George R. TalaricoAndre K. CizmarikEDWARDS WILDMAN PALMER LLPAttorneys for Plaintifls

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

44 V[hippany RoadMorristown, NJ 07960Phone: (973)376-7700

UNITED STATES DISTRICT COURTDISTRICT OF NEW JERSEY

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

Civil Action No.

Plaintiffs,COMPLAINT

Amneal Pharmaceuticals, LLC,

Defendant.

Plaintifß, 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 defendant Amneal Pharmaceuticals, LLC ("Amneal"),

allege as follows:

V

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. $$ 271(e)(2),271(b),

271(c),and28l-283. Subjectmatterjurisdictionisproperunder23 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

defendant in New Jersey is proper because defendant is located in and 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,

including Livalo@.

5. Upon information and belief, Amneal is incorporated in Delaware having a place

of business in Bridgewater, New Jersey. Upon information and belief, Amneal filed Abbreviated

New Drug Application ("ANDA") No. 20-596I.

6. Upon information and belief; Amneal is currently transacting business in the

District of New Jersey, 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.

2

7. Upon information and belief, Amneal 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 Jersey and the District of New Jersey. Upon information

and belief, Amneal has its "Business Development & Corporate Offices" in the state of New

Jersey. By filing its ANDA, Amneal has committed, and unless enjoined, will continue to

commit a tortious act without the state of New Jersey, that Amneal expects or should reasonably

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

The New Drug Application

8. KPA sells drug products containing pitavastatin calcium (the "pitavastatin 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).

g. 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.

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

on August 3,2009.

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

approved.

The Patents in Suit

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

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

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

-t

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

inter alia, the pitavastatin drug product, and amethod for reducing hyperlipidemia,

hyperlipoproteinemia or atherosclerosis, which comprises administering an effective amount of

the pitavastatin drug product.

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

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.

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

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

B, was duly issued on October 15,2013 to inventors Paul Adriaan Van Der Schaaf, 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.

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

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

holds a license from KCL for the '993 patent.

16. 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.

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

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

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

remedy at law.

4

COUNT I

INFRINGEMENT OF'THE '336 PA UNDER 35 U.S.C. S 2Tllell2llAl

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

each ofthe foregoing paragraphs.

20. Upon information and belief, defendant Amneal filed an Abbreviated New Drug

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

355(J) (ANDA No. 20-5961) seeking approval to market 1 -9, 2^g, and 4 mg tablets

comprising pitavastatin calcium.

21. By this ANDA filing, Amneal 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, andlor sale, or inducement thereof of Plaintiffs' patented pitavastatin drug

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

filing, Amneal has indicated that its drug product is bioequivalent to Plaintiffs' pitavastatin drug

product.

22. By its ANDA filing, Amneal seeks to obtain approval to commercially

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

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

23. By a letter dated March 5,2014 (the "Notice Letter"), Amneal informed KCL and

NCI that Amneal had filed a certification to the FDA, pursuant to 21 U.S.C. $ 355(lx2)@)(iv)(I).

Upon information and belief, on or about March 7,2014, KCL received the Notice letter. On or

about March '7,2014, NCI received the Notice Letter.

24. The Notice Letter,purporting to be Amneal's Notification Pursuant to 21 U.S.C. $

355(iX2XBXiiXD, asserts that in Amneal's opinion, the '336 patent purportedly is

5

o'unenforceable, invalid, andlor not infringed, either literally or under the doctrine of equivalents,

by the manufacture, use, sale, offer for sale, andlor importation of the drug product for which

ANDA No. 205961 has been submitted by Amneal."

25. Amneal's filing of ANDA No. 20-5961 for the pulpose of obtaining FDA

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

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

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

26. Amneal's manufacture, use, importation, offer for sale, andlor sale, or inducement

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

at least one claim of the '336 patent under 35 U.S.C. g 271(e)(2)(A).

27. Upon information and belief, Amneal's proposed label for its pitavastatin drug

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

atherosclerosis.

28. Unless Amneal is enjoined from infringing and inducing the infringement of the

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

remedy at law.

COUNT II

INFRINGEMENT OF'THE CLAIM OF THE '336 PATENTUNDER 35 U.S.C. 8 271(b)

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

each ofthe foregoing paragraphs.

30. Upon information and belief approval of ANDA 20-5961is substantially likely to

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

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

6

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

and prior to the expiration of the '336 patent.

31. Upon information and belief, Amneal's proposed label for its pitavastatin drug

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

atherosclerosis.

32. Upon information and belief, Amneal is aware or reasonably should be aware, of

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

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

HDL-C in adult patients with primary hyperlipidemia or mixed 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 hyperlipidernia or mixed dyslipidemia would be readily apparent to

customers of Amneal (e.g., including, without limitation, physicians, pharmacists, pharmacy

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

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

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

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

33. Unless Amneal is enjoined from infringing and inducing the infüngement of the

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

remedy at law.

7

COUNT III

INFRINGEMENT OF THE METHOD CLAIM OF THE 6336 PATENTUNDER 35 U.S.C. I271(c)

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

each ofthe foregoing paragraphs.

35. Upon information and belief, Amneal's proposed pitavastatin drug product

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

36. Upon information and belief, Amneal's proposed pitavastatin drug product will be

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

37. Upon information and belief, Amneal knows that Amneal's proposed pitavastatin

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

patent.

38. Upon information and belief, sale of Amneal's proposed pitavastatin drug product

will result in direct infringement of the'336 patent.

39. Upon information and belief, Amneal's proposed pitavastatin drug product is not

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

40. Upon information and belief Amneal knows that Amneal's proposed pitavastatin

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

noninfringing use.

41. Upon information and belief, approval of ANDA 20-5961is substantially likely to

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

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

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

upon approval of the ANDA.

8

42. Plaintifß will be substantially and irreparably harmed if defendant is not enjoined

from contributing to the infringement of the '336 patent Plaintiffs have no adequate remedy at

law.

