 592 meth¿tnt¡l-chlorotbrm) ro obtai¡ the -- lFI,Jr=l8tIzJ.=7117¡ 6.66(m,1FI) 7.0-8 {m,BH)dcsired procluct as a pure colorless oily substance. 70 mg -"(Yielcl: 647a)

il-NMR (cDC].) ô pprn: 1.30(r,3il,J:8trz) 13e(c1,óIl,J= 9j.*".1-*..;,OTï:10""' uinolin-3'-8FIz) 1.4-r.8(n.zø¡;').+z1tr,zri,t=tírz¡ 3.û3.8'("',irO llllllLll'l-119'-v vran-2-one3.-st(m,lH) :.u-+.o(m,zt¡ 4.20(q,2H,J=.3FIz-; ;.:-sim,rnj ...

('iÏPj'.1'l,t:?.6.5e(m,1Fr) 7.r0-8.i8(m.sH) ' ''---' ó0

,"#.ic*.TlåT'"*,irï, of erhanot, ""d ,n Í,îi.lt;rlExample 2 pall¿clium-uarbon was ¿cldecl theret<¡. The mixture was

Soclium salt oi (L,)-3,-5<tihydroxi,-7-[4'-(4"-tÌuorophenS4)- sti¡recl uncler a hyclrogen ¡ìtmosphere. Al'ter conlìrming t.l-re

2'-(1"-methylethyl)-quinolin-3 '-yl]-hcpt-6-enoic acicl clisappearance of the starting substance ancl the appearance(compouod I--51) o-s ol'a new spot by lhiú layer chromatography, the pailaclium-

60 mg (0 1-3-3 mmol) of cornpou ncl I-11 was dissolvecl in carl¡on w¡s frlterecl off, ancl eth¿nol was cìistillecl oft'tr¡ obtainJ ml of cthanol. I'hcn, ().26 ml of a 0 5N sodium hvclroxidc color.lcss oil.


5,856.336t9

This oil was puritecl by preparative thin layer chroma-tograpby !o obtain 16 mg of the clesired product as purecolo¡less oil.

MS(nrie): 408(lvf*+H), 407(M*), 366, 292, 278In tbe same mÂnner as in Exam.ple l-a, compouncls VII-2 5

fo YII-27 were preparecl lhe physicai properties of thesecompounds a¡c sho',vn in läblc 4. (In thc lhblc, Iìr, Iì.2, R3,Ra, R5 ancl R21 corresponcl to the suLrstitients of compounclVII.)

20

TABLE 5

(Comporrnds i¡ this'làble are compounds o[ Lhe

lormula VI wherein Ró is hydroqen.)

Compound Rr Rz R:' R4 Rs cc,)

TÄBLE 4

(Compourds ín this Täble are compounds of LheVfT Rd is hvdropen I

HHp-FHCH'II FI H TI CH.FIHHHi-Pr6.CITIÛHCII.6-ClHHHi-PrH [I 2-l' H iP¡r--NleHHHi-PrH t{ 4-Cl H iPrHH4-OlvlcHi-PrFI Il 4-Me ll iPr6-ClH2-ClHi-P¡H H 4-CFj ËI i-P¡H lf -: Me 4-F i-PrH FI 3-Me 5-Me i-Pr6-N1e 7-OMe 4-F H i-PrÉIH4-FHCrH5HH4-FHn-Pr6-Cl H 4-F tl i-PrHH4-l.Hc-PrHH4-OPnHi-P¡6-Cl s'Cl 4-F H i PL

6-CIHHHPh6-Cl U II Il c-PrtI ÉI 4-F II sec-BL6-Me !1 4-t H i-Pr6-OMe 7-OMe 4-F H c-Pr

4-F TI CÉI3H H CFI:.H H i-PrHHCE.H H i-Pr]-F It i-PrH H i-Pr4-Cl H i-Pr+-O^\4e H i-Pr4-Me H i Pr:-CI H i-PI4-CFj fI i-Pr3-M€ +F i-Pr3-Ve 5-Me i-Pr

HHHHLIHHHHFITIËI

HH

CrtLCrH.C.ItCrHtCrI!czflsC"H.crt{_.CrHtc2FlsCrI!CJI"c:IrsC.HtCrHtcH3c2Flsc:Êr5cH.C.HuC.HtC.HtCH'CH.

1,11,-1)2102-10? 585i5.5100 5-101 5105 5-106 5

.10 r 0-102 0oil134 0-r36 5

88.C¡-49,0r08 5-t09.5lu11 0-103 0

117 -s-_119 0oiloil96.0-93 r)

139 0-139 5oil94 -s-95 5113 5-.116.-s

oil96.0-98.0113 8-119 5

97.0--9S 5

oil

Yf-2vt-3

10 vt-4vI-5VI-6vl-7VT8vI-9

t-s vt-10VT-I IvI-1?vI-13vI-14\rl 15

rn v[-1ó-" vL1-l

vt-I8VT-19VI-20yl-)J,yt-12

25 wztw-24vI-25vf-76vI-27

149-15i130-130 5

t39-1,471Ci8-169140.5-141.015-ç.0-157,0192 0-1q5 0186.0-138 s161.0-_r64 0122.O-12+.O183 0-186 0t6 \.D-162.st-17 0 1-18 01ó4 0-.165 014:L -5-143,5146.5-148.51'110-\7).O720-12615J 0-154,09S_5-10-?

7'11 S-t12 3.c4.0-36.0119 0-121.0tó0.0-161 516?.0-16-3,0

Com-pound RL Rr Rr Rr R5 R2'

mP.('c.)

VIt-3VII-4vII--iVII-6VII-7VII-8VII-9vtI-10VII I]vtI-11VII-13vII-14vII-15vtl- t6vII- 17vII-1SvII-1ç)vlr-20\¡II-t.1vIt-22vIl-2-rvIt-24vII-2s

ó-cl6-CtH

vil-26vlt-7i

6-Me II6-O\4e 7-OMe

HHH6-Ct6-ClFI7- \Ie

HH

HHHIIHFI

HHTT

FI

IIH

IIHH6-CIIIIH6-OMe 7-OMe 4-FFI H 4-FËI FI 4-F6-Cl U 4-FHH4-FH rI 4-OPh6-Cl .\-Lll 4-F

30

35

HHHHHHHHHH

tIH

i-PrC"H.n-Pri-Prc-Pri-Pri-PLPbo-P¡scc-Bui-Prc-Pr

Ht:I

H

HH4-F

4-F+-F

In thc samc manncr as in Examplc 1-c, compouncls V-2 toV-2'7 werc prcpared. (In 'lhb1c 6, Rl, Rr, R3, lìa and l{5correspoocl 10 the substitueDts of compound of V)

TABLE 6

(Compounds iD this TàbÌe are cornpoulds of thecrtls 109 0-111.0cH. 153.0-15-1 -ç

Rd is hydrc'cen )

4ll conrpo.n,l Rl R2 Rrn.p

Rr Rs ('c_)VII-8II-NMR (in CDCÌJ ò ppm: O.92 (,3II,J:7IIz), t.4l

(cl,6H,J=óHz); 2.a7 $,3H),3 27 (HeptdpleL,I[J=6Hzl 3.96(q,2H,t :1 Hz), 7.0-7, c3(m, sH)VII-14

H-NlvIR (in CDCI.) ò ppm: l.0l (I,3H,.T:7H2.), 1.42(d,6FI,J=6FIz); 2.-18 (s,3HJ:3Hz), 3.25(Heptapler, lH,J=6LIz) 4.()4 (q,ZII,J=7flz), 6.9 -A.I(m,7llz)VII-I5

FI-NMR(in CDCU ð ppm: 0.97(t,3H,I=7Hz),1.43 (d,6H, 5rr

l=6LIz);2.29 (s,6H) 3.25 (Heptaplet, lHJ:6Hz) a.OO (q,2H,I=1Hz), 6.8-3.0(m,7H)VII-I8

H-NMR (in CDCI.) ò ppm: 0.98 (t,3H,J=7Hz), 1,.O2 _-(f ,3H J =7 Hz); 1.6-2.3(m,2r\, 2. 8-3. 1 (m,2H) 4. 03 (q,2 FrJ= :r7Hz), 6.9-8.1(m,BH)vu 21

H-NMR (in CDC13) ò ppm: 1 03 (t,3HJ=7Hz), I4I(d.6H,J=6ÉIz); 3.25(Heptapet. IFI,J=óHz), 4.05(q,2H,J=

0,,7Hz),6.8-8.t(m, 13H)vtI-25

FI-NMR (iu CDCI.) ò ppm: 0.97 (cl,6FI,J:6Hz), 2.O-2 6( m,l H); 2.85 (c1,2H,J=7FIz), 3.-s t(s,3H), ó.s-8. I (m,sH)

In the sar¡e manner as in l,xample L-b, compounds VI-2 6sLo YI-27 werc prepar..ùd. (In Table -5, Rt, R2, R3, R'+ aLrcl R5co¡rcspond to thc substihtcnts in compouncl VI )

In Lbe same manner as in Exitmple 1-d, compouncls IV-2to IV-6 rvere preptred. (In Table 7, Rr, R2, Rt. Ro and Rscofresponcl to thc substituents oI compouû(l IV)

45

v-2v-3Y,4v-_s

v-riv-'7v-8\,'9v-10v-11v-12v-1-?

v-1,1v- t5v't6v-77v-18v-19v-20v-21

\r'-23

v-26v-27

p-¡TI

HtT

trl-FFI

4-Cl4-Oñle4-Mc2-Cl4-CFr3-Nfe3 N4e

4-F4-F4-F4-¡',1-F

4-OPh

HFI

F]6-Ct6-CtTI

7-MeFIHH6-ClHH.H6-OMeHH6-CtHH

6-Cl6-CìFI

6-Me6-OMe

Il crl lH CH.H i-Pru cHlIl i-P¡H i-PrH i-PrH i-PrH ì-PrH i-PrFI ;PfH i-Pr+F ì-Pr

i-PrCrHtn-Pri-P¡c-Pri-PriP¡Phc-Prscc-Bri-Prc-Pr

5-Me i-Pr

t2-5-12S143-1,4691-93

t4ù-140 5

t2) 5-12101{J5._t-109.2747 0-14i.8'1-15.6- t36 I11,9.4)1A 4t0_5_8-106 9't63'7-\64.2

161.:l-108 1

1fû.3-122,3't64 4-165.21+3.1 1442150.2-155 3t64 5-1ri5,3150.1-151.6106J-107 7.t35.0-13-i 7

174.8-175 _1

157 5-158 0125 0-12rt -Í155 0-15 7 0200 0-200.5

7-OMe HHHHHHHHHLI

TI

H

HÉI

fIHH

6-Cl 8-C 4-tHHHH7-OMe

HTI4-F4-F4-F


5,856.33621

TABLE 7

)7

TABLE 9-continued

fV

Conrpouud Rr R2 Rr R I R5 rn.p (.C,t

(Coorpounds itr this tàbte are compocrnds o[ theRó ìs hvdropr¡r I

(Cornpounds in this làble are coopou0ds of ühe

tormuìa ot lf wherein Rd ís hvdroqe¡.)-)

Com-pound Rl R2 Ri R{ R_- R 1l

rìr P,cc.)lv-2

IV:3IV-4IV-5IV-6

H FI +þ' H CH.HHHHCH.ËIHËIHi-Pr6-Cì HHHCÉLtt-Cl t'I II tI i-Pr

I1'7-t /9II.1OtI-11

'10 II-12II- 1 -lII-14tl-15tt-16tf t7

1_i tI-18II-19II-]OII-21tr-22IT-23

4 O\,fe4-O\4c2-C1

4-C[i53-\4e-ì--\4e4-F4-t-4-F4-['4-F4-OPh

C.H,c,H-crI{.c2[IsC.HtC],H.c2H,.

c-u-CrItCrH.c.H,C.H-CrHtc'2[r_s

C.H.

CrHtCrH.

HH6-ClHHFI

6-OMeHH6-ClIIH

HHttTI

ËI

H

iPrtsPri-P¡r-Prr-Prr-PriPr

o-Pri-Prc-Pri-Pri-P¡Phc-Prscc-Bui-Prc-P r

HHHII+F5-MeTIHHTIHHHÉT

HH

c"Its c,H.

78.0-78 575.0-7S 0oil73.0--8.1.0

66 0-71 0oits3.0 90 094.0-97--0oil111 0-113.-.91.0-9,3.012.1 0-125 0oitoil69 0-,1 ), t)

oil

oiloil

In the same manner as iü Example l-e, compounds III-2lo lll-27 were prepared. (In Table 8, Rt, Rr, R3, R'and R5corfespond to the sutrstituents of compound IIL)

TABLE 8

lCbnrpountls in tiis lhblc are cornpoun<Js o[ thelbrmula fll rvhe¡ei¡ R'j is hvrlrout,rr.r

7-OMegHIIÉIH

6-Cl 8-Ct 4-F6CI H H6-CI H HHH4.F

,n II-14

Com¡round Rt R2 II-]6lL)1

6-lvle H 4-F6-OMe 7-OMe 4-t

nr P-('c ) H

HtlI-]ITI.3TII-4III-5TII-6TTI.7

III-3III.9lTr- r0

TII-11Itr- t2III- L-I

tII-14TIT.1.5

IIt- 1 6fiI- t1ITI-13IIT-]I9III-]0IIT-21IÍI 22III-].]IlI-24III-25TII-}6ill-li

HHH6-Cl6-ClH7-MeFI

HÛrt-clHTI

FI

6-OlvIeHtIrt-ctHtt6-Ct6-Cl6-CltIû-ùte6-Or\le

FÌ

FIHIITI

HH}IHuIIH11

t{7-ONle¡{IIHHHs-clHI{IIH7-()Me

4-þ'TI

HIItIl-1,'TI4-Cr4-OMe4-NIe2-CI+cF._?-Me

-l- ñfe4-F+F4-F+F4-F4-OPh+FHH+F4-F4-y

HHt{IIHHHHHI'IHËI

4-F5'MeÉT

HfiFI

HHHHHHHH

CTLCH"i-P¡cIl..i-P¡i-Pri-Pri-Pri-P¡i-P¡i-PriPri-Pri-Pri-Prc.H,n-Pri-Prc-Pri-Pri-PrPhc-Prsec-Bui-Prc-Pr

ilt-22H-NMl{(in CIDCL) ô ppm: 1.40(d6H,J=7FIz), 3.44

(Heptaplet,lHJ=7FIz); -5.93(clcl,1 Il,J:8Hz,J=1 6Hz), 6.8-a. I(m,14H) e.34(d,1 FI,J=8Hz)

In the same fianner as ìn Example 1-1, compouncls II-2 to -so

ll-27 wcrc prcparcd. (In 'làblc 9, Rr, lì2, R3, l{+ ancl l{5correspond lo the sìrbstitueÙts of compound II.)