COUNT IV

INFRINGEMENT OF THE '993 PATENT UNDER 35 U.S.C. I271(el(21(Al

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

each ofthe foregoing paragraphs.

44. Amneal's Notice Letter, purporting to be Amneal's Notice of Certification under

2l U.S.C.$ 355(D(2XB)(iv), indicates that Amneal intends to manufacture, use, sell, or offer for

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

45. The Notice Letter asserts that in Amneal's opinion, the'993patent purportedly is

"unenforceable, invali d, andlornot infringed, either literally or under the doctrine of equivalents,

by the manufacture, use, sale, offer for sale, andlor importation of the drug product for which

ANDA No. 205961 has been submitted byAmneal."

46. Amneal's filing of ANDA No. 20-5961 for the purpose of obtaining FDA

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

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

'993 patent is an act of infringement under 35 U.S.C. $ 271(eX2XA).

47. Amneal's manufacture, use, importation, offer for sale, sale, and/or importation of

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

claim of the '993 patent under 35 U.S.C. $ 271(e)(2)(A).

48. Unless Amneal is enjoined from infringing the '993 patent, plaintiffs will suffer

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

9

(a)

WHEREFORE, Plaintiffs request the following relief:

(b)

a declaratory judgment pursuant to 28 U.S.C. ç 2201et !eq. that making, using,

selling, offering to sell andlor importing Amneal'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;

a declaratory judgment pursuant to 28 U.S.C. ç 220I et !eq. that the making,

using, offering for sale, selling and/or importing of Amneal'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;

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

using, offering for sale, selling and/or importing of Amneal'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;

a declaratory judgment pursuant to 28 U.S.C . ç 2201et g9g. and an order

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

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

import its pitavastatin drug product or any drug product containing pitavastatin

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

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

a permanent injunction restraining and enjoining against any infringement by

defendant, its officers, agents, attorneys, employees, successors or assigns, or

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

(c)

(d)

(e)

l0

(Ð

Dated: April 18,2014

(e)

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

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

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

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

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

Court may deem just and proper.

Kowa Company, Ltd.,Kowa Pharmaceuticals Ameri ca, Inc.,and Nissan Chemical Industries, Ltd.

By their attorneys,

/s/ Andre K. CizmarikGeorge R. TalaricoAndre K. CizmarikEDV/ARDS WILDMAN PALMER LLP44 Whippany RoadMorristown, NJ 07960Phone: (973)376-7700

Andre K. CizmarikJennifer L. DerekaEDWARDS WILDMAN PALMER LLP750 Lexington AvenueNew York, New Yorkl0022Phone: (212)308-4411

David G. Conlin (to be admittedpro hac vice)Kathleen B. Carr (to be admittedpro hac vice)Adam P. Samansky (to be admittedpro hac vice)EDWARDS WILDMAN PALMER LLP111 Huntington AvenueBoston, MA02199-7613Phone: (617)239-0100

11

CERTIF'ICATION PTIRSUANT TO L. CIV. R. T 1.2

I certify that to the best of my knowledge, the matter in controversy is the subject of thefollowing action:

Kowa Company, Ltd. et al. v. Amneal Pharmaceuticals LLC,CivilAction No. 14-cv-2758, filed on April 17, 2014 in the Southem District of New York.

Dated: April 18,2014

Respectfully submitted,

/s/ Andre K. CizmarikGeorge R. TalaricoAndre K. CizmarikEDWARDS WILDMAN PALMER LLP44 Whippany RoadMorristown, NJ 07960Phone: (973)376-7700

Andre K. CizmarikJennifer L. DerekaEDWARDS WILDMAN PALMER LLP750 Lexington AvenueNew York, New York 10022Phone: (212)308-4411

David G. Conlin (to be admittedpro hac vice)Kathleen B. Carr (to be admittedpro hac vice)Adam P. Samansky (to be admittedpro hac vice)EDWARDS WILDMAN PALMER LLPI l1 Huntington AvenueBoston, MA 02199-7613Phone: (617)239-0100

a

t2

EXITIBIT A

ililll ilIllllilil1|lililllilililll]llilililil tilil ililili]ill ]lllllll

United States Patent rlel

Fujikawa et al.

us0058563364

Patent Number:

Date of Patent:[11]

[4sl

5,856,336

Jan. 5, 1999

[54ì QUINOLINETYPEMEVALONOLACTONES

l75l Inventors: Yoshihiro Fujikawa; Mikio Suzuki;Hiroshi lwasaki, all of Funabashi;Mitsuaki Sakashita; Masaki Kitaharã,both of Shiraoka-machi, all of Japan

l73l Assignee: Nissan Chemical Industries Ltd.,Tokyo, Japan

lztl Appl. No.:883¡98

[22] Filed: May 15, 1992

Related U.S. Application Data

1621 Division of Ser. No. 63LA92, Dec. 19, 1990, which is acontinuation of Ser. No. 233,752, Aug. 19, 1988.

[30] Foreign Application Priority Data

Pritnary Examiner-Iau.ra L. Stockton

Attorney, Agent, or Finn--Ol¡Ion, Spivak, McClelland,Maier & Neustadt, P.C.

[s7] AI}S'I'RACT

A compound of the formula

A6lK3ll47; COTD 2r5l12l52l U.S. Cl. 5l4l3tl:5461I73[58] Field of Search ............ 5461173; 51.4131.1.

[56] References Clted

U.S, PATENT DOCUMENTS

5,753,675 5/1998 Wattanasin ..................... ......... 51,4131,1

tAI

Z

N c-Pr

Z=-CH(oH)-CH2-CH(oH)-CH2-CO O.YzCa

have HMG-CoA inhibiting eIIects, making them use-

ful as inhibitors of cholesterol biosynthesis. The com-pouncl may be prepared as a pharmaceutical for recluc-

ing hyperlipidemia, hyperlipoproteinemia orathcrosclerosis.

2 Claims, No Drawings

Í.

Aug.2O,1987Jan.26, 1988Aug. 3, 1988

[51] Int. Cl.6

pPl[JP]UP]

JapanJapanJapan

62-20722463-15585

63-193606

5,856,3361

QUINOLINE TYPE MEVALONOLACTONES

This is a division, of application Ser. No. 071631,,092,filed on Dec. 19, 1990, which is a continuation of O71233,752,fr1ed4ug.19,1988. s

The present invention relates to novel mevalonolactoneshaving a quinoline ring, processes for their produclion,pharmaceutical compositions containing them and theirpharmaceutical uses particularly as anti-hyperlipidemic,hypolipoproteinemic and anti-atherosclerotic agents, and .^intermediates useful for their production and processes for '"the production of such intermediates.

Some fermentation metabolic products such ascompactine, CS-514, Mevinolin or semi-synthetic deriva-tives or fully synthetic derivatives thereof are known to beinhibitors against HMG-CoA reductase which is a ratelimiting enzyme for cholesterol biosynthesis. (4. Endo J.Med Chem., 28(4) 4OL (1985)

CS-514 ancl Mevinolin have been clinically proved to bepotentially useful anti-hyperlipoproteinemic agents, andthey are consiclered to be effective for curing or preventingdiseases of coronary artery sclerosis or atherosclcrosis.(IXth Int. Symp. Drugs Affect. L.ipid Metab., 1986, p30,p31, p66)

Howeve¡ with respect to fully synthetic derivatives,particularly hetero aromalic derivatives of inhibitors againstHMG-CoA reductase , limited information is disclosed in thefollowing literatures:

wPI ACC NO. 84-158675, 86-028274, 86-098816,86-332tJ70, 87 -1245L9, 87 -220987, 88-07781, 88-008460,88-091798 and 88-112505.

The present inventors have found that mevalonolactonederivatives having a quinoline ring, the corresponding dihy-droxy carboxylic acids and salts and esters thereof have highinhibitory activities against cholesterol biosynthesis whcroinHMG-CoA reductase acts as a rate limiting enzyme. Thepresent invention has been accomplished on the b¿sis of thisdiscovery.

The novel mevalonolactone derivatives of the presentinvention are represented by the following formula I:

Rj R1 (r)

R2

(wherein Q is -C(O)-, -C(OR'3)2- or

-CH(OH)-;__ w is -C(oF, -c(oRr3)2-

or -c(RIXOHF; R" is

't hytlrogen or Cr-. alkyll Rr: is hydrogen or Rla (wherein Rtais physiologically hydrolyzable alkyl or M (wherein M isNII*, sodium, potassium, % calcium or a hydrate of loweralkylamine, dilower alkylamine or tri-lower alkylamine));two R13 ar-e inclependently primary or secondary Òr-o alkyl;

zo or twg^Rl3 together form {CHr)2- or --(iurl-' rittand R18 are independently hydrogèn or Cr_, aikyl;'and R5 ishydrogen, Cr_u alkyl, Cr_, alkenyl, C.-u cycloalkyl,

t

::;{--(

ç"

o o

o

l,,ro Rrr

Re

COzRt2

2.5

Rt

wherein Rr, R2, R3, Ro and Ró are independently hydrogen,Cr-u alkyl, C.-u cycloalkyl, Cr_. alkox¡ n-butoxy, ibutox¡sec-butoxy, R7R8N- (wherein R7 and R8 are independentiy sshydrogen or Cr-. alþl), trifluoromethyl, trifluoromethoxy,difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy,benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or

-O(CII'),OR1e (wherein

Rre is hydrogen or Cr-. alkyl, and I is I,2 or 3); or whenlocated at the ortho position to each other, R1 and R2, or R3ancl Ra together form

-CH:CH-CH:CH-; or whenlocatcd at the ortho position to each other, Iì1 and Rztogether form

-OC(R15)(R16)O{wherein R15 and Rr6 are

independently hydrogen or Cr_, alkyl); Y is -CH"-,

-CH'CH2-, -CH:CH-, -CH2-CH:CH- or

-CH:CH-CH.-; aml Z is -Q-CHz}VCH2-CO.R12,

(wherein Rn is hydrogen, Cr_o alkyl, Cr_. alkoxy, fluoro,:o chloro, bromo or trifluoromethyl), phenyl-(CHr)",-

(wherein m is 1, 2 or 3), -<CHr,,CH(CI{.)-phenyl orphenyl-(CFI)"Cf(CH3)- (wherein n is 0, 1 or 2).

Various substituents in the formula I will be described incletail with reference to specific examples. However, it

., should be understood that the present invention is by nomeans restricted by sucb specific examples.

C,-o alkyl for lìr, R2, R=, Ru, Ru and Ro includes, forexample, methyl, ethyi, n-propyl, i-propy1, n-butyl, i-butyl,sec-buty1 and tbutyl. Cr_" alkoxy for R], R2, R3, Ra and R6

,,, includes, for example, methoxy, ethox¡ n-propoxy ancl'' r-propoxy.

Cr-. alkyl for Rll includes, for example, methyl, ethyl,n-propyl and i-propyl.

C.-. alkyl tbr R13 includes, for example, methyl, ethyl,n-propyl and i-propyl.

4s Alkyl tbr R1'1 includes, for example, methyl, ethyl,n-propyl, i-propyl, n-butyl and i-butyl.

M is a metal capable of forming a pharmaceuticallyacceptable salt, and it includes, for example, sodium andpotassium.

s0 COrM includcs, for example, -C()2NH4

and -CO'H.(primary to tertiary lower alkylamine such as

trimethylamine).Cr-u alkyl for Rs includes, for example, methyl, ethyl,

n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,n-pentyl and n-hexyl.

Cr-u cycloalkyl for Rs includes, for example, cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

Cr-, alkenyl for Rs includes, for example, vinyl andi-propenyl.

60 Phenyl-(CH.)",- for Rs includes, for example, benzyl,B-phenylethyl and y-phenylpropyl.

Phenyl-(CHr),CH(CH3)- for Rs includes, for example,ct-phenylethyl and cr-bcnzylethyl.