TABLE 9

Corn-pound

(CìonrpounrJs ir llìis làble lre compounds o[ Llre

t-otrnuìa of [I wherein Rd is hvdrogen.)

R, R2 Rj Rr R.i ilö

25 Il-',zH-NMR(in CDCL) ò ppm: 1.21(t,3HJ=7tIz), t.32(ct,6H,

I:6Hz); 2.2-2.4(m,2H), 2.5 2.7(m,IH) 3.28(s,1H), 3.34(Hep taplet, 1H,J=6Hz) 4.t)8(q,2H,I =7 Ílz), 1.34.6(tn,IH)5.28(dcl,llI,J:6Ilz,J: IÍfIzl, 6.-s3(dd,rtIJ:1 .51Iz,J =15llz),

:o 6.9-8.0(m,8H)1l-12

H-NMR(in CDC13) ò ppm: I 25(t,3ÍI,I=7ÉIz), r.33(ct,6H,t =6Hz) ; 2.2-2.4(m,2H), 2.s-2. 8(m,1 H) ; 3.32(s,2H), 3.38(Hep tapler, lFI, J=6 Hz) ; 4.1 3 (q,2H J =7 Hz), 4 24.6(n, lH) ;

35 5 34(dd, 1H,J -6H'¿, J=1 5ÉIz), 6.53(r,lcl,rHJ=1 5FIzJ:1-5Hz),7.0-4.0(m,7H)II-15

II-NMR (in CDCIr) ò ppm: 1.23(t,317,1=7llz),1.35(d,6[I,I =6Hz'); 2.2-2.4(m,2ÍI), 2.3 l(s,6H); 2.6-2.8(m,rFf . -3.32(s.

40 2H) : 3.35(Hep1ap1ct,IH,J =6llz), 4. l2(<1,2H,J -7 Hz) ; 4.34.7(nr,rH), 5.-30(dd,1HJ=6Hz,I =l.6Hz\: 6.5 1(clcl,rH,J= lFIz,J=16Hz), 6.7-8.0(m,7H)II.TB

H-NMR (in C-DC1_]) ô ppm: 1.00 (t,3HJ:iHz), 1.26(t,+s 3ll,I =7tlz); 1.6-2..3(m,2Íl\, 2.12 (d, 2lIJ:6fIz): 2.61.2(m,

3H), 3 3s(s,2FI) a Í(t2H):7ttz).4.3-4.7(n,1H) 5.27(dd,1.H) :6Elz,J=76H2) 6 46(dcì,1H,J:1 -sllzJ:lóLlz), 6.9-S.0(m,8H)tI22

H-NMR(in CDCI3) ð ppm: 1 26(t,3H,J=7ÍIz), 1.-13(d,6H,J=6lrlz); 2.43(c1,2Íl,I:6Hz), 2.6-2.9(m,lFI) 3.36(s, 2H), 3.44(Heplap le t, 1 FI,J=6 Hz) 4. t 3(q,2H,I :7 ÍIz.), 4.34 7 (m,1 H)-5.30(dd,1H,J=6Hz,I=I6tI¿), 6.53(dd,1H.J:1 sHz,I = L6Hz),7.0--7,6(m,6II)

-ss tI-23H - N Ml{(in CDO.) ti ppm : 1.23(r,3 H ) :7 trtz), 2.2 I(cl,Zt:t,

I=6Hz); 2.4-2.6(m, tH), 3 2-5(s,2H) 4 09(q,2LI,J:1Hz),a. 1-a.4(m,1H) -5.08(dcl,IFI,J=6 Hz,I:16Íl'z), ó.26(dd,1Fl,J:I 5Hz,l=l6Hz), 7.0-8.0 (m, L3H)

60 II2-5H-NMR(in CDCIJ ò ppm: 0.96(d,6H,.1=6ÍIz), t.26(f,3H,

I =7 H ¿), 1 . 8 2.4(m, 1 H), 2.43 (cl,2H,J : 6Hz), 2.6-2.9 (m, \H),2.8 8(rt,21 | ) :7 f I z), 3.3 6(s,2ll), 4. I 4( q,zf I ) =7 IIz). 4.3 4 .7(rn,lFl), 5 0--5 5(ur,lFl), 6 3-6 7(m,1H), 6 9 8.Ì(rn,3FI)

6s II-26FI-NMR(ìn CDCI3) ò ppü: 1.25(r,3H,I=7Hz), 1.32(<t,6H.

J =6LIz), 2.32(s,3Íl), 2..39(c1,2H, J =7 Hz), 2.ó-3.1(m, r H),

t94-:t961'70-171 5107-10s.5\92-t94125 5-.127

,30 1-{0.2D1.t-t22 3r48 0-t49 l)37.+-'140 I1_tl 6-11-].1s-r.8-s4,-s\26 2-\28.8t24.3-1'Jb 4117Êt:0-l147 8-150.9124 3-718 5

117.S-111 51-15 2-135.9141.3-144 roiL

117-122141 8-144 3161 0-161 578.0-.3t 01-r7 0-137,_s

189,5-191_0

It-2tl-3TI-4II..S

II-6l-1tI-8If-9

HFIH6-Cl6-ClH7, \{eH

HFI

HtIHHHH

p-FHFIIIH'i-v-

H4-Cl

HFITI

IIFI

Él

ÉI

H

CH. C.H,CH. C:FI5i-Pr C:FI5cflr c.tLi-Pr C.H,i-Pr C:H,i-Pr C.H.i-Pr CrH.

oil1ß5-:t0(i88 5-90 577-S296-9Soil65.5-74 0I 1.0-94 t)


233 3 6(s,2FI), 3.41 (Hcp taple t, LFI,J = 6Hz), 4 Ll\t1,2H

"I :7 flz),

4 34.7 (m,Ill), 5.0-5.s (m,1 FI), 6 3 -6.1 ( m, IÍI), 6.8-7. 9( m,7H)II-27

H-NMR (in CDCI") ò ppm: 0.8-1.5(m,ag, 1.26(t,3H,J: 57 Hz), 2.0-2.9(m,4H), 3.42(s,2H), 3. 7 I (s,3ÉI), 4.00(s,-lH),4.20(q,2H,I :7 Hz), 4. 4- 4.8(n, 1H), 5.-3--5.8(n, I tI), 6.44 9(rn,1H), 6.s8(s,1H), 7.0-7.s(m'5H)

In the same manner as in Example l-g, compouncls I-12Lo I-727 *,ere prepared.

10

TABLE 10

5,856.33624

3.49(Hep taplel., 1H,J=6 Flz) 3. 6-3.8(m,1 H), 3. 9-4.2( m, l. H)4.20(<1,2L1 J =1 Hz), 4.3 -4.5( m,7H) s.2-s. s (m,1 tI), 6.-5-ó.8(m,1 FI) 7.ii-8.2(m,8FI)I-110

FI-NMR (in CDCI.) ò ppm: 1 .29(t,3H,J=7tIz,),1 .40(d,6FI,l=6Hz); 1.5-1 6(m,2H), 2.3-2.5(n,2H) 2.8--1.0(m,1FI),3.4-3.6(m,1H) 3.-52(Hep t aplet, t H,J:6Hz), -3.8.9(s,-3H)3.9-4. r(m,lH), 4.20(q,2H,J =1Hz) 4.3 4. 5 (n,LH), 5.3-s.5(m,1H) 6.s-6.7(m,1H), 6-9-s.1(m,8H)

H-NMR (in CDCI-.) ò ppm: 1 30(1,3H J=7}]rz),1 3-1 -s(m,2H); r 3 9(d,óH,J =6Hz), 2.3 -2.5 (m,2ÍI) 2.43( s,3H), 2.8-3 t)(m,1 H) 3.50(Heptapict,l H,J=6 Hz). 3.5-3.7(m, IÍl) 394.2(m, I H), 4.L9(q,2H,t =7 Hz) 4.24.5(m,1 H), s.2--s.6(m, I H)6.4-6.8(m, I H), 6.e-8.2(m,8FI)t- Il.21-s H-NMR (in CDCI) c\pprn: 1.30(r,3H,I:7Hz),1.-l-1.6(m,2Ll);1.37(ct,6H,t=6ÉIz),2.3-2.s(m,2Ír)2.912(m,ttI),3.41(FIep taplet, lH,I =6ÍIz) 3.5-3 -8(m, 1H), 3. 9-4. 1(m,1H) 4. 19(q,z}l,l =7Hz), 4.2-4.s(m, tH) s 3-5.7(m,1FI), 6.5-6.8(m,1H) 7 1-8.1(m,7H)

?0 I-113H-NMR(in CDCI.) ò ppm: 1.0-J..3(m,2FI), 1.30(I,3FI,J=

7Hz) ; I 40(1,6H,J=6Hz), 2.3-2.4(m,2H) 3 3-3.s(m, 1H),3.49 (Fleptaplel, rH,J=6Hz) 3.6-3.7( m, f H), 3. 9-4. 1(m,1H)4. I 8(q,2FI,J=7FIz), 4.2-4 -s( m, t r! s. 1 --5.s(m,1 FI), 6 -5-6.8

zs (m,lH) 7.2-8.2(m,8H)I-IT4

H-NMR (in CDCI.) t\ ppin: 1.2-1.4(r,2H), 130(I,3FI,J=7 Hz); t.39(d,6H,I = 6Hz), 2. 32(bs,3 Fl) 2.3-2. 5 (m,2H),3 0-3.3(m,1H) 3.50(Flepra¡rlet, LÍI,J =6Hz), 3. 6 3.8(m,1H)

.¡o -1.8-4. 1 (m,1 H), 4.21t(q,2H,J =7 Hz) 4.3-4. 6(m, r H), 5.2-s, 6(m, I H) 6..5-6.8(m, 1 H), 7.O-8.2(m,7FI)I-115

H-NMR (in CDC1.) ò ppm: 1.1-1.4(m,2II), 1 30(t,3ll,J=1 H z); 1.40(d,6[I.J=óHz). 2.2 2.5(m,2H) 2.35(s,6H),

35 2 7-3.I(m,lH) 3.5r(Hcptaplct, IHJ:óHz), 3.6-3.7(m,1H)-1.8-a 1(m,1H), 420 (q,zH,J=TÊIz\ 4.2-4 6(m,1FI), s 2-s.6(m,1 H) ó.4-6.8(m,1H), ó.8-8.2(m,7Fl)I-116

H-NMR (in CDCI.) ò ppm: i.30(t,3H):7Hz). r.37(d,óH,+o I=6H2.); 1.-5-1.8(nr,2H), 2.3-2.5(m,2H) 2.9-3.2(m,1H),

3 46 (HepLapler,tFI,J=6Hz) 3 6-3:8(m,rH), 3.7-5(s.3H)3. 9-4. 1 (m,1 H ), 4.07(s,3I I ) 1.2{t(q,2Il,J :7 l7z), 4.24.5 (m,1H) -5.1-5.s(m,1H). 6,4 5.8(rn,2H) 7. t-7.5(n,sH)r-11,7

4-{ H-NMR(iLr ClDCl3) ò ppm: 1.30(r,3FI,J:1Hz), 1.37(r,3H,J =7 Hz): L4-1.1 (n.2H), 2.2-2.6(m,2H) 2..e-3.2(m,3H),3 6-3.9(m,1H) 3 9-4.7(m,.lu), -s.2--5 7(m,1FI) 6.3-67(m,lFI) 7 0-8.2(m,8H)I-118

50 H-NMR (in CDCI') ò ppm: 1-01(1,3HJ=lLIz), 1.27(L,3tI,I =7 tlz) ; t .4-2.1(m,4H), 2.3-2. 6(m,2H) ; 2.8-3.3(m,3FI),3.6-3.3(m,1H)r 3 9-4 l(rn,tH), 4 18(q,2FI.J=7[Iz); 4.24.5(m,1If , 5.2-5.6(m,1 If ; 6.4-6.7 (m,Lfl), 7.0-8. l(rn,B II);I-119

H-NMIì (in CDCll.) ò ppm: 1.2-1.-5(m,2H), r 3[(r,3H,J=1 Hz). t .37 (c1,6Ít,l =1 Hz), 2. 3-2. 6 (r;lt,2Íl) ; -3. i)-3. 4( m, I FI),

-1.49(Heptaplet,lH,J=óFIz); 3,6-3.8(m,IFI), 3.8-4,2(m,1H);1.2tt(q,2Ft,I =7 H z), I 34.5 (m,1 F{); -5. 2-.5.6( m, I H), 6.4i.8(m,1H); 7.0-8 Ì(m,7H);I-r20

H-NIvlR (rn CDCI3) ò ppm: 0.Íì-1.8(rn,6Ël), 1.-10(r,3FIJ=7 Hz); 2.1-2.6(m,3FI), 2.e-3.3(rn,1Il); 3.4-3.7(m,rH).3.8-4 6(m,2FI);42{t(q.2.H,J=7FIz), 5 4-5.8(m,LH); 6.4 6 3(m,1 H), 6.8-8.0(m,BFI);r-121