Cr-. alkyl for R7 ancl R8 inclucles, for example, methyl,65 ethy1, n-propyl and i-propyl.

Fufher, these compounclsmay have at least one or twoasymmetric carbon atoms and may have at least two to four

-{ -7.

N Rs

5,856,3363

optical isomers.'I.he compounds of the tbrmula I include allof thcso optical isomers and all of the mixtures thcrcof.

Among compounds having carboxylic acid moieties fall-ing outside the definition of

-CO'RI¿ of the carboxylic

acid moiety of substiluent Z of the compounds of the present 5invention, those which undergo physiological hydrolysis,after intake, to produce the corresponding carboxylìc acids(compounds wherein thc

-COrR1: moiety is -{O"H) are

equivalent to the compounds of the present invention.Now, preferred substituents of the compounds of the

,opresent invention will be describecl.In the following preferrecl, more preferrecl still further

perferred and most preferred examples, the numerals lor thepositions of the substituents indicate the positions on thequinolinc ring. For examplc, N' shown by e,g. 1' or 2'indicatcs the position of the substituent on thc phenyl 1s

substi¡u¡ed at the 4-position of the quinoline ring (the carbonconnected to the quinoline ring is designated as 1). Themeanings of the respective substituents are the same as theahove-ment ioned meanings.

Preferred substituents for R1, R2 and R6 are hydrogen, 20

fluoro, chloro, bromo, Cr_. alkyl, Cr_, alkoxy, C.-ucycloalkyl, dimethylamino, hydroxy, hydroxymethyl,hydroxyethyl, trifluoromethyl, lrilluoromethoxy,difluoromethox¡ phenoxy and benzyloxy.

Further, when R6 is hydrogen, it is preferred that Rr and 2s

R2 together form methylenedioxy.As preferred examples for R3 and Iì4, when Ra is

hydrogen, R3 is hydrogen, 3'-fluoro, 3'-chloro, 3'-methyl,4'-mcthyl, 4'-chloro and 4'-fluoro.

Other preferred combinations of R3 ancl Ra include 30

3'-methyl-4'-chloro, 3',5'-dichloro, 3',5'-difluoro, 3',5'-dimethyl and 3'-methyl-4'-fluoro.

Preferred examples for Rs include primary ancl secondaryCr_u alkyl and C.-u cycloalkyl.

Preferred examples for Y include -CH2-{H'-

and 35

-CII:CII-.Preferred examples for Z include

o o40

o o

4dimethyl, ó,8-dimethyl, 6,7-dimethoxy, 6,7 -diethoxy, 6,7 -dibromo or 6,8-dibromo.

When R1, R2 and R6 are not hydrogen, they togetherrepresent 5,7-dimethoxy-8-hydroxy, 5,8-dichloro-6-hydroxy, 6,7,8-trimethoxy, 6,7,8-trimethyl, 6,7,8-trichloro,5-fl uoro-ó,8-dibromo or 5-chloro-ó,8-dibromo.

As more preferred examples for R3 and Ra, when R3 ishydrogen, Ra is hydrogcn, 4'-methyl, 4'-chloro or 4'-fluoro.When both R' ancl Ro are not hydrogen, they togetherrepresent 3',5'-dimethyl or 3'-methyl-4'-fluoro.

As more prefened exalnples for R), the above-mentioneclprefered examples of R' may be mentionecl.

As prefenecl examples for Y, -CH.--{Hr- ancl (E)-

-CH:CH-may be mentioned. As more preferredexamplcs for Z, the above prefcrred examples for Z may bementioned.

Now, still further preferred substituents of the compoundsof the presenl invention will be described. As examples forR', R: ancl R6 , when both R2 and R6 are hydrogeñ, R'ishydrogen, 6-methyl, 6-ethy1, 6{rifluoromethyl, 6-hydroxy,6-methoxy, 6-chloro, 6-bromo, 6-n-butyl and7-dimethylamino.

When only R6 is hydrogen, Rl and R2 represent ó,8-dichloro, 5,8-dimethyl, 6,8-dimethyl, 6,7 -dimethoxy, 6,7 -diethoxy, ó,7-dibromo, 6,8-dibromo, 6,7-difluoro and 6,8-difluoro.

As still further preferred examples for R3 and Ra, when R3is hyclrogen, R't is hydrogen, 4'-chloro or 4'-fluoro, or R3 andRa together repres€nt 3'-methyl-4'-fluoro.

Still furlher preferre<1 examples for R5 include ethyl,n-propyl, i-propyl and cyclopropyl.

Still further preferred examples t'or Y include (E)-CH:CH-.

As still further preferred examples for Z, the above-mentioned preferred example for Z may be mentioned.

Now, the most preferred substituents for the compoundsof the present invention will be described.

As the most preferred examples for R1, R2 and R6, whenboth R2 and R6 are hydrogen, Rl is hyclrogen, 6-methyl or6-chloro.

Vy'hen only R6 is hydrogen, R1 and R2 together represent,for example, 6,7-dimethoxy.

As the most preferred examples for R3 and R4, R3 ishydrogen and R4 is hydrogen, 4'-chloro or 4'-fluoro.

The most preferred examples for Rs inciucle i-propyl andcyclopropyl. The most preferrecl exampie for Y may be(E)-CH:cH-.

As the most preferred examples for Z, the above-mentioned preferred examples for Z may be mentioned.

Now, particularly preferred speciflc compounds of thepresent invention will be presented. The fbilowing com-pounds (a) to (z) are shown in the form of carboxylic acids.However, the present invention include not only the com-pounds in the form of carboxylic acids but also the corre-sponding lactones formcd by the condensation of the car-boxylic acids with hydroxy at the S-position, and socliumsalts and lower alkyl cstcrs (such as methyl, ethyl, i-propyland n-propyl esters) of the carboxylic acids, which can bephysiologically hydrolyzed to the carboxylic acids.