FI-NMR (in CDCI.) ò ppm: 1,29(1.311,J:7Hz),1.39(cl,6H,I=6H2,); 1 .4-l .9(m,2Ét), 2 3-2.5(m,2ll); 21-3 2(m,1H),

l-1RJ Rj

N R5

OH

--Ð OHR¿

m.p ('c )Con- Nfasspound R1 Rr R3 R+ Rs Rr2 spectrum

t12 H H 4-F H ClHr Cl.Ê15 oilM/e +23- 292

't64,249II CII3 CrtI5 92-105H i-PL C,ËL 97-10r)H CHr CrH, oilH i-P¡ C.fI, oilH i Pr C,ÉI,. oilH i-Pr C¡H. oilH i-Pr CrHs 98-104U i-Pr C?tIr 94-98H i-Pr Cl,Hs 79-l-sH i-Pr CrH, oiìH i-Pr C:flj 117-113+F i-Pr C.,ÉI- 85-925-Me i-Pr CrH. oiìH i-Pr CrH. gum[I C,tls C-II5 oilH l-Pr C2H5 oilH i-Pr C2I{, 79-32H c-Pr C¿Hr 100-104H ì-Pr C"H- oilH i-Pr CzH¡ 133-143tI Ph Crtls gumH c- Pr CrH-, oiJ

FI sec-Bu C,tI. oilH i.Pr CrH, oilH c-Pr CrH= gum

II IIHH6.CI Hô-cl FIHH1-Me lIHHII IIHH6-Ct HHHHHHH6-OMe 7-OMet.I IIHH6-CI HHHËIH6-cl S-Cl6-CI II6-Ct t{FIH6-Me H6-O!1e 7 OMe

t-13l- 14

t-15{-1ót,17t-1st-19t-110I-1I II-112I-11-ìt-1't 4t-1 15

I-116t-1i 7I-1lst-1 Ic)

t-130I 121

f-t-'lT.114I- t25Í-726L t),1

fIHÉI

TI2-FH4-C.l4-OVe4-\4e2-Ct4-Crl,"-f -Me3--\4c

4-F4-F4-þ4F4-OPh4-FuII4-F4-F4-F

I-1,7H-NMR (in CDCI.) ò ppm : I .29(t,3tI,t=7H2,), 1 .40(d,6ÉI,

J=6ÍIz); 1.4-1 7(m,2FI), 2.3-2.5(m,2ÍI) 2.9-3.2(m. rH),3.49(l Iep raple t, 1[I,J:6lIz) 3.5-3.8(m,1 fl), 3.9 4.5(m,2II)4.20(q,2H.I =1 Hz), 5 .2-5 .7 ( n,1 FI) 6.s-6. 9(m, 1FI), 7 0-s 2(m,BIÌ)r-18

H-NMI{ (in CDCI.) t\ ppm: 1.(È1.4(m,2H), 1 31(I,3FI,J:7 ÍIz) ; 1.39 (ê',6tl,J = 6Ír'z), 2.3 -2. 5 (m,2H) 2 52(s,3Ír),3. t-3.4 ( m, I FI) 3.48(Hep taplet, rH,J6 FIz),3.5-3.8(m, 1 FI)-1.8-4. 1(nr,1 FI), 4.2O(q,2H,J =7 tIz) 4.2-4.5(m,1,Í\, 5 .2-5 6(m,1H) 6.4-6.8(m,rH), 7.0-8.0(m,8H)I-19

FI-NMR (in CDCI,) ò pprn: 1.29(t,3Íl,l=7lH^z),1.38G1,6H,J :6IIz); 1.4-1.8( m,2l I), 2.3-2.s{m,2II) 3.2-3.a(m, 1l f ,

-\f,

6l)

65


253.5 l(Hept ap le 1,1Íl J =6Hz); 3.6-3 S(m. 1 H), 3942(m,7H}4.19(q,2Il,J :7 rlz), 4.34. 6(m,1 [I); -5. 2-s. ó( m, I I D, ó.4-6. 8(rn,l$; 6 9-8.2(m,13ÍI);l-122

H-MNR (in CDCI.) ò ppm: 1 l-l 8(m,2FI), 13r(r,3HJ=7 Hz); 1.4 I(II,6H,J =6Hz), 2.3-2 5(m,2H); 2.9-3.4(m,IH),3.50(Hepraplet,7H) =6tIz); 3.6-3.8(m,rH), 3 9--4._5(m,2H);+ 20(q,2H.J:7Hz), 5.1-5.ó(m,lH); 6.1-ó.8 (m,l H), 7.1-7.3( m,.5 FI); 7 .7 2(d, IH,t =6tlz);r-723

H-NMR (in CDCI.) ò ppm: 0.8-1.-5(n,zÍI),7.29(r,3H,I:7 Hz) ; 2 2-2.4 (n,2H), 2. 6-2.9(n, IH); 3.2-3.6(m, IH),3.7 4.3(m,2Ll) ; 4. 17 (q,zfI,J =7 llz), 5.0-5.4(n 1 I I) ; 6.1 -6.-s(m,1 FI), 7.tÈ€.2(m,1 3H);I-124

FI-NN4R ( in CDCI.) ò ppm: 0.8-l .8(m,6H), t .29(t,3H.I=7Hz), 2.2-2 6(m,3ÉI), 2.8-3.2(m,rg, 3.3-3.7(m,1H),3.9 - 4. s(m,ZH). 4. t 9 (q,2H,J =7H2.), 5.4-5 .8(m, 1 I{), 6.s-6 8(m,1H), 7.1-8.0(m,8ÉI),

5,856.33626

l-125NMR (in CDCI3) ò ppm: 0.94(d,6FI,t=6llz), 1.0-1.7(m,

3ll), 1 .27 (t,3H,I =7 tIy,), t . 9-2. -í( m,3H), 2.9 0(d,2H ) =7 Hz.),3.3-4.4(m.3 FI), 4. 12(,2L1 ) ='|Hz), 5.G-5.5(m, 1 ÍI), 6 2-6 1

s (m,1II), 6.9+.0(m,8II),I-t26

H-NMI( (in CDCI.) ð ppm: 1.0-1.ó(m,3H), t.zl(r,3H)=1Hz), 1.34(d,6FI,.I:óHz), 2.3a(s,3H), 2.37 (d,2H,J :7Hz),

,,, 2.e -3.7 (m )FI), 3.8-4.s( m, 2H), a. ß(q,2H,I =7Hz), 5 .0-s . 5'" (m,1H). 6..1-6.7(m,tH). 6.9-8.0(m.7H).

t-r27II-NMR (in CDCI,) ò ppm: 0.8-1.9(m,BII), t 29(L,3LI,J=

lHz),1-s 2.I-2,6(m,3H), 2.8-3.2(m,IH), 3.7 2(s,3H), 4.02(s,311),

4. t9(q,2H,I =7 Hz), 4.3 4.6(m, rH), 5.a-5.8(m, 1H), 6.4-6 S(m,1FI), 6..56(s,1H), 7.0-7.4(m,sH)

In the same manner as in Exmple 2, compouncls I--52 tol-527 were preparerl.

TABLE 11

I-i(RLz=ñalRJ oËr

(l{6 = H) otrRt

R5N

Compound R1 Rr Ri R{ R.-mP('c )

t--i2

t-53

t--i4

t--55

t-.56

r-57

I-58

I59

I 510

t-5:tl

L-5 t2

t--- I 3

t5 t4

t-51-5

t-516

I--s I 7

t--< L8

H

TI

EI

çct

6-Ct

t{

7-Me

FI

H

H

6-Cl

H

H

H

6-OMe

II

II

t{

H

TI

H

H

H

H

H

H

H

H

Èl

FI

TI

7-ONle

TI

II

+F

FI

H

H

Él

2-F

H

4-Cl

4-OMc

4-Mc

+cttj

j-Me

-l-Me

.1-F

4-F

+F

H

H

H

FI

tl

H

H

H

FI

H

H

H

4-F

5-Me

ÉI

TI

II

CH,.

CH,,

i-Pr

CH.

iPr

i-Pr

i-Pr

iPr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-P¡

i-Pr

c.Il.

ù-Pr

Na

Na

Na

N¡

Na

Na

N¡r

Na

Na

Na

iria

Na

Na

ña

Na

Na

Na

t38-t42(decomposed)

't30-1,32

(dccomposcd)196-197

(decornposed)21,t-aß

(decomposed)I 9i-193

(decornposed)

193-2.n1

(decompose,l)

t7i)-I'?5(deconrposed)

193-202(decomposed,l

175-193(decomposed)

18?-?00(decomposed)

103-f0r)(dccomposcd)

20tt212(dccomposcd)

195-100(clccomposcd)

19¿-197(decomposed)

239:245(decornposed;

230-23i(decorrposed,ì

I9-3-200(iJecom¡roserl)


5,856,33627

'lABt.E ll-continued

28

Rj Rr oItI_-i (Rrz= N¿)

n,p-Rtz fc.)

=H) OHRl

f{

CompouucJ Rr Rr Rl R4 Rj

R5

I-519

t--s20

I-521

l-521

r--i23

I-5X4

I-525Í-526

I-527

6-Ct

TI

H

6-Cl

6-Cl

6-Cl

tT6-Nfc

6-ONle

H

TI

FI

8Ct

II

H

HH

7-OMe

+F

+F

+oPb

4-F

TI

H

+F+F

4-F

Na

Na

N_a

Na

Na

Na

NaNa

Na

f{

u

H

H

TI

H

HH

H

i-Pr

c-P¡

i-P¡

i-Pr

Ph

c-Pr

sec-Bui-P¡

c-Pr

19J-198(decomposed,ì

\97-l99(decontlnsed!

13{)-139(deco mposed)

lg3-187(deconrposed)

190-196(decomposed)

2t)A:l]Í)(decomposed)

204-208(decomposed)

134-)38(deconrposed)

I-57 35 FI-NMR (in DMSO-d6) ô ppm: 0 9-1.-3(m,2 H), 1.35(d,H_-\\4R. (in DMSo-dd) ð ppm: 0.e 1.2(n,2H), 1.37(ct,

-- 6H,I=7Hz); r.7-2.r(m,zÉ), 2.zoça,zU,t=Z'ttz); ¡.0 ¡.4(ìr,

!\J7lHz);1.6-2.\(m,ZH),3.4B(Heptaplet,lH,J:óHz); 3FI),3.5l(Heptaplet,ttl,t=tlfz¡;3.9-4.3(rn,rFÛ,5.3-5.6(m,31-43(m,aH). 5.3-5.ó(m,lH); 6,4-6.7(m,1H), 7.r-8.1(m. rH); 6.3-6 6(n:r,1H), 6,9-8.1(m,7H);8H); tt-s1-5I--58 H-NMR (in DIVtSO-ct6) ò ppm: 1.0-1.2(m,2H), 1.35(d,

H_Wti (rn DMSo-d) ð ppm:0.9-1.2(m,2Fr), 1.31(cr, *'' 6H,J=7Hz); 1.6-2.2(m,24),'i.:-s1s,oH;; à.0-:.'Ú1.,:lrg,6H,I:1ÉIz); 1 7-2.2(m,2H1, 2.-50(s,3H); 3.-l-4.5(m,.5H), 3..51(Heprapter,lH,.T:7Hz); +.O-+ 3(m,tH), 5 3-5.6(m,tH);-5.2-5.6(m,lH); 6.3-6.6(m,tH), 7.1-7.9(m,8H); 6.3-6 6(m,1H), li.B-s.0(m,7Ét):I--59 I--516

H-NMR (in DMSO-d6) ò ppm: 0.9-l 3Qn,2H), 1.33(cl, FI-NIvIR (in DMSO-d6) ò ppm: 0.9-1.-3(rn,2H), 1.31(ct,6H,J=7LIz); I.6-2.2(m,2H), 3.48(Heptaplcr.tH,J=7Hz). 4s 6H,J=ltIz); L1-2.O(m.2H), 3.:-3.l(m.aH); 3.62(s.3H),3.5-a.6(m,4FI). 5.2-5.6(m,2H); ó.3-6 6(m,1H), 7.r-8 1(m. 3.9-4.2(m,1FI); 3 94(s,3H),5 1-5.5(m,rH); 6.2-6.6(m,1H).8H); 7.0-7.5(m.óH);I-510 t-511

H-NMR (in DMSO-dl ò ppm: 1.0-t .3(m,2H), L32(rl, H-NMR (in DMSO-ct6) ò ppm: 0.9-t.-5(m,2H), 1.34(r,3H,6I-l,J=7Hz); L6 2.2(n,2ÍI), 3,0-38(ur,4FI); 386(s,3H), sa J=7Hz); t.6-22(nt,2l{), 27-3.4(m,4H); 3.6-4 3(m,2I{),4.0-4.3(m,1LI); -5.3--5.6(m,1[I),6.3-6.6(m,1II);6.9-8.1(m, 5.2-5.1(n,1It);6.1-6.ó(m,1I!,6.9-8.1(m,BII);8H); I-s18I-511 FI-NMI{ (in DMSO-(Jó) ò ppm: 0.8-1.3(m,2H), 1.01(r,3H,

H-\MR (in DMSO-d6) ð ¡rpm; 0.9-1.-3(m,2H), 1.3-3(cl, J=7Hz); t.6-2 r(r1,4Íl), 2.i4 8(m,5H); 3.9-4.3(m,tH),6Íl,J=7Hz): 1.7-2.1(m.217), 2.4r(s,3H); 3.2-4.3(m,5H), 5s -5.2-5.7(m,1H); 6.3-6.6(m,1H), 7.1-S.1(m,SFI),5 3-5.6(m,1H); 6.3-6.6(m,1H), 7.0-8.3(m,BH); I-.5 l9l-512 H-NMR (in DNISO-d6) ò ppur: 0.9-1.3(m,2FI). 1.33(cl,

II-NMR (in DMSo-ctd) ò ppm: 0.9-1.3(m,2ll), 1.33(d, 6fI,I=7Ilz);r.6-2.2(m,2ÍÍ),24-.sçm,tnS; 3.49(Ileprapler,6Íl)=7Hz); L6-22(rn,2H), I 1-3 8(n,3FI); 3.48(Hepraplet, 1H,J=7FIz),4.0-4.-l(m,1FI); 5.-3-5.6(m,1H), 6 -3-6 6(m,1H);LH)=1Ltz),3.9-4.2(m,rFI): 5.3-5 7(m,1H), 6,3_6.7(m,1H); oo 7.2-8.1(m,7Ll);7.t)-8.1(m,7H): I-52oI-sL3 FI-NMR (in DMSo-d") ò ppm: 0.8-1.5(n,6ÍI), 17-2.2FÌ-NMR (in DMSO-cl6) t\ ppn: 0.8-l 3(m,21-I), 1._i4(ct,6Fl, (m,2H); 2.3-27(n,t[), 3 0-J.9(m,3H); 4.0-43(m,tFI),J=7Hz); 1.6-2^2(m,2H),2.1-3 9(m,3H); -3.219(Heptaplet,lFI, 5.5-5.8(m,1FI); 6.:+-6 7(m,1FI), 7.2-S Q(m,SFI);I=7Ht,), 3.9-4.3(m,1 FI); -5.2--5.6(m, I H), 6.3-6.7(m,lFI); o-s J--52 t7.1-8.1(m,.eFI); H-NMR (in DMSO-d") ò ppm:09-r-5(m,2FI), 1.36(cr,r-st4 6rr,I=7ftz); t.7-2.3(m,2rr),3.0--3.9(m,3ll); 3.50(tleprapler,


5,856.33629

tH,J :6Hz), 4.0-4 3(rn, lH) ; s.2-s. 6(m, rH) 6.4-6.7 (m, IÍt) ;7 0-8.1 (m,13II);

I-522

H-NMR (in DMSo-d6) ò ppm: 0 8-1.3(m,2H), r 37(d. l6ItJ :7Ilz); L 6-2..2(m,2ÍI), 3. 1-3.9(m,3rI); 3.51(Heptaplet,LH J :7 Hz),4.o-4.3(m, lH) ; 5.3-5 7(m,1 H), {t.3-6.1 (m,tH) ;7.1-8.0(m,6II):

30

.IABLE 13

t--1R:t R4

N R5

OII

- FI) o o

R2 R3 Rr R-s

I-523

FI-NMR (in DMSO-d6) ò ppm: 0..9-1.4(n,2H), 1.6-2..1(m,Zlr); 2.9 -3.7 (m,3II), 3.7 -4.1(m,ll\ ; 5. 1-5.4(m,1 l!,ó 1-ó.4(m,1FI); 7 1-8.2(m,13H);

r-524

II-NMR (in DMSo-d6) ò ppm: 0.8-L.5(m,5rl, 1.6-2.2(nr,2H); 2.3-2.1 (nt,2H), 3.0-3.S(m,3H); 3. 9-4.3( m, 1 H),-5.4--5.8(m,1H) ; 6 3-6.6(m,7H), 7.t}-s.0(m,SH);

r-525

H-NMR (in DMSO-dd) ò ppm: 0.9-1.6(m,2H) 0.96(cl,6H,J = 6Hz) ; t .t -2. 6 (m,3tr), 2. 89 (d,2 H, J -7Þlz) ; 3. 0-3 . 8 ( m, -1FI ),3.9-4.2(m,1FI); 5 2-5 6(n,IH), 6.2-6.6(m,1H); 7.1-8 1(m, zs8H);

l-526

H-NMR (in DMSO-cld) ò ppm: l..lo(d,6H,J=7Hz), _^

t 1 -z.tt(m,2H), 2.34(s,3H), 2.a-2. 6 (m,tIH} 3. (!-3.3 (m, 2H), "3..1-3.tì(m,3H); 3.9-4 2(m, 1H), -5.2--5.6(m, 1 H); 6.3-6. 6( m,1H), 7.0-8.0(m.7H);

I-52735

FI-NMR (in DMSO-c16) ð ppm: 0.7-1 .-5(m,-5H), 1.S-2.2(nr,2ÉI), 2.2-2.6(n,2H), 3. r-3.3(m,2H), 3.se(s,3FI), 3.94.2(m,2I I), 3.e1(s,3l I), s.4-s.7(m, llf , 6.3-6.ó(m,ll I), 6.52(s,lI{), 7.0-7.4(m,sH);

10RL

1-5 ('ompound

I-,r2I-_r3

I-34I-35I-.i6

HHH6-Cl6-Ct

4-FTIHHf]

E.FIHHFI

HÉI

HH

cFr3cFIsiPrCH.i-Pr20

40

6U

TableLs

FORMULAITON EXAMPLE l

Compound I-51lictoseCrvstal celluLose porvderCo¡n stu¡chHvdroxvpropyl celluìoseCMC-CaMagnesiun srearate

Total

105.0

s.0301.0

15

e

Iec!

20.0 g

Thc above components were mixed by a usual methodand then tabletted to produce 100 tablets each containing l[)nrg of thu active ingredient.

IIORMULAI'ION EXAMPLI 2

In the same manner ¿s in Example 3, compouncls I-22 toI-26 can be prepared.

TABLE 12

Cnpsules

1.0 g

10.r) g0.i

L-j

50

Compound I-51LactoseCrvstal cellulose porvderMagnesium steâruLe

: FI)

Compound R

otI

OFI

R¡ RJ R4

Ri Rl

N

To tûl 1-s0I

Tbe above components were mix ecl by a usual method¿nd then packed in No- 4 geÌatin ciìpsules to otrtain 10[)c¿rpsules each cont¿rining l0 mg of the autive ingredient.

I. OI{MULAIION BXAMPLË 3

Soft epsules

Rl

-\)

R

In the same manner irs in Example 4, compouncl^s I-32 toI-36 can be preparecl.

Conrpound I-51PEG (polverhvlene gLvcol) 400Saturated fattv acid triglvceridePeppermûìt oilPolysoLbate 8l)

TotÂl 20.0t) g

The above compouents were mixed ancl packed in Nc¡ 3soll gelatin capsules þy a usual method to obtain 100 soltctpsules e¿ch containing l0 mg of the ¿cLive ingreclient.

t-12t-23t-24t-?5t-16

HHTI

FI

H

CH,cH.i-PrCII-.i-Pr

HHII6-C6-C

+FHIIIItl

HHIII'tf{

1-00 g3S9 c

:l-5 00 g0.{)1 g0l{Jg

6-5


5,856.33631

FORMULAIION EXAMPLE 4

32FORMULATTON EXAMPLE 7

Ointßenl Graoules

Compound f-51Liquid ¡rarafrnCcta trolrñhite vaseliueEthylparâLreo

10 _e (100l0 0 g (10.0

68,4 g (s9.40.1 g (0,1 g)0 -i g (0,5 g)

100 l) g

)s)c)g,r

Compountl I-51Lac!oscCrystal cellulæc powderCo¡n sta¡chHydroxypropvl celluloseMagüesilLm stearate

1,0ri0ó-5

501.0

L-merthol

'fhr^ I

.10

Tot^ 20.{) g

The above componËnts were mixecl b5r a usual methocl toobtain a L'/o (l(l7o) ointment.

F'OIìMULAIION EXAMPLE 5

Suppos itory

1-\ The atrove components were granulated by a usualmethod and packaged to obtain 100 packages each contaìo-ing 200 mg of the granules so thrt each package contains l0nrg oF the active ingreclient.

We claim:1. A compouncl of the fomrula,

tAl

N^

35

Z=-CH( O H)--CHa--{-H( OH)-CH,-CO O.%Ca.2. A mcthod tbr reducing hypcrlipidemia, hyperlipopro-

teinemia or atberosclerosis, which comprises administering¿rn clfec¿ive ¿rmount of the compounrl of lormula A ¿s

ao defined in claim 1.

Compound I-51\\'itepsol Il15'Witepsol V/35'Polvsorbate 80

Totrì

t-o g46.9 g

0.1 g

100.0 g

10

25

F

"Tradc¡na¡k tbr triglyccridc compouud

The alrc¡vc componenls were mclt-mixecl bv a usu¿lmelhoc[ and poured into suppository containers, fbllowecl bycoolitrg t'or solidifrcation lo o[r1aio 100 suppositories of 1 g 30

cach containing l() mg of thc activu componcnt.

I.OI{MULAI]ON E)IAMI'LE 6

Injeclioo [ormulabion

Compound I-51Dislilled wate¡ tbriljection tbrmrLlatioI

The tbrmulation is prepared by clissolving the compoundin the tlistillecl wâter whenever it is require<l.

z

mg¡rl


EXHIBIT B


I ilt ilililt ilt ililt ill] llllt llllt ]ilt ll]t llilt lll|t ilIil llf ilt ilt

(12) United States PatentVan der Schaafet al.

us00855 7993 B2

(ro) Patent No.:1+s; Date of Patent:

us 8,557,993 B2Oct. 15,2013

(s4)

(71)

(t2)

CRYSTALT,INE FORVIS OF PIT.{\ASANINC¿\LC]IUM;\pplicant: Nissan Chemical lndustries, Ltd,

Toþo (JP)

lnventors: Paul Adriaan Van der Schaaf.Hagenthal-le-Flaut (FR); Fritz Blatter,Reinach (CH); Ma rtiu Szelagierdcz.Muenchens tein (OLl); Kai-UrveSchoening. Obc'nvil (CH)

Assignee: Nissan (lhemical Industries [.td.,Toþo (JP)

Nolice: SLrbject to anv <lisclaimer, tìre terLn of Lhìspatcnt is exteudcd or adjustcd undcr 35LI.S.C. ls4(b) by 0 days.

.A,ppl No : L3/664,498

Filed: Oct. 31,2012Prior Publication D¿ta

US 2013/0053413 Al Feb. 28. 2013

Int. CI.c07D 21s/38 (2006.01)u.s. cl.USPC s46n0lFicld of Classification SearchI.JSPC 546i t01Scc application fllc lor comp.lctc search history

Rcfercnccs (litcd

L] S. P,{TENT DOCLIMENI'S

FOREIGN P.{TENT DOCLTMENTS

EPEPEPltPEPF]PJPJPJPJPJPJPJPJP!vowowoWOWOWO

0304063 21989o 520 406 t2;t992I 099 694 ri200It 412 227 l,'2004t 472228 11,',2004I 691 3)6 9i2006

6t-\11460 8,'198605-148231 5i 199-ì

6-92970 4i19948-12674 l,'1996

2005--s00382 1i20052005-5 160ó4 6,'20051005-5208t4 7t20052007-5169i2 6i2007

03/016317 2i200303j064382 8i2003

wo 03i06439? 812003rd/O 0310707t7 8;'2003

03¡'0tì7091 1012003WO 2004i072040 8i'2004

OTI-IER PUB LIC,.\1'IONS

(73)

(*)

(21)(22)(6s)

(sl )

(s2)

(58)

Related U.S. Application Data

(63) Continuation of application No. 13,i280.^131, filed onOct.25,201.1. now abaudoned. whichis a continuationofapplication No. I21331.086. filed on Dec. 9, 2008,norv abandonecl, which is a conLinuation of applicaLionNo 10/544,752. filcd as applicarion No.PCTiDP200¡11050066 on Feb. 2, 2004. Dolvabandoned.

(30) Foreign *\pplication Prio rifv Data

Feb 12.2003 (EP) 03405080

J¿n 21, 2010 Subrnissior of References in .rP 2006-501997 (JPcounterpilt to ptesent appLication) w-ith English trarslation.lvlu ì, 20 t 0 Subrni ssion of Ref'erences in .lP 2006-_50 l gg7 (.IP coun-terpil't to present application) with Inglish tra¡slationNI¿¡,26,2010 Subrnission ol Retèrences in .lP 2006-i01997 (JPcounterpzul to present application) with English traaslation.Jun 29, 2010 Office Action in .rP 2006-50199? (JP counteçart topresent âppl;cflrion) u'ith English translârionAug. 23. 2010 Submission of Refèrences in .IP 2006-501997 (JPeounterpilt to ptesentâpplication) with English translaLion.Dec 27, 2010 Subrnission of References in JP 2006--501997 (.rpcounterpaft to present application) rvilh English trmslationJan 21, 2010 Subrnission ot References in JP 2006-520594 (.IPcounterpart [o related U S .{ppl No 13t487.289) with English rrms-l¿rtion.Mro, 3. 2010 Submission of Rclbrenccs in JP 2006-520594 (JP coun-lerptrt to rel¿ted U S Appl, \o, 131487,289) with Ënglish trmsla-tiun.NIa 26, 2010 Subr¡ission of Refer.ences in ,IP 2006-52C1594 (JPcoÌrntcrprtlo rclatctl Li S Appl, No 11,'487,289) with English trals-latíon.,\pr t2, 201 t O1lìce Action in.lP 2006-520594 (JP counterpzur rorela¡cd L; S Appt No l-ì;487,289) rvith English trmslarion.Akiba et al . "Six-ìvfonth Repated Oral Toxicity StrLdy ot \K-104 iaRats." The.Iournal olToxicological Sciences. vol 2-ì, Supplernent!',7 t3-720. t998Aug. 26, 2004 Intern¿tion¿l Search Report in E,P 2004-707232 (EPcounterpart to present âppl icet¡on)Mru 14, 2006 C)fficc Action inEP 2004-70i 232 (EP counrcJpâfr ropresent application)Dec 14,2006Thirtl Party Submission in EP 2004-70723? ([Pcoun-lerpilt lo present applicalion)

(Cìontinued)

Prirnar;, Examiner -l) iVI Sezunan(74) .4ttorne-¡t. ^ gent. or Firnt -Oblo¡. Spivak.McClellancl, Maier & Neustadt. L,.L.P

(s7) ABS'IR{CTThc present invention is directcd to ltL-\4' crystâllinc loruìs ofPitavastatin hemicalciurn salt, reJèrred to hereinafter as poly-molphic Fomrs A, B, C, D. E ancl F. as well as the amorphonsf-om. Furthennore, the present inventiolÌ is directed to pro-eesses ft)r the preparation ol-these oñstalljne lìrms trnd theanìorphou s t'orrn and pharruâccu tic¿ìl cornpo sitions cornpris -ing these orvstallinc fomrs or the arnorphous i'onns