(a) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2' -(1" -methylethyl)-quinolin-3'-yI]-hept-6-enoic acid

(b) (E)-3,5-dihydroxy-7-[4'-(4" -fluorophenyl)-z' -(I" -methylethyl)-6'-chloro-quinoli¡-l'-yl]-hept-6-enoic acid

(c) (E)-3,-5-dihydroxy-7-[4'-(4" -fluorophenyl)-2'-( 1 "-methylethyl)-6'-methyl-quinolin-3'-yl]-hept-6-enoic acicl

(d) (E)-3,5-dihydroxy-7-[4'-(4" -fl uorophenyl)-2'-(l "methylethyl)-6',7'-dimethoxy-quinolin-3'-y1l-hept-6-enoic acid

-cH(oH)cH" cH2(oH)cH2co2R12,

-cH(oH)cH2c(o)cH2COzRl2 and -CH(OH)CH2C(OR13)2CH2CO2R12.Now, more preferred substituents of the compounds of the

present invention will be described.As more preferred examples for R1, R2 and R6, when both

R2 and R6 are hydrogen, R1 is hyclrogen,S-fluoro,6-fluoro,7-fluoro, S-fluoro, S-chloro, 6-chloro, 7-chloro, 8-chloro,S-bromo, ó-bromo, 7-bromo, 8-bromo, S-methyl, 6-methyl,7-methy1, 8-methyl, 5-methox.v, 6-methoxy, 7-methoxy,8-methoxy, 5-trifluoromethyl, 6-trifluoromelhyl,7-trifluoromethyl, 8-trifluoromethyl, 6-trifluoromethoxy,6-difluoromethoxy, 8-hydroxyethyl, 5-hydrox¡ 6-hydrox¡7-hydroxy, B-hydroxy, 6-ethy1, ó-n-butyl and7-dimethylamino.

When I{6 is hydrogen, Iì1 and Iì2 togcthcr represent6-chloro-8-methyl, 6-bromo-7-methoxy, 6-methyl-7-ch1oro,6-chloro-8-hydroxy, 5-methyl-2-hydroxy, ó-mcthoxy-7-chloro, 6-chloro-7-methoxy, 6-hyclroxy-7-chloro, 6-chloro-7-hydroxy, ó-chloro-8-bromo, 5-chloro-ó-hydroxy,6-bromo-8-ch1oro, 6-bromo-8-hydroxy, -5-methyl-8-ch1oro,7-hydroxy-8-chloro, 6-bromo-8-hydroxy, ó-methoxy-7-methyl, 6-chloro-8-bromo, 6-methyl-8-bromo, 6,7-dilluoro,ó,8-clilluoro, 6,7-methylenedioxy, 6,8-dichloro, 5,8-

45

50

55

60

65

5,856,3365

(c) (E)-3,5-dihydroxy-7-[4'-(4" -fl uoroph enyl)-2' -cyclopropyl-quinolin-3'-y1]-hept-6-enoic acid

(f) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2' -cyclopropyl-6' -chloro-quinolin-3'-yl]-hept-6-enoic acid

(g) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'- scyclopropyl-6'-methyl-quinolin-3-yl]-hept-6-enoic acid

(h) (E) -3,5 -d ihy d,r oxy -7 -14' -(4 " -fluo rop h e ny l) -2' -cyclopropyl-6',7'-dimethoxy-quinolin -3'-yl]-hepf -6-enoicacid

(Ð (E)-3,5-dihydroxy-7-[4'-(4"-chlorophenyl)-2'-(1"- romethylethyl)-quinoli¡-l'-yll-hept-6-enoic acid

C) (E)-3,5-dihydroxy-7-[4'-(4"-chlorophenyl)-z' -(1," -methylethyl)-6'-chloro-quinoli¡-l'-yl]-hept-6-enoic acid

(k) (E)-3,5-dihydroxy-7-[4'-(4" -chlorophenyl)-2' -(1," -methylethyl)-6'-methyl-quinolin-3'-yl]-hept-6-enoic acid 1s

(1) (E)-3,s-dihy droxy -7 -14' -(4"-chlorophenyt)-2' -(t" -methylethyl)-ó',7'-dimethoxy-quinolin-3'-y1]-hept-6-enoicacid

(m) (E)-3,5-dihydroxy-7-[4'-(4" -chloroph enyl)-2' -cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid 20

(n) (E)-3,5-dihydroxy-7-[4' -(4 " -chloroph enyl) -2' -cyclopropyl-6'-chloro-quinolin-3'-yl]-hept-ó-enoic acid

(o) (E)-3,5-dihydroxy-7-[4'-(4"-chlorophenyl)-2'-cyclopropyl-6'-methyl-quinoli¡-l'-y1]-hept-6-enoic acid

(p) (E) -:,5 -dihydroxy- 7-[4'-(4" -chloroph enyl) -2' - zscyclopropyl-6'7'-dimethoxy-quinolin-3'-y1]-hept-6-enoicacid

(q) (E)-3,5-clihydroxy-7-[4'-phenyl-2'-(1"-methylethyl)-quinolin-3'-yll-hept-ó-enoic acid

O (E)-3,5-dihydroxy-7-[4'-phenyi-2'-(1"-methylethyl)- :o6'-chloro-quinolin-3'-yl]-hept-ó-enoic acid

(s) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-(1."-methylethyl)-6'-methyl-quinolin-3'-yl]-hept-6-enoic acid

(t) (E)-3,5-dihyclroxy-7-[4'-ph enyl-2' -( 1 " -methylethyl)-6',7'-dimethoxy-quinolin-3'-yl]-hept-6-enoic acid 3s

(u) (E)-3,5-dihydroxy-7-[4' -phenyl-Z' -cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid

(v) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-cyclopropyl-6!-chloro-quinolin-3'-yl]-hept-ó-enoic ¿rcid