39 Clairns,9 Drarving Sheets

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us 8,557,993 B2Page 2

(56) References Cited

OTÉIER PUBLICATIONSAug 11. 2008 Tiird Prty Submission inEP 2004-707232 (EPcounterpart to present application)Feb 17. 2010 C)ffice Action inEP 2004-70i232 (EP counterpzur ropresent application)Sep 29, 20 I Cì fhird Party Submission in EP 2004-707232 (EP coun-terpart to present applicat¡on)Jan. 25, 20 I I C)ffice Action Â Þ:P 2004-701232 (EP counterpat toplesent applicatiotr)Jul 15. 2005 Inrernat¡onal Search Report in EP 2004-807807 1EPcùunterp¿rt to related U S A¡rpl No 13/487.289)Sorbera et al , "Nll-104: Ily¡¡olipidemic llMC-CoA RedrrctaseInìibitor." Drugs ofthe Futule 1998,23(8). pp. 847-859Nov 14. 2005 lnternational Prelirninary Report o¡ Patentability inEP 2004-807807 (EP colÌnterp¿rt to related US Appl Notlir'487,289).ln. 19,200i Ollce Action in EP 2004-807807 (EP counterpart torel¿tedU.S Appl No 13148i,289)Apr 4. 2008 Office Acrion ín FP 2004-807807 (EP counterpart rorelâted U.S, Appl. No 131487,2ti9).Aug 2, 2010 OfÊce Action in EP 2004-807807 (EP counterpzut to¡elateclU.S ;\ppl No 13,487.239).Sep- 29. 2010 Tlird Palry- Subrnission in EP 2004-807807 (EP cotur-terpaÍtorelatedLIS Appl No 13t487.289)Feb 8.2011Office Action ìn EP 2004-807807 (EP coLmterpart tor elated Li S Ap¡rl. \o 1J1481 .289)Apr. 1 1. 201 I Thild Paty Submission ìn EP 2004-807807 (EP corm-rer?ârt to relafedlj.S, Appt No t3l48?,289).By.rn el al , Solid State Chernistry of Drugs. 2d ed.. SSCI. Inc , 1998,pp 59-64The United States Phalmacopeia20l l. TheN¿tional Fonnular_v. USP34NF29,vot IBrittain. Polyrnorphism in Pha.nnaceutical Solids, 2cl ed, I¡form¿Healtlrca¡e USA, 1999, 2009Berse et al , "Phannaceutical Salts." Jou¡lal ofPhmuaceutical Sci-ences, vol.66. No l. Ja¡ l9ii. pp I to 18

Takahasbi et al, "Synthesis of an .A¡iificial ÉfMG-CoA ReductaseI¡hibitor NK-104 vi¿ a Flytirosilylation-Cioss-Coupling Reaction,"Bull. Chcm, Soc. Jpn , 68, 2649-2656 (199-s)Miyachi et aJ., 'ì\ Novel Synthetic Method of HlvfG-CoÂ Reduct¿seInhibitol NK-104 Vi:r a Hytlroboration-Cross Corrpling Sequence,"Totrahedron Lcttcrs, vol 34. No -5 l, pp 8267-8270, 1993Bhattacharya, et al . "Therrnoa.nat¡ical and Crystallographic N,leth-ods." Polyrnorphìsrn in PhamaceLrtic¿l Solids. Bittarn H. ed . 2d ed,.Informa Healtlcare USA, Inc , 2009. pp 3 t 8-31-5Iv¿¡íso,ic, et al.. "Uses ol'X-Ray Powtlel DilTìaction in the Ph¿um¿-ceutical Industry," Pha¡m Fo¡m Qnal , 201 l, pp 30-33.Evaluation Rcports for App'oval for Prcscription Drug: PitavastatinCalcium, LI\âLO tablet I mg, LI\I{LO t:ùlet 2 mg, http:r,'wwwinfopmdagojpi. nrade public Sep t0,2003. rvith pzutìal EnglishtlalslarionFeb 5. 2013 Office Actio¡ in JP 201 I-260984 (JP counterparr rorelatetl U S Appl No t3;487.289). wittr pzutial English trmslation.

Ogata, How lo Oper¿te Chernic¿l Experirnent, vol. l. 1963, pp154-155. 185-199 (Feb 5, 2013 t)ffice.\ctior in JP 20ll-260984)Dec. 10, 2012 Submìssion of l(elèr'ences in .fP 2006-50t997 (JPcounterpârt to prescnt applicâtion) witl English üânslâtionNov 6. 2012 Submission ofReièrencesir JP2006-520594 (JPcom-terpalt to rel¿ted LI S Âppl. No. t3i487,289), with Englìsh tra.nsla-tron."l¿fedical SrLpplies Lnten'iew Fo¡rn: HMG-Co.{ reductase inhibitoldesignated rfrrgs LIVALO T¿btet 1 mg and LI\ALO Tablet 2 rng,".Iâpânese Society ofHospital Phalmacists. Sep. 2003, with Englíshtr¿nslation.Aug t9. 2010 Subrnission ofReferences .in.rP 2006-501997 (JPcounterpârt lo present application) wiilr paltiaI Englrsh trmslation\,la', 8. 20ll OfÏce Action in JP 2006-501997 (JP cormterpart topresent application) lr,rth English kanslationÀpr' 26. 20ll Subrnission of Retèr'ences in JP 2006-501997 (JPcounterput to pr esent applicaiion)Sep 30. 2010 Subrnission of Refelences in JP 2006-520594 (Jlcounterpilt to lelatetl Ii S Appt No 131487,289), u'ith pâÌtiâlEnglish translationIntroductor,v Chemistry Course 2, Ph.vsical Chemistry. pp. 321-341,Aug. 28, 1997 (Sep 30..10 I I Submission of Relerences in JP2006-52U594)Apr. 26, 2011 Strbnússion of References in JP 2006-520594 (JPcounte4)fl.I1 to related U S Àppl. I'io 131487,289), with partialEnglish trmslationJapmese Phalrnacopoeia, Foruteenth Editìon. pp 49-51 ivfr 30.201 t (Apr, 26. 2011 Submission ofRetèrences in JP 2006-520594).Mu 27, Z0l? Ofâce AcLion in JP 2006-520594 (JP cornter!ilt torelated Ll S Appl No 13i487,289). with English t¡a¡slationInform¿tjon Oftèr Fol ln dispatchetl Apr. 6. 2010 in Japmese PatentApplication No 2006-500 1997 (with EnglishJanguage translation).lnfonnation L)fi'cl Form dispatchcd Fcb. 73,2010 in Japmesc PatcntApplication No 2006-501997 (rvith English-language trmslation)Information Offer Forrn dispalched Apr. 27. 20 [0 in Japa.nese PatentApplication No 2006-501 997 (rvith English-lmguage translation).Official Action dispatched Jnn. 29, 20 l0 in Japalese Patent.,\pplica-tion No. 2006-501997 (with EnglishJanguage trurslation)M Suzuki et al, Fi¡st Systematic Chiral Syntheses ofTwo Pails o[Enantiorners u,itl 3.5-Dihy'droxyhepteno¡c Acid Chain, .4,ssoci¿tedri,itlr a Potent S¡nthetic Statir NK-104, Biorganic & Me¿licinalChemistD; Letters, 9, (1999), 297i -2982Tlirct Pafy C)bsenation Subrniitecl on Aug. 21, 20t0 in JP 2006-501 977 (including excerpt trorn .IP-A-2005--520814)Englìsh Lmguage Translation of årrg 21. 2010 Thitd Put). Obser-v¿tion Submitted in JP 2006--501977 (inclu<ling excerpr -ûorn Wo03t064932. which is a counterpari to .fP-A-2005-.5208 t4)Suz¡ki. Mikio, Development \York fot HMG-CoA Reductase Inhibi-tor NK- [04, (200 t), (partial English trmslation altachett)Ceriifìcate for Lrbrruy \2l¿terial stoled in the National Diet Libr.ary,Dcvcloprncnt Work for HMG-CoA Rcductasc Inhibitor NK-104.Published (200 I ) lblurne Heisei- I 3. Chiel' L ibr¿r i¿rn ol' Kansai-kmofNational Diet Library, Kaar¡rkiYiutaguchi (prutial English trms-latìon attachcd )

* cited by examiner


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(iRYS'l'ALLtNl,l ¡'ORùIS Ot'PI.I'AVASIAl'IN polymorphism. Polymorphism is oommonly delìned as theC¡ILCIUII ability of any snbstance to have two or more diftèrent crystal

strucfures. Drug substances may also encapsnlate scrlventCROSS REFERENCES TO REL,{IED molecules u,hen crystallized. These solvates or hydrates are

.{PPLIC.{TIONS -5 refè¡¡ed to as psendopolyruorphs. It is also possible that thearnorphous fonn is encounterecl. Differcnt polyrnorphs,

TLis applicatioL is a continualit¡n of LI.S. patent applica- pseudopolymorphs or the amorphous fon¡ differ in theirîion Scr. No. 13i280.431, filccl Oct. 25,2011, which is a physic:il propeitie int, solubiliry etc.contimmtion of lI.S, patentapplìcationSer. No. 12i331,086. These can apprec.i cer-rr.ical propertiesfileclonDec.9,2008.no,wabandoled;whichisacontinuation l,) suchas¿irruì,ìtiun .l!isalsoeconomi_olU.S, patent application Ser. No. i0154 t theproduct is stable forextendeclperiods8, 2005. uow abandoned; *.hich ivas a 3Patcnt Application No PCT/EP 2004i050 leed t-or specializcd stomge conditions lt

2004, and clairns priority to luropean Pat ant to evaluate polynorphism of dmg sub-

03405080.7, fi1ed on Feb. 12. 2003. all of re. the discovery ofnew crystalline poly-a dnrg enlarge the repefclire o1 materi¿lsl'alec lìerelI Dy retereucc llì tnelr entlfelle

The preseLri inve¡tio¡ is directecl to ¡ei scientist has w'ith lvhich to design a phar-

anrl the amorphous fom of Pitavastati' ¡ : lonn o[ a c1rug "vith

a targetecl release

forthcprcparãtiouthercoiandphannacq ;ircdcharactcristìcs lv-cnowhavcsu4rris-

comprising these forms. ^ c4,sta1line forms of Pitavastatin calcium,

rre present invention relates to ne\.v cl" as fonu A' B, c' D, E ald F, and the

the au-rorphous fomr of pitavastatin calci rf Pitavastalh calcimn'

also known b¡i the uames NK-t04, Itavas e present i¡vention is di¡ected to the pol,v-

tin. Pitavastaiin calci.m is lor.rvu by th P'C, D'E ancl F, and the arnorphr'rus fomt

(3R.5s)-7-[2-cyclopropyl-4-(4-fluoroih"r :rum salt (2: l)'j,-s-¿irr--v¿rò^y_-e(E)lh"pt"',oi. acid hémic re inve.ntion is a crystalline polymorph ofastatin calcitun has the follorving formula. )propyl-4-('1-fluorophen¡'l) quinolin-3-

yll -3,5 <lihydrox.v-6(E)-heptenoic acid hemicalcium salt.

OH

herein clesignatecl as Fonn A, which exhìbits a characteristic3¡ X-ray porvder cliffiaction pattern wilh characteristic pealis

expressed in cl-vahres (À) aud in 20 as given in Table 1

(vs-rzery strong intensiry s=strong intensity. rn:rnediurnintc-nsify. rv=veak intensity, \ À:very r"'eak intetsity).

T,{BI,F, ICrl* l¡

4i

50

.t5

60

65

d-spacing [Â]

rl-cñr¡rino< rn,l )Ê ¿¡tslcs lìrr Form -A

-ùgLe l20l Rel lntensitv

Pitavastatin calcium has recently been developed as a newchernically synthesized and pou,erlìrl statin by Kowa Corn-paly Ltd. Japan. On the basis ofreported data, the poteucy ofPilar,astarin is dose-dependent aud appears to be equir,alent tothat ofAlorvâstatin. This new statiu is safc ancl well toleratcdin the treafinent of patielts rvith hypercholesterolaemia. Sig-uificant interacLions with a mrmbe¡ of other commonly trseddrugs can be crrnsidered to be extremel,v- low

Processes ttrr the preparation ofPitav'¿statin are clescribedin EP-A-0304063 and EP-A- 10!)9694 antl in thepublicationsby N. Ivfiyachi et al. in Tetrahedron Letters (1993) vol. 34.pages 8267-8270 and by K. Takahashi et al iu Bull. Chem.Soc, Jpn. (1995) i.ol. 68.2649-2656. These ptrblicationsdescribe the synthesis ofPitavastatir in great delail but do notclescribe the hemicalcium sa.lt of Pitavastatin. The publica-tions by L A Sorbera et al. in Dmgs of the Furure (1998) r.ol.23, pages 847-859 and by iVI Su:mki et al. in Bioorganic &Vfedicinal Chemistry Letters ( I 999) vol. 9, pages 2977 -2982describe Pitavasiatír calcium, however. a precise procedurelor its prepzLration is not given.,,\ lull synthetic pmceclure lirrthe preparation of Pitavâstatin calcirun ìs described in l,lP-A-0520406. In the process described in this patent Pitavastatincalciunr is obtained by precipitatioLt fr'orn rur aqueous solutioras a rvlúie c4;stallirre material witha melting point of I90-t 92C. Il is know-n that phiurnaceutical substance-s can exhibit

Another object of the invention is a crystalline polvrnorphoï (3R,5S)-7-[2-cvclopropyl-4-(4-lluorophenyl)quinolin-3-y1l-3,5-dih¡'droxy-6(E)-heptenoic acid hemicalcium salt,herein designated as Form B, which exhibits a characte¡isticX-rav ptrrvcler diflraclion pattcru lvith characteristic peaksexpressed in d-values (,4.) and in 20 as given in Table 2.

s

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us 8,557,993 823

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19 ()

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.{nother object of the inveution is a cr_vstalline polynìorphl0 of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophcnyl)quioolin-3-

yll-3,5-dihydroxy-6(E)-heptenoic acid heuicalcium salr,herein designate<l as Fonn E, which exhibits a char¿ìcteristicX-ray powder diffraction pattem with characteristic peakse'xpressed in d-valnes (Å) an<l in 20 as given in l'able 5

li

't,\uf ,r-t sofv1lherein desìguated as Form C. which exhibits a characleristicX-ray powdcr cliffractiou patlcrn witlr ch¿rractcristic peaks 40

cxprcsscd iu d-valucs (A) ancl in 20 as givcu in Table 3.

d-.^À^;^-. "-¡ )a ¡ nol¿s Êor Fonr F

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rl-sn¡¡inos qnrl lA atsles t'or Fornr C

d-spacirg [-4] Argle [20] Rel Intensity

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55

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vherein designated as Form D, which exhibits a cluracteristic 65

X-ray powder dilfraction pâttu'ru with characteristic peaksexpressed in d-r,alues (Å) and in 20 as given in Table 4.