(w) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-cyclopropyl-6'- +o

methyl-quinolin-3'-yl]-hept-6-enoic acid(x) (E)-3,5-dihydroxy-7-[4'-phenyl-2'-cyclopropyl-6',7' -

dimethory-quinolin-3'-yl]-hept-ó-enoic acid(y) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-z' -(1" -

methylethyl)-6'-methoxy-quinolin-3'-y1]-hept-6-enoic acid 4s(z) (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2' -

cyclopropyl-6'-methoxy-quinolin-3'-yl]-hept6-enoic acidThe mevalonolactones ofthe formula I can be prepared by

the following reaction scheme. The enal III can also beprepared by processes K, L and M. 50

R3 R4

CO2R2r

-ã->

6

R1R3

VIRl

R3 R4

N Rs

IVR3 R4

N Rs

IIIRr

Rs

-continued

CHzOH

Rs

R5

cHo

->

-õ->

-D->

Co2Rl2

T>

Rl

N

R3

cHo

N

R

OH

oEr

OH

Rr

R

-E->

R1

R3

Rr

55

60

N

IfN

VII

Rs

875,856,336

Rl-continuedR1

COzR22

Rl

10

N Rs

VIIIR1

cH2oH

20

N Rs

Rr

CHO

R5

3_5 RIIT

R4 OH

CO2Rr2

OH

R-ñ->

Rs

R1

OII

CO2Rr2

Rs

I-6

In the above reaction scheme, R1, R2, R3, Ra, R5, R6 andR12 are as defined above with respect to the formula I, and

R4Ri-continued

N Rs

I-1

R5

OH

OH

OH

OH

OH

o o

co2R12 15

-c->

->

-E->

CO2Rt2

5

R2-r->

-M>

Rr

RiR3

-->R2

R2

R2

N

RrR325IXRr I-2(R12:Ð

I-5 (Rrz - Na)

R3 R4

R4

30

N

N Rs

cHo

R3R

OHR3

I-3

o o

40

45

50

RsN

N

I-1Rj

Rr

R3

f-4

R4

R2

N

Rr

6{)

N

Rl

Rs

65

5,856,336910

l{21 and Ilrz indcpcndcntly represent C,-o lowcr alkyl such carbon in a solvent such as methanol, cthanol, tetrahydro-as methyl, ethyl, n-propyl, i-propyl or n-butyl. furan or acetonitrile ât a temperature of from 0" to -50' C.,

Step A represents a reduction reaction of the ester to a pretèrably from 10" Lo 25" C.primary alcohol. Such recluction reaction can be conclucted Step K represents a reaction for the synthesis of anby using various metal hydricles, preferably cliisobutylalu- s cr,Ê-unsaturatèd carbgxylic acicl esler, whereúy a trans_formminium hydride, in a solvent such ¿s tetrahydrofuran or a,þ-unsaturated carboxylic acicl estei can be ãbtained by atoluene at a temperature of lrom -2Oo to 2O" C., preferably so-callecl Horner_Wittig reaction by using an alkoxycarúo_from -10o to 10" C.

step B represenrs an oxicration reacrion or the primary lJ.i"#iliålå.*::i:liåï:îl',i,T""::tffi13t,TïTialcohol to an aldehyde, which can be conducted by using 10 terrahydrófuran at ; temperature of from _:0" to 0" C.,various oxidizing agents. Preferably, the reaction can be pretèrãblv from -20o to -15. c.conductcd by using pyridinium chlorochromate in methyl- Step i represents a reduction reaction of the cr,l3_ene chloride at a temperature of from 0o to 25 o C., or by ,*"iir""A

"libåxylic acicl ester to an allyl alcohol. Thisusing oxalyl chloride, dimcthyl sult'oxidc and a tertiary ."¿u"tioo ."*tiào óun U" conductecl by using various mctal

amine such as trielhylamine (Swem oxiclation), or by using ,t tvä.ia"t, pi"i".rury diisoburylaluminíumhyãricle, in a sol-a sulfur trioxide pyricline complex' venl such as clry tetrahyclrofuran or toluene at a temperature

Step C represenls a synthesis of a 3-ethoxy-1-hyclroxy- of from _j0" rå 10. i., pref.erably from _10" to 0ô C.2-propenc dcrivative, which can be prepared by rcactinu a ^.compoundvrorithiumcompoundwhichhastr""np."liåil ^,^t^tTY^l"tlesents

an oxidation reaction of the allyl

narily fbrmect by trearing cis-1-ethoxy-2-(tri-n-butylstan;;¡ 20 ,1:::.T] jt.1l,l.11t: thi" oxidation reaction can be conducted

ethylene with butyl lithium in tetrahydrofuran. "'r't '" by using various oxiclizing agents, particularly active man-

As rhe reaction remperature, it is preferred to employ " l::,"..:- *:l*l^t" a solvent such as tetrahydrofuran,

low temperature at a lêvel of fiom -ó0" to -7g. c. "r - acelone, ethyl ether or elhy1 acetate at a temperatrue of from

step D represents a synthesìs of an enal by acidic hydroly- 0" to 100' c'' preferably fìom 15" to 50" c'sis. Ai the ácict catalysi, it is prefèrred to employ p-iol,-,"i. :s f tel N represents a reaction for the synthesis of an

sulfonic acid, hydrochloric aìid or sulfuric-acicl, ancl the cr.,B-unsaturated ketone by the selective oxidation of the

reactionmaybeãonducteclinasolventmìxlureofwaterand clihydroxy carlroxylic acid ester. This reaclion can be con-

tetrahydrofuran or ethanol at a temperatùre of tiom 10o to duclcd by, using activatcd mangancsc dioxide in a solvcnt

ZS. a. 1'he 3-ethoxy-l-hydroxy-2-propcnc dcrivativc such as ethyl ether, tetrahyclroÊlran, benzene or toluene at a

obtainedinStepCcanbeu""ãinst"po*iihoutpuriflcation :o l$n;rature of from 20o to 80" C., preferably from 40o to

i.e. by simply removing tctra-n-buiyi tin formôcl simulla- 80" C'

neously. In addition to thc compounds discloscd in Examplcs givenStep E represents a clouble anion conclensalion reaction hereinafter, compounds of the formulas I-2 and I-5 given in

between the enal III and an acetoacetate. Such conclensation lablc 1 can be prcparcd by the proccss of the prcscntreaclion is preferably conrluctecl by using soclium hydride 3-q invention. In Tatrle I, i- means iso, sec- means secondaryand n-butyl lithium as the base in tetrahydrofuran at a and c- mcans cyclo. Likcwisc, Me means mcthyl, Et meanstemperature of from -80" to 0" C., pret'erably ftom -30o to ethyl, Pr means propyl, Bu means lrutyl, Pent means pentyl,_10" C. Hcx mcans hcxyl and ph mcans phenyl.