Another objo-ct of the inv.ention is a cr)'stallinc polymorphof (3R,55)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yll-3.5-dihydroxy-6(E)heptenoic acid hemicalcium salr.herein designated as Fonlr F: which ¡.'xhibits a chamcteristicX-ray powtler dil'lraction pattcnl with charucteristic peaksexpressed in d-ralues (Ä) ancl in 20 as given in Table 6.

T.A.BLE 6

¡l-<nnni¡o ¡n¡ 2A anñlpc ¡àr F^"- Ê

us 8,557,993 826

t,urthennore, lhe present invenLion is directerl to processest'or the preparation of Fomr A, B, C, D, E and F, and theamorpholrs tòrn of Pitavastatil ca.lcium.

Form A can be geuera.lly prepared from Pitavastatin

-s sodium npon reaction ,with CaCl, in an aqueous reactionmediun. Al ¡ernatively, Form A of the inventìon mav also beobtailed iu situ liorn tile flee acid ((3R,5S)-7-[2-cycloprt p.vl-4-(4-fl norophenyl)quinolin-3 -y.ll -3.5 -diþdroxy-6(E)-hep-tenoic acid) or the corresponcling lactone with Ca(OH)r,

,,, advautagcously als(ì in an aqucous reâctio1l mcdium. The" aqucous rcaction mcdiru usrnll-v corrtaius at least 809/o b.w..o1 w'ater; prefèrably it is water or ,n'ater containing rninorarnounts of solvents and./of reactanls from prevìous steps.Form A rnay contain Lrp to l5%o water. prelerably aboul 3 tcr

- l2oto, morapreferabl¡, 9 to I l9lo ul'water.l-\ Fonu B can be generally prepared by suspending formA inethanol containing *,ater as a co solvent. The aruoruìt ofrÄ/ateris preferably about 1 to 50%.

Forln C can be geuerally prepared by suspending formA iuìsopropanol contaiuing r:r'ater as a co solveut. The amouut of

2r) water is preferably about I to 50%. especiallv 1 to 20?ó audmore preferably about 57o. Forur C can also be prepared homa mixhr¡e of isoprop:utol and a ketone solvent. corrlainiugwâter as a ccl soh,ent. Preferably, the ketone solvert isacetone- an<l the amount ofketone solvelt are abor¡t 1 to 30%,

2,s lnore prelerably about l0%. The aurount of water is prefer-ablv about I fo 2oyo. more preferably about 57o.

Folm D can be generally prepared by suspending fonnA inabsolnte ethalol.

Form E can be generally prepared by suspending fbrm.4. inr0 1,4-djoxane containing water as a co solvent. The amount of

lvate¡ is prelèrably about I to 5070.Folm F can be generally prepared by suspending formA ìn

rueth¿urol coutaining water as a co solveut. The arnorurt of,'vater is preterably about I to 507o.

Ii ln the above trleffioned processes sm¿.ll ¡rnounts of seecl-ing cr¡stals of the desi¡ed crystalline t-orm may be added tothe reaction rnixture. Preferably sr¡all amounts are about I to20 weiglrt 7ó, more prelèrably about 5 weiglit 9/o. Seedingcrystals nray be added before or, where appropriate, alier the

40 stcp initiating the crvsrallizatiou (e. g. coolilg, additiou ol-non-solvcnt ctc. as dcscribcd above). Acldition bcforc initiat-ing the crystallizatic¡n is of specific teclmical interest,

The amorphous fomr cal be generally prepared by additionoJ a uon-solvett tLt a cr)[centrated solutiorr of Pilavastatil

4-; calciuru it an orgaric solvent. As ton-solvent may be taken1br ç*nurnt" heptane t'rr methyl rercbutyl ether, whereasexarnplcs 1-or thc org:u.ric solvcnl are 1,4-clioxane, tctrahydro-ftrran and etþl methyl ketone. It is preferable rhat the uor-solvent and st¡lvent are miscible. The arnorphous t-crrn c¿ur

so also be prepared b.v l"vophilization of al aqueons solution ofPit¡vastatin calcium.

5'll\B[,F,5-continued

r1-"-n¡cino"- ¡nrl ?Ét rnol¿s fãr Fnnn F

d-specirg [À] .AÌgle [20] Rel. lnteusiry

_10 2

l4 rJ

296264

d-spacing [.4] Argle [20] Ret lntetrsity

r7.21_\.8

12.610-r)

8.78.r7.8147.1,

686-i628.04t70

570.5 28i.034.854.6t4.514304184.083.91-r

1,843t43.693.-59

t463 41)

i tl3.14i.023.tr0289

_5. I567t)8.396

1ì.2tD91 t.ill91l il-ì 0

t.l 7t4414115 ili 5

16.8t,1 6

18..1

19..)

19.72062t.22 1.822.92ll2t.8

248l-i.726.226 ti

26.9?8.4295298iù.9

m

s

lÌ1

s

ol

mIts

ms

It

s rou de

m

mItnltrl

s

s

s

s

m

m

IN

Snall changes in the experimental details can cause srnall , C, D. E' F as welldeviation ir the d-vaiues and 20 ofcharacteristic pezrks il the substantially pure

he educt specified,

of 55 ' and solvents ancv

rl-ch Processes fbr

tatin calcium

depicted in I'lG' 7. . -.ï ,rl particularly. tLre ro processes

Powde¡ X-ruy diffraotion is perlbrmed on a Philips ì 7l() for tire preparati.' ef ç1a¡r1.11i'e l-orms of pitavastatil cal_por.vder X-ray diÍÌractoneter using Cu k (crl) radiation ci¡¡resie¡iirlly treeol-rúsiclualorganicsolve¡tbyexposìng(1.54060 À): 20 angles are recorcled with an experirnental ilre crystalline ibnn oTPitavasrarinialciun to an atmosphereerrorof*O'1-0-2o.AdìsctrssionofthetheoryofX-raypt'xvder with a delìned relative air hrmidit-v. lVfore particularly, thedilïraction patterns çan be t-ound in "X+ay difi'action proce- os present invention is directed to a proóess lbr rhe preparation ofdures" by H. P' Klug and L E. r\lexander, J Wiley, NewYork ãnv crystalline lÌrmr or mno.pLu, lolm of'piiavastatin cal-(1974)' qittn which is esseutial.ly liee of residual organic solvent.


us 9,557,993 8278

'flesecan. t'orexample.bepreparedbyexposingtheowslal- novel lorms to prepare such solulions is considereil to beline t-onn or amorphous lorm to an a rmosphere rvith a relative within the contemplation of the inve¡tionair humidiry of5 to 100%o. Preferably'. these are prepared b¡z Capsule dosages, ofcourse. will contain the solid conìpo_exposu¡e to an irìer1 gas streânì with a defined relative air sitiourvithjnacapsulewhichmaybemadeofgelatinorotherhuruiditytoexchangeresidualorganicsolvelrtwithw'ater. Il 5 colventioual elcapsulatilg material. Tablets and powdersgeneral, a rclative air humidity of 5 to 100%. especially 40 to may be coatcd. Tablets ald powders may bc coatcd r.vith an8070' is used. enteric coating. The enteric coated powder forms may lrave

Ano ther oblect o f t be present ìnven tion are phannaoeu tìcal coa tings cornprising phtirulic acid cclhrlclse aceta(c, hyd¡1lx-co an effectiv ,,. ypropylnethvl-cellulose phthalate, polyvinvl alcohol phtha-po l, I), Fì or F ''' late, carboxymethyleLhvlcellukrse. a coprrlynLer of styreneoi d a phanna and maleic acid a copolymer of rnethacrylicacid arrd meth14ne-r. melhacrylate. and like materials, and if desired, they may be

hese polymorphic fomrs mav be used as single compo- employed rvith suitable plasticizers ancL/qr extending age¡tsnentol'asrnixtureswithotherctystallinefomrsortheauror- l-\ Acoated¡abletrnayhaveacoatingonthesurtàceolthetabletpholts fi¡¡¡1n. or may be a tablet cornprising a porvcler or granrles wíth an

As to t1'Lenovel polymorphic forms and amorphons fonn of enteric-coating.PiL¡vaslatin calcium it is pret-erred that these contain PrelerredLuritdosagesofthephamraceuLical cùmpositions25-100% b¡' weight, especially 50-100% by *.eight. of at ofthis invention rypically conrain from 0.5 ro 100 mg oftheleast one of the novel tìtrrns, hase<ì on the Lot¿rl arroun[ ol' 29 novel Pitavastatin calcium tÌlmrs or mixtures tliereof withPitavastatin calcium. Preferabl¡,; such an amount of the novel each other ol other forms of Pitavastatin calcirun. lVlore usn-Poll'¡1to*1ú" fonlrs or amorphous fonu of Pitavastatin cal- ally. the crrrubined weight of thecium is 75-100% byrveight. especially 90-100% bvweight: pitavastatincalciumibrmsofaunitdosagcarclrom2 5mgHigù1y plefèrred is an amount of 9-5- 100% by weiglrt. to g0 mg, for exarnple 5. lO, 20 or 40 mg.

Thecompositionsoftheinv.enlionincludepowders.grauu- u-s The i.ollowiug Examples illustrate the inve¡tio¡ in morelates. aggregates and other solid cornpositious cornprising at detait. Tentperatìrres are gi'en i¡ degrees Celsins.least one of the novel forms. In addition. the composìtions 'that are contemplated by the present invention may f,rfiher EXAIVIpLE Iinc.lude diluents, such as cellulose-derived tnaterials likepowclerecl cellulose, microcrystalline cellulose. mic¡otìne ¡ocellulose. methyl celhilose, eth!.1 cellulose, hydroxyerlyl cei-

Prep:uation ofform A

luiose,hvdrox,r'propylcellulose,hydroxyprupyLnetþlcelìu- .1.15 gr of (3R,5s)-7-[2-cyclopropyl-4-(4-fluor.opheryl)lose,carboxymethyl,cellulosesaltsa¡rdothersubstitutedand _.-,..^;_"-; :,i ì-:'unsubs[ituted cellu]oscs: srarch: pregelarinir"a ,n."tr; i,iur] 3]Ïl",l.L^1.y1]^],'5-dihydroxy-6(E)-heptenoic

acid tert-but'vl

galic cliluents like calciurn carbonare ancl calcium aiffi- r. cslc.rlPitavlstatùr tcrt-bulv1 estcr) wâs suspcnded in 52 ml oÌ'

phate and other dilue[ts knorvn to the pharuraceutical ñd;;- - a nr.ixture of methyl tert-btrtyl ether and methanol (10:3). TLr

try. YeÌ other suitable cliluents incluåe waxes. ,ugur,4d thismixturcrvcrcaddcd2.lTurl ofa4M¿ìqucollssolutionofsugar alcohols like man_¡itol and sorbitol, acrylate pll¡rmers NaOIl. ¿urd thetestrlting yellori'ish solution was stirred fbr2.5anã ctrpol¡rrners, as w-e1l as pectfu. dextrin aná gelaìin. hours at 50' (l- 'lhe reaction nrixture was ctxrled to roc-.m

Furtherexcipientsthatareu,ithinthecontemplationof the 40 tenperature followed by the addition oi50 ml water audprescrlt invctrtiou inclucle bindcrs. such as acaciã gum, prr'gc- stirring ftrr an additiolal hour. The aqueous plnse was sepa-latirized starch, sodium a.lgiuate, glucose and other binders rated and once extr¿cted r,'t ith 20 rnl trf ruethy I terl-butyl ether.used in *et ancl dry granulatìou and di-r-ect compression Ttr this aqueous solution were added a solution ol 0.58 grta bleting processes. Excipients that also may be present in the CaCl, in 80 rnl of wator ovcr a pcriod ol I horu The rcsu.ltingsolid cornpositious ftlrther include disirtegrants like sodirrm 4-i suspension was stirred for about l6 hours at roonr tenpera-starch glycolat. crospoviclone, low-substituted hydrox,u-pro- ture. The suspension w'as filte¡ecl and tlìe oblailìed solicl rvaspyl cellulosc and others. In addition, excipicnts may includc dried at 40. C. and 50 mbar for about 16 horus. The obtainedtab_leting lubric¿rnts Iike magnesium ancl calciun stearate and proclucr is crystal Fonn A wtich is characterize¿ by an X-raysodium stear"vl flumarate: flavorings: sweeteners: presera/a- potvder cliffràctiou pattcm as shorvn in h-IG. 1. Funher char_tives; pharmaceuticall,v acceptable dyes andg.lidants such as so àcterization ol the obtainerL Fonn A by thermogravimetrysiLicon dioxide.

rhe crosages ircr.cre dosages suirabre rt r o¡ar, bnccar, rec- ï:li-Îö;tlSÏiå"'åîlï::Hl'r" .i:i*li":::*;ll.'jtal. parenteral (including snbcutaneous, intranuscula¡ and r¡elti¡g pqi¡t of 95,, C.intravenous), inhalaut aud ophthalmic administration.Although the most suitable route in anv given case will s_s EX-\lvIpLE 2depend on the nature and severitv of dre couditiou beinglreated, the most prelèrred route of'the present inventiou is preparation crl Form Boral. The dosages may be conveniently presented in urútdosage form ald prepared by any of the ruethods well-kuowu 100 urg Pitavastatin calcirul lor.mA was suspeuded in 2 ¡rlintheafiofphanuacy. oo rvaterandstirreclatrooruternper.atrrefor30ruiu, f-ollowedb¡r

Dosage l-ollns include solid dosage l'onls. like tablets, the addition of 2 ml of ethanõl and additional stirri¡g for lBpowclers. capsuìes. suppositories, sachets, t¡oches an<l losen- hours '[ he suspensiou rvas lìltered aml clried in aìr, ,vieldingges as well as liqLrid snspensions ancl elixirs IvVhile the 36rngofFo.mrB.TheobtainedcrystalFormBisc[aracter-description is uot intended to be limiting, the inventiou is also ized by an X-rav polvder <liffraction pattem as shown in FIG.not ilte[ded to per1ain to true solutions of Pitavastatin cal- os 2. Furt]rer cha¡acterizatiol of the obtained ljorm B by ther-ciutn rvherettpon the properties that distiuguish rhe solid mogravirnetry cor-rpled with FTIR spectroscopv revéaled afomrs o f Pitavastatiu calciurrr are lost. Htrw-ever. the use of the watcr contcnt oT abo ut 1070.


us 8,557,993 829 10

l',X^M Pf ,f i 3 sol irl dried in air. 'lhe obtainetl crys ta I F,'onn F is cbaracterizedby an X-ray powder diffracrion pattem as show'n in FIG. 6.