Step F represents a reduction reaction of the carbonylgroup, which can be conudcted by using a metal hydride, +o

pret'erably sodium borohydride in ethanol at a temperatureof from -10" lo 25o C., preferably from -10" to 5" C.

Further, the reduction reaction may be conducted by usingzinc borohydride in dry ethyl ether or dry tetrahydrofuran ata temperature of -10Oo to 25o C., preferably from -80o to +5

-50'c.Step G is a step for hydrolyzing the ester. The hydrolysis

can be conducted bv using an equimolar amount of a base,preferably potassium hyclroxide or sodium hydroxide, in asc¡lvent mixture of water an<l methanol <¡r ethanol at a 50

temperature of from 10" to 2-5" C. The free acid herebyoblainecl may be converted to a salt with a suitable base.

Step H is a step f'or fbrming a mevalonolactone by thedehydration reaction of the free hydroxy acid I-2. Thedehydration reaction can be conducted in benzene or toluene 5s

as N-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodümicle p-toluene sulfonate at a temperature of from10" 1o 35 " C., prelerably from 20o to 25" C.

Step J represents a reaction for hydrogenating the cloublel¡ond connecting the mevalonolactone moiety and the quino- os

line ring. This hydrogenation reaction can be conductecl byusing a catalytic amount of pallaclium-carbon or rhoclium-

TABLE 1

Rl R4

N R5

R: R3 R4 R5

I-2 (Rt2 = H)I-5 (RL: = Na)

R6

OH

tl

R6 OII

Rr

R1

uncler reflux while removing the resulting water or by adding å-3ll!a suitablc dchydrating agcnt such as molecuiar sicvc. 6_].tFurther, the dehydration reaction may be conducted in dry 6-Me

melhylene chloride by using a lactonc-forming agent such as 7-oMe

carbodümicle, preferably a water soluble carbocliimicle such 60 6-8'

HHII

H4-F4-F4-F4-t2,F

4-F

HH[IHHH

H

HHIIHHH

H

i'Pri-Pri-Pri-P¡i-P¡i-Pr

8-Me

H8-OMe

6,'1 i- Pr

Further, pharmaceutically acceptable salts such as potas-sium salts or eslers such as ethyl esters or methyl esters ofthese compounds can be prepared in the same manner.

'Ihe compounds of thc prescnt invcntion exhibit highinhibitory activities against the cholesterol biosynthesiswherein HMG-CoAreductase acts as a rate limiting enzyme,as shown by the test results given hereinatter, and thus arecapable of suppressing or reducing the amount of cholesterolin blood as lipoprote in. 'lhus, thc compounds of the prcsentinvention are useful as curing agents against hyperlipidemia,hyperlipoproteinemia and atheroscleosis.

5,856,33612

'I'hcy may be formulatcd into various suitablc formula'tions depcnding upon thc manner of thc administration.'I'hccompounds of the present inven¡ion may be administered inthe form of free acids or in the form of physiologically

5 hydrolyzable and acceptable esters or lactones, or pharma-ceuticaily acceptable sa1ts.

The pharmaceutical composition of the present inventionis prcferably administcrcd orally in thc form of the com-pound of the present invention per se or in the form of

1n powders. granules, tablets or capsules lormulated by mixing'" thc compound of the prescnt invention with a suitablepharmaceutically acceptable carrier inclucling a lrinder suchas hydroxypropyl cellulose, syrup, gum arabic, gelatin,sorl¡itol, tragacanth gum, polyvinyl pynolidone or CMC-Ca,

,. an excipient such as lactose, sugar, corn slarch, calciumphosphate, sorbitol, glycine or crystal cellulose powder, alubricant such as magnesium slearate, talk, polyethyleneglycol or silica, and a disintegrator such as potato starch.

However, the pharmaceutical composition of the present

,^ invention is not limited to such oral administration and it is'" applicable lor parenteral aclministrati<ln. For example, it may

be administered in the fbrm of e.g. a suppository formulatedby using oily base material such as cacao butter, polyethyl-ene glycoi, lanolin or fatty acid triglyceride, a transdermal

". therapeutic base formulated by using liquid paraffin, whitevaseline, a higher alcohol, Macrogol ointment, hydrophilicointment or hyclro-gel base material, an injection formula-tion formulated by using one or morc materials selectedfrom the group consisting ofpolyethylene glycol, hydro-gel

,n base material, distilled wate¡ distilled water for injectionand excipient such as lactose or corn starch, or a formulationfior administration through mucous membranes such as an

ocular mucous membrane, a nasal mucous membrane and anoral mucous membrane.

rs Further, the compounds of the present invention may be-- combined with basic ion-exchange resins which are capableof binding bile acids and yet not beìng absorbed in gas-trointestinal tract.

'I'he daily dose of the compound of the formula I is from,,, 0.05 to 500 mg, preferably from 0.5 to 50 mg for an adult.'" It is administered from once to threc timcs per day. fhe dose

may of course be variecl depending upon the age, the weightor the condition of illness of the patient.

The compounds of the formulas II to VII are novel, and

,. they are imporfant intermediates for the preparation of the-- compounds o[1he formula I. Accordingly, the present inven-tion relates also to the compounds of the formulas II to VIIand the processes for their production.