Preparation of Fomr (

EXANIPLE 8

62 urg Pitavastatin calcitun Fonu A was suspended .in 2 ml s

isopropanol containing 50,ó rvater. This snspclsiou was Preparationofthe,{morphousFonnheated to 60" C., rvhich led to almost complete dissolntion ofþtrrm .À. ancl again coole<l tu roorn ternpeiature. Ar this tem- 62 m-e of Pitavastatin calcium Fonn A r¡zs dissolvecl in 0.3

perature the suspensiru r.vas stirred for 6( tÌris stirred sohrtion was slclu'ly addecl 2.3

ing suspension rvas lìlterecJ, once lvashe ooln temperâture' alrd stirred for an addi-

panor containiug 5e/o waïer. aû<l driedi ,å:îljTåi"i'ffil)äìi:.ìiïÎl:.r.;#f,icrystal Forur c is cha¡acterized by an X- .:n patten given il FlG 7 (top).tion pattern as shown in FIG. 3. Frufher 1(

the obtained Fonu c by theunogravinetry coupled with FT- ,,. l.lx^Nlpl.þ: 9IR spectroscop)r revealed that the sample contains about 6 37o

-

isopropalol and a silrall amoult of wat preparatiou of the.¿\morphous Form

EXAMPLE 4 60 mg of Pitavastatin calcium Form.â. was dissolved il I .5

prepa,.atio, of.Fonu ( " il"i:i:ffå^JJs',""'äi jiiÌ";.,*:iliäå1f,i;'lLlï5'iljresnlting snspensiou was stirred at room temperarure 1òr

6-s rng PitalasraLin calcium Form A u,-as snspended iu a about 16 Ìrorus. The suspensionwas filtered and the obtainedmixtureof0.9m-lisoproparol,0.lrnlacetoleand4Oplwater. solid.¡,as dried in air. Au X-ray dift-action snrdy on theStirring this suspension for abc¡ut t hour led to near.ll, com- 2-r prodnct sho'wed it to be amorphous, see FlG. 7 (bottom).plete dissolution. Seeding rvith 4 mg of Form C (froru Fnrthe¡characlenz,ati<¡t't oltheobtainedpnrductbythernro-examplc 3) and stirring f'or 2 hours led to thc f'omtation of a gravimctry couplccl w-ith FT-IR specÍoscopy rcvealed thatconcentrated suspension. This strspension was {iluted with !h9 ¡arnple contaíned about 5.5% meth¡rl tert-butyl ether.

t¡e same amount tif'solvent nixfttre as ab¡ve and stirred fi¡r Diflèrenrial scarLning caloriuretry showed the sample to have

all additional :10 hours. The snspension was filtered and the ]fr a glass lransition te11ìperature ofabout 68' C,

obt¿rinecl solid was dried :,rl 40u C. fìrr aboLrt I0 min. Analb-v X-ra¡r powderclìflraction i¡dicates rhe product ," b- "i;:

BRIÜF DDSCRIPTION OF TII[' DR{W]NGS

tal Fo¡n c as shou'n irì FIG 3' F IG. L is a characteristic X-ray powder diilaction pattern

tiX:\MPl .f,l 5 r; lbr Form AFIG. 2 is a characte¡istic X-ray pow'der difliaction pattem

preparation ofForn D ftlr Fonn BFIGS. 3A atd 38 are tw-o characteristic X-ray powder

cliiÌiaction natterns lbr Fornr C.60 ng of FormA was suspended in- I un Fl(i. 4 is a charactcristic X-ray powcler <lillraction paltem

ml absolute ât rclorr tenperature t'or 20 fôr Ft¡n¡ D.hotus. The r was filtered and dried in air. FlG. 5 is a characleristic X-ray powcler diffraction pattem'l he obtained crysta1 nÌrrnr Ì) is characterized by an X-ray forForm E.powder dillraction pattem as showr in FIr 4. FIG. 6 is a characteristic X-ray powder diifraction pattem

DXAMPLE 6 o-' '.¡'Ta:ttfl l,n "tu 7Ìì are tw. characteristic X-ray powdercliflraction pattcrn for the aurorphous fomr.

Preparation of Fonn E

60 rngofPitavastatin calcium F-orur-A was suspeuded in a 56luixtru'e ol l.¿l-dioxane and water (1:ll, and stined for 18horus at roorn t¿ìmperatre. The resulting srrsperxion wasIìltered ancl dried iu air. The obtained crystal Fonn E is char-acterized by an X-ray powder ditìiaction patLem as shoi.vn inFIG 5. i-ì

'lhe irvention claimed is:1. A cr.vstalline polvmorph A, B, C. D. E, F. or the amor-

phous f-orm. of (3R,--sS)-7-[2-cyclopropyl-4-(4-fluo-rophenye)quìnolin-3-yl l-3,5-dihyctroxy-6(E)-heptenoic acidhemicalcium salt wherein

A) poll'ruorph A exhibits a characteristic X-ray pow'derdiffraction patteru with clmracteristic peaks expressed in20 at5.0 (s),6.8 (s).9.1 (s). 10.0(w), I0.5 (m). 11.0 (ur),13 3 (vw). 13.7 (s). 14.0 (w), 1a.7 (w). 15.9 (vw), 16.9(w'), 17.1 (vw). 18.4 (tlr). 19 I (N'), 20.8 (vs), 2l.l (m).2 1 6 (m). 22 e (m). 23 7 (n), 24.2 (s), 2s.2 (w). 27 . | (n),29 6 (vw). 30.2 (w).34.0 (w);

B) polyrnorph B exhibits a cha¡acteristic X-ray þowderdi lliaction put.tem with characteristic peaks expressecl in28 ar.4.6 (w'), 5 3 (vs), 6.2 (s), 7 7 (s), 9 2 (m). 9.6 (rn),10 3 (w). 1 1 3 (m). 11.7 (rv). 12.6 (vw). 13.0 (w). 13.9(m). 14 7 (vw), 14 9 (rv). 15.6 (w). 16,3 (ru). 17.0 (vw'),17.4 (v*'). 18.0 (w-), 18.7 (m), t9.3 (m),20.0 (s),20.5(u.),20.8 (n).21.2 (,'v, shoulder),21.5 (m),22.4 (m),

EXAMPT,E 7

Preparation of For¡n I60

60 mg ol Pitavastatin calcirun Fonn A was suspended in 3r¡rl nrethanol containìng 2Oo/o*aler, and stirretlat40" (1. Iitr 1

hclur. The resulting suspension w'as slowJy coolecl to roomtenperature ancl stirring r¡uas contiuued l-or 4 hours The sus-pension was heated again to 40o C.. stirred lor 30 rr. in, slowly o:cocled to room tenpelature and stirred ttrr an addititually 15hours. TLre snspension was fìltered ancl the obtained white


us 9,557,993 B211 12

23 2 (s),23.13 (rn). 24.4 (vw),25 2 (tv. broad), 26.0 (r.v). 7 ,{ process lirr preparing the crystalÌine polyrnorph or26'4 (vr¡,'), 27 0 (w),27.9 (vw),28.9 (rv); âmorp.hous ft-rm according to clain l, wherein:

Cl) polymorph C exhibits a cha¡acterìstic X-ray powder the crvstalliue polymorph or amorphous form being pre-difhaction pattem with chamcteristic peaks expressed iu pared is the crystallirie pol¡imorph C; and20at4.l (tu).5.6(s).7.8(ur),8.3(m), 10.3(rn). 11.6(w), -s the process comprises suspending the crystalline poJy-17.5 (rv). 17.9 (w),1S.7 (rn), 19.5 (s),206 (m).21 5 morphAinamixtureofisopropanolandakctoucsol-(vw),2l .9 (m),23.I (m),24.0(rv),248(rv); velt.containinglrarerasacosolvelt.

l)) polvmorpb I) exhibits a ch¿r¡ac¡eristic X-ray porvder ll.'lhe process according to clair¡ 7. lvherein the kek¡rediffractionpatternwithcharacteristicpeaksexpressedin soh'ent is acetone.20a1 5.{)(m),6.5(m),6.8(s),8.7(rrr).ttl.tt¡rr;, ltt.Z(rn¡, r0 9.-lheprocessaccorclingtoclair¡T,rvhereinrheketone108 (m), 13 1 (w), 13..-i (m), 14.3 (s), 15.3 (vw). 16.1 solventispresenrinaramorutoll to30-gzobyvolumeoftheQu). 16'8 (rv), 18.2 (w), 18.5 (m), 19,0 (w-), 199 (m). suspensioir. of (3R.5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)20.5(m).21.0(r's),21.7(s),22.3(w).23.4(m).2a.0@), quinolin-3-¡r1l-3,5-dihydroxy-6(E)ieptenoic acid hemical-25.6 (w). 26.2 (n); ,., cium salt.

E) poly¡1sryh E exhibits a characteristic X-ray pcrw-cler --

t0.TheprocessaccorclingtoclaimT.whereinlhewaterisdilïraction pattem w-ith characteristic peaks expressed in present in an amount of I lo 20%o bv volune of the suspension20at4.4(vw).5.0(s).6.6(s),6.8(s),tì9(s), l0.0Qn). ol (3R,5S)-7-[2-cyc1oprcp¡..1-4-(4-fìuorcrphenyl)<¡uinolin-3-10,3 G). 10.8 Qn), 13.3 (s), 13.6 tn), 14.0 (s), 15.2 (vw), yll-3,5-diþdroxy-6(E)-heprenoic ¿rcid hemicalcìum salr.159(w'), 16.4(rv), 16.9(vrv), 17.t3(r'w), 1fì.3(m). 18.9 2¡ 1'l .,,\processlìrrpreparingthecrystallinepolvmorphor(rv). 20.2 (vs), 20.4 (nt),2O 7 (m), 20.9 ¡u). 21.1 (vs), zunorphous fì:rm accolding to claim 1, wherein:21 6(n),21.7 (m),22.3 (ru),23.5 (m),23.8 (rn),21.1 the cr-vstallinepolymorphoranorphous tòrm beirg pre-(rv). 2:1.7 (vN'). 2,5.4 (wv ), 26.6 (m). 30.2 (w). 34.0 (r'rv'); pared is the crvstalline polymorph D; andand tire process comprises suspencling the crystallile poly-

F) polymttrpir F exhibits a cluracteristic X-ray powder z.s morph A in absolnte ethauol.dillractionpattemwithcharacteristicpeaksexpressedin 12. A process for preparing the crystallire polymorph or20 at -5.1 (m)' 5 6 þv). 7.0 (s), 8.8 (rn). 9.6 (s), 10.2 (w), amorphous fomr according to claim l, wherein:10,9(m), ll.3(w), 11.9(ru), 12.5(n),13.0(s). l3.7Qn). the cr,vstallinepolyrnorphorarn¡rphous fqrur beingpre-14 4 (s). 14.7 (m). 15 3 (vw)- 15 5 (w), 16.8 (rr), 17.6 pared is the crystalline polyruorph E; antl(tt). 18.3 (m). 19 -l (n). 19 7 (m). 20 6 (n),21.2 (vs). ro the process colDprises susperding the crystalline poly-2 I 8 (s), 22.8 (s). 23 1 (iv), 23.8 (w, shoulder). 24. I (s). morphA in I,4-dioxane conraiuilg r,varer as a cosolvent.21 8 (s),25.7 Qn), 26.2 (vw).26.6 (m), 26.9 (w),28.4 13.Theprocessaccordingtoclaim12.u'hereinthewareris(w). 29 5 (w). 29.8 (r,rv), 30.9 (m); rvherein, ttrr each of present in the amotutt of I to 50% by volume of the suspe¡-said polvmorphs. (vs) st¿rnds lbr very strong sion of (3R.5S)-7-12-cyclopropyl-4-(4-lìuorophenyl)quìno-jntelìsity; (s) stands firr strong intemity; (rn) stancls 1'or rr lin-3-yll-3.5-dihydroxy-6(E)-treptenoic acid hemicajciummedium iutensitv; (w) stands for."veak inrensity; (vw) sa1t.stands for verv- weak intensit¡.. 14. A process lor perparing the crystalline polymorph or

2 A process l'or preparing the crystalline pol,vmorah or aLuorphous fonn accordingto claim 1. wherein:amorphous t-orm according to cl¿¡im l, whereiu: the crysta.llile polymorph or amorphous form beiug pre-

Lhe r:;rystalline polymorph or amorpLrous ftrrm being pre- +o pared is the crystalline polymorph F.; an<ìpared is thc cr-vstalline polvrnorphA; ancl the process compriscs suspcnding the crystallinc poly-

the process conprìses reacting (3R,5S)-7-[2-cyclopropvl- urorph A iu meìhanol containinfrvater ai a cosolvìni.4-(4-fluorophenyl)quinolin-3-yl] -3,5-ctihydroxy-tí(E)- .15. The process according to claim l.{, wherein the water isheptenoic acid sodiurn s¿ìlt w'ith CaCl2 in au aqueous prese¡ti¡anamt¡untofl to509/ob)rvolut¡eofthesnspe¡siq¡reactior medjl-rnr. 4: of (3R.5S)-7-[2-cyclopropyl-4-(4-fluorophe¡yl)quinolin-3-

3' .{ process i'or preparìng the crystalline polymorph or yll-3.5-dihydroxy-6(E)ìeptenoic acid hemicalciun salt.amorphons fbru accorclìng to claiur l. rvherein: 16 Theproccss accorcliirgttr claim 2, wherein (3R,5S)-7-

the cr-vstalli¡e polyrnorph or amorphons form being pre- [2-cyclopropyl-4-(4-fluoroplrenyl)quinolin-3-yl]-3.5-dihy-pared is the crystalline polymotph B: and droxy-6(E)-heptenoic aci<l hemicalcium salt'is isolated by

dte process cornprìses suspendìlg the crystalline pol,v- so filtratio¡ aud dried in air orvacuum.morph A in ethanol containing water as a cosolvenr I7. The process accorcling to claim 2, wherein seedirìg ìs

4 Theprocessaccorclìngtoclaim3,whereinthewateris carriedoutwithcrvstalsofthedesiredcrvstallinepolymorph.presellt in al1âmount of 1 to 50%o by volume of the suspension 18 Aprocess preparil1g the crystalliue polymorph or amor-of (3R,55)-7-[2-cvclopropyl-4-(4-fluorophenyl)qrúnolin-3- phons fomr according claitr 1, wherein:yl]-3'5-dihydroxy--6(E)-heptenoìc acicl heuricalciurn salt. 55 the crvstalline pol.vmorph or amorphons flcmr being pre-

5. A process for preparing the crystallile pol-vmorph or pared is the amorphcrus form; atdamorphous fom accorclin¡5 to cl¡itn l, wherein: the prclcess comprises adding a non-solvenl to a solution of

the crystalline polynoryh or zrmorphons form being pre- (3R,5S)-7-[2-cyclopropyl-4-(4-lìr"rorophenyl)quinoliu-pared is the crystalline polymorph C; and 3-yll-3,5-dihydroxy-6(È)-heptenoic ácid Íremjcalcirun

the process comprises suspending the crystalline poly- ao salt iu an organic solvent.nlorphA üre process cornplisc's suspending the cr--vstal- 19. The process according to claim lS, wherein the no¡-line polyrnorph .'\ in isopropanol containiug rvaler as a strlvclt ís selectecl liorn heptane uncJ methyl tert-butyl ether.coso.lveul 20. The process according to claim l8. wherein theorganic

6 Theprocess according 1o claitn 5, w-hereiu thewateris solvent is selected frorn l,4-dioxane, tetrahydrofuran ardpresentinanamorurtof l to509óbyvohuneofthesuspensiou es ethyl methyl ketoneof (3R,5s)-7-[2-c¡'clopropyl-4-(4-lìuorophenyl)quinolin-3- 21. A process 1'orpreparing Lhe crvstalline polymorph oryll-3'5-dihydroxy-6(E)-heptenoic acid hemicalcitun salt. amorphous fonu accordiug claiur l. wherein:

-


us 9,557,993 B213 l4

Lhe r;rystalline polyrnorph or amorphous lorm being pre- intensity. (m) stau<ls fur me<lium intensiLy, (w.) stanils lìrrpared is the arnorphous t'omr; and rveak intensiti,', ãnd (vw) stancls f'or very wóak intensity

the process comprises drying an aqueous solution of (3R, 29. -A. crystalline poly'morph C of (åR,5s)-7[2-cyciopro-5S)-7-[2-cyclopropyl-4-(4-fluoropherryl)quinolin-3- pyl-4-(4-fluorophem't)quinolin-3-yl]-3,5-diþdrox¡6@j-y1l-3,5-diþdrory-6(E)Jreptenoic acid hemicalcirun s heptenoic acid-hemicalcium salt.-havilg un X-rny. p.íd"tsalt by lyophilization. clilliaction partern substanlially as depicted in F'IGS. 3Å ¡ncj

22. .{ phamraceutical corì'tposition conrprising an eflèctive 38.atlroturt of the crysralline polymorph or arnorphous fonn 30. -{ cr,vstalline polymorph D of (3R.5S)-7[2-c;,clopro-according to clairn 1. aud a pharmaceutìcallv acceptable car- py1-4-(4-lìtrorophenyl)quinoûn-:-y¡-3,S-aifrl,arixy-6¡p)-

ro heptenoic acid hernicalciurn salt, w,hich exhibits a character-

_ 23. A crystal.line polvrnorphA, B, Cl, D. E, F, or the zulor- islic X-ray powcler dìflraction patreru with characteristic

pht'rtts l'omr. ol (3 R.5 S)-7-12-cyclopropyl-4-(4-tìuorophe- purks expies.secl in 20 ar 5.0 (m). O ; 1-;. O.S (s), Í3.7 (ru), 10.0nyl)quinolin-3 -yll-3,5-dihydroxy-6(E)-hcpteuoic acid (m). 10.2 (m), l0.S (m). l3.l (rv). 13 5 imj. t+.: (s), 15.3henicalcirun salt of claim 1, wherein pol-r'morph A has an (l,,w), 16.1 (n), 16.8 (r). f a z 6vj, tS.s fr"j, f S.o 1w1. f l.OX--raypowclerdiftiactionpalte¡nsubstautiallyasdepictedin r-s (m).20.5(n1).21.O(vs).21.7(s).22,3(w),23.4(m;)+.0(rn\,FIG l. polymorph B has an X-rav powder cliffraotion pattcm 25.6 (w), and 26.2 (m). wherein (vs)'stands t* í"ry rt.or.gsubstantiallv as depictedinFlG.2. polyrnorph C has anX-ray iureßit'', (s) stauds l'or strong intensitv. (n¡ stânds foipora'cler clìffraction pattem substantially as depicted ìn FIGS. medium intensity.. (w) stands I'or weak intensiry, a¡d (vw)3.4. and 38, polymorph l) has an X-ray powder diffraction stancls for very weak intcnsity.pattenl substantiallv as depicted in FlG, 4. polyno¡ph E has :o 3l. A cr,vsta1lìne polymorph D of (3R.-ss)-7[2-c_v-clopro-au X-ray pou'der difliactiou patteru substanlially as depicted pyl-4-(4-fluorophenyl)quinolin-3-yll -3,5-dihydròxy-6G)-i¡ FIG. 5. polyrnorph F has an X-ra1'po'wder difl¡action lìeptenoic acid heticaÈium salt.-hãr,ing a1 X-ray powtlerpatlern substanrially as depicted in FIG. 6, aLrd dilfractìon patterl substantially as depict-ed in FtC. 4.

the arnorphorts lom has an X-ray powder difiiact.ion pat- 32. { crystalline polymorpìr E of (3R.5S)-7[2-cyclopro-ternsubstantiallyasdepicteclirFIGS.7Aand7B z.r pyl-4-(4-fluorophenyl)cluinolìn-3-yll-3.5-dihydroxy-61pj-

24 4 crystalline polymorph "\

of (3R,5S)-7[2-cyclopro- heptenoic acid hemicalòium salt, which exhiúits a character-py1-4-(4-tìuorophenyl)quinolin-3-yll-3.5-dihydroxy-6(E)- istic X-ray po*'cler diffraction pattern with characteristichepteuorcaciclttenúcalciurnsalt. lvhichexhibitsa clìaracter- peaks expieÑecl in 20 at 4.4 (v1,r,), 5.0 (s), 6.6 (s). 6.g (s).istic X-ray powcler dilliaction pattern with characteristic 8.9(s). 10.0(ni), 10.3G). 10.S(rn). 13.3 þ).-13.6(mj, t+.Oisl,peaksexpressedin20at5.0(s).68G),9.1(s), 10.0(w), 10.5 30 15.2(vw).t5.9(w), 164(w), 169(vw),í7.s(vw.¡. 18.3(m),(n), I1.0(m), 13.3 (vrl,). 137(s), 14.0 (w),14.1(rv). l5.e 18.9(w),20.2(vs),zo.¿inil.201@j,zo.qÌm),21.1(ìs).(vr), 16.9 (r*'). 17.1 (vw). 18.,1 (m), t9.l (n'), 20.8 (vs), 21.1 21.6 (m), 21.7 (m), 22.3 (m),23.5 (m)t,23.8 iÐ, 2a.r (w)i,(nr),21.6 (nt).22.9 (m).23.7 (m),24.2 (s).25.2 (w), 27.1 (m). 21.7 (vw). 25.4 (vw). 26ì.6'(n¡, :o.z 1w;. and-34.0 (r,w j.29'6(vw),30.2(w).ancJ-34.0(w),wherein(vs)sLatrds ftrrvery rvherein (vs) stands t'or very .srrong i¡tensity, (s) sr.rn<I.s lorstrongintersitv,(s)staldslirrstrongintensity,(m)stanclslbr 3i strongilrellsiry,(m) standsfbrmediumintensiìy,(rv)sta¡clsmeditlm intetuity. (w) stands for weak ilrensity, and (r,rv) lòr '¡'eak intensilv. ard (r,w) sta¡ds 1'or very *eak ìntensiry.stalds fcrr very weak iutensir¡r. 33. A crystallile polymoryh E of (3R.53)_7_[2-cyclopio_

25. A crystalline polyrnorph A of (3R,5S)-7[2-cyclopropyl-4-(4-fluorophen¡'l)quinolin-3-yl]-3,5-dihydràxy-O(Bl-pyl-4-(4-fluorophenyl)quinolil-3-yll-3,5-dihydroxy-6(E)- heptenoic acid hemicaÈium salt,-having ariX-ra;, powderheptenoic acid hemicalcirun saft. having an X-ray powtler +o cüilraction pâttern substantially as cìepici-etl in t'l(i 5.diffiaction paÍ cnl substantialll' as dcpictcd in FlG. 1. 34. A cr-vitalline polymorphir of (3R.5s)-7[2-cyclopropyl-

26 A crystalline polymorph B of (3R,5S)-7-[2-cyclopro- 4-(4-fluorophenyl)c¡rinolin-3-yl]-¡,-s-¿¡try¿roxy-OqE¡-¡.i,-pyl-4-(4-fluorophenyl)quinoliri-3-yll-3,5-dihydroxy-6(E)- tenoic acid hemicaliium salt, which exhiiits a characreriìricheptenoic acid hemicalcium salt. which exhibits a character- X-ray powder diffraction patterl with characteristic peaksistic X-rzry pou'der dilfraction pattem with characteristic +s expresôed in20 at 5.1 (m). 5.6 (w),7.0 (s). LS (m).9 6 (s).peaksexpressedú20at4.6(w),53(vs),6.2 1s).7.1 (s),9.2 102(w). 109(m), 11,3(w), 11.9(rn), 12.5(m). 13.0(s).t3J(m).96(m), 10-j(w). 11.3(rn), 11.7(w), 12.6(vw), 13.0(w), (ru). 144(s), 14.7(rn), 15.3(vr,v), 155(w),.16.8(n),n.e13.9 (nr), 14.7 (vw), 11.9 (w), 15.6 (w). 16.3 (m). 17.0 (vw). (w). 18.3 (m). 19.3 (ni). 19.7 (m). 20.6 @)ì.21.2 (r,s),21.s (s),17.-1 (vw), 18.0 (w), 18.7 (ra), 19.3 (rn),20.0 (s).20.s (w), 22.8 (s),23.1 (w).23.8(w-, shoul<ler), )+.1 Gl, )+.sç";.zs.l20.8(n),21 .2(tv,shonlder).21.5(n),224(nt),23.2(s).23.8 so (rn).26.2(vw).26.6(rn),26.9(w).28.4(u).295(w),29.8(n),24 4 (vw'),25.2 (rv, broacl), 26.0 (w). 26.a þ,w),27 .0 (w). (vr.v). and 30.9 (m), wherein (vs j shncls lor very srrong inten-27 9 (.nw), ancl 28.!) (w), wherein (vs) stands l-or very strorìg sity, (s) sÎ¿nds frrr srrong iniensily, (m) stand-s lòr rnecliumintensify. (s) stands ftrr strong intensity. (rn) stalds for intensity. (w) stands for weak irtensity'- and (vr,v) sta¡ds I'orrnedium intensity', (w) stands for weak intensiq,. aud (vlv) very weak intensity.stands lb¡ verv ra'eak intensity. 5s 35. A crystallìne poll,morph F o1 (3R,5s)-7[2-cyclopropyl-

27. A crystalline polymorph B of (3R,5s)-7-[2-cyclopr.r- 4-(4-fluor.ophenyl)quinolin-3-¡,1]-:,s-ail¡,aroxy-o¡e;-¡"ô-pyl-4-(4-iìuorophenyl)quinolin-3-yll-3,-5-dihydroxy-6(E)- tenc¡ic acid hemicaicium sa1t,'lmving anX-ray porvcleràif'-hepteuoic acid hemjcalcirun salt. having an X-ray powder fracrion patteriì subsrartially as clepiãted in ftô. 6.diftiaction pattern substantially as depicted ìn FIG. 2 36. Theamorphous form óf (3R.SS¡Z¡Z-cyclopropyl-4-(4-

28. A crystalline polyurorph C of (3R,5S)-7[2-cyclopro- eo lìuorophenyl)quinolin-3-yl]-3,5-clihydrox-v-01e1-n*i""ot¡pyi-;1-(4-tluorophenyl)quinolin-3-yll-3,5-clihydrox)L6(E)- acict hemicalcium salt.bepLenoic acid hemicalciurn sall. ,ur.hich exhibits a character- 3T. t heamoryhous lonu ol(3R,5S)-7[2-cyclopropyl-4-(4-istic X-ray pou'der clilÏlaction pârem with characterisric fìuorophen;,l)quinolin-3-yll-3,5_dìlryclrory_k(E)_he¡ienoi;peaks expressed in20 at 4.1 (m). 5.6 (s), 7.8 (rn). 8 3 (m). 10.3 acid hemioalcium sal¡. havrng un ,{-."y io*à"r cliftiaction(m). 11.6(w)'175(rv). 17.9(w). 18.7(ru), 19,5(s),20.6(m). o-s patternsubstartiallyasdepicredinFlcS 7Aand78.2 I .5 (vw). 21 .9 (rn), 23 ' I þn). 24.0 (w ), and 24.8 (r.v), wtrereiu 38. .4. process I'or preparing the cr-r'stalline polymorph or(vs) slands t'or ver,v stroLrg intensitv, (s) stands fcrr stroug amorphous lorm accõrdilg to clai¡ i, rvhereìn:


us 9,557,993 B2l5

the cryslalline polyrnrrrph or amorplLous l'orm being pre-pared is the crystalline polymorph F; and

the process coruprises suspellding the crystalline poly-lnolphA i¡ Luethanol containing water as a cosolvent.

39. The process according to claiur 38, wherein the water js _s

prcsent in an âmount o f 1 to 50o/o by vohme of thc suspensi()no i (3 R.5S)-7 [2-cyc lopropyl -4-(4-tluorophenyl )quinol in-3 -yll-3,5-dihydroxy-6(E)-heptenoic acid hcmicalcium salr.

**,t**

l6


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