Now, the present invention wili be described in further-n detail with reference to Test Examples tbr the pharmaco-"" logical activities of the compounds of the present invention,

their Prcparation Examplcs and Formulation Examplcs.However, it should be unclerstood that the present inventionis by no means restricted by such specifìc Examples,

5-S PI{ÀRMACOLOGICAL TEST EXAMPLES'Ibst A: Inhibition of cholestcrol biosynthcsis from acetate invitro

Enzyme solution was prepared from liver of male Wistarrat billialy cannulated and discharged bile for over 24 hours.

oo Liver was cut out at mid-dark and microsome and superna-tant fiaction which was precipitable with 40-80% of satu-ration of ammonium sulfate (sup fraction) were prepareclfrom liver homogenate according to the modified method ofK¡auss et. a1.; Kurocla, M., et. al., Biochim. Biophys. Acta,

6s 489, LIg (1977). For assay of cholesterol biosynthesis,microsome (0.1 mg protein) and sup fraction (1.0 mgprotein) werc incubatcd for 2 hours at 37" C. in 200 1¿l of thc

11

TAIILE l-continued

í-2f-.5

(Rtt(ntz

H)Na)Rl R¡

N R5

OH

OH

R4 R5

L2

R6

R

R1 R2 R3 R6

H 4-F H H

HH6-Cl6-Cl6-OCH.PhHH6-Cl6-MerN6-Me6-i-Pr7-tr4e6-OMe6-B¡6-i-Pr6-C1

5-F6-OMe6-Me6-C1

IIfI6-OMe6-OMe6-OMe6-OMc6-Olvte6-Me6-Me6-Me6-Me6-Me6-Cl6-Cl6-Cló-cl6-ClHI'IHHH

HHHIIHHHHHHHHHHH8-Cl6-B¡7-OMe7-Me7-ClHH7-OMe7-OMe7-OMe7-OMc7-OMeIIHHHHHHHHHHHHHH

i-P¡i-Prc-P¡sec-Bui-Pri-BuÇ-Pentc-Penti-P¡c-Pri-Prc-Prc-Prc-Prc-Prc-Pri-Pri-Pri-P¡i-Prc-Bilc-Hexi-P¡i-P¡c-Prc-Prc-Pri-Pri-P¡c-Prc-Prc-Pri-Pri-P¡c-Prc-Prc-Pri-Pri-P¡c-Prc-Prc-P¡

HHHÍIHHHHHHHHHHHII8-Br8-OMe8-Me8-ClHHHHHHIIIIHHHHHHHHHHTI

HHH

4-PhCH.4-Ph H

HHHHHHHHHHHHHH[IHHHHHHHHHHIiHHHHHHHHHHHIIHHH

4-F4-F4-F1-F4-F4-F4-F4-F4-F4-F4-!-4-F4-F4-F4-F4-F4-F4-F4-F4-FH4-ClH4-Cl4-FFI4-C1H4-Cl4-FH4-ClH4-Cl4-FH4-ClH4-Cl4-F

5,856,33613

reaction mixture conlaining AI'P; 1 mM, Glutathionc; ó mM,Glucose-1-phosphate; 10 mM, NAD;0.25 mM, NADP;0.25mM, CoA; 0.04 mM and 0.2 mM [2-raC]sodium acetate (O.2pCi) with 4 pl of test compouncl solution dissolvecl in wateror dimethyl sultbxidc.'lb stop rcaction and saponify, 1 ml of s

L5% E|OH-KOH was added to the reactions and heated at75" C. for t hour. Nonsaponifìable lipids were extracted withpetroleum ether and incorporatecl 1aC radioactivity wascounted. Inhibitory activity of compounds was indicatedwith IC50. - 10

Test B: Inhibition of cholesterol biosynthesis in culture cells

Hep G2 cells at over 5th passage were seeded to 12 wellplates and incubatcd with Dulbecco's modified Eaglc(DME) medium containing llVo oÍ fetal bovine serum 1s

(FBS) at 37" C., 5o/o CO, until cells were confluent for about7 days. Cells were exposed to the DME medium containingSVo of lipoprotein deficienl serum (LpDS) prepared byultracentrifugation method for over 24 hours. Medium waschanged to 0.5 ml of fiesh 5% LpDS containing DME beftrre 20

assay and 10 pl of test compound solution dissolved in wateror DMSO were added. 0.2 ltci of l2-l4Clsodium acerarc (2Opl) was added at O h(B-l) or 4 hrs(B-2) after acldition ofcompounds. After 4 hrs furthcr incubation with [2-14C]sodium acetate, medium was removed and cells were 2-5

washed with phosphate bulfered saline(PBS) chilled aL 4" C.Cells were scraped with rubber policeman and collected totubes with PBS and digested with 0.2 ml of 0.5N KOH at37o C. Aliquot of digestion was used for protein arralysis andremaining was saponified with 1 ml of 15% EIOH-KOH at 30

75" C. tbr 1- hour. Nonsaponifiable lipids were extracted withpetroleum ether and 1aC radioactivity was counted. Countswere revised by cell protein and indicated with DPM/mgprotein. Inhibitory activity of compounds was indicated withIC50. 3s

Test C: Inhibition of cholesterol biosynthesis in vivoMale Sprague-Dawley rats weighing about 150 g were fed

normal Purina chow diet and water ad libitum, and exposedto 12 hours li,ghtll2 hours dark lighting pattern (2:00 ,nI'M-2:00 AM dark) prior to use for in vivo inhibition test of '"

cholesterol biosynthesis. Ânimals were separated groupsconsisting of flve rats as to be average mean body weight ineach groups. Test compounds at closage of 0.02-{.2 mg/kgbody weight (0.4 ml/100 g body weight), were clissolved in ,.water or suspended or in 0.5Va methyl cellulose and orally -'administered at 2-3 hours before mid-dark (8:00 PM), whilecholesterol biosynthesis reaches to maximum in rats. Ascontrol, rats were oral1y a<lministered only water or vehicle.At 90 minutes afler sample administration, rats were <^injected intraperitoneally with 10 pCi of l2-laC]sodium

-"

acetate at volume of 0,2 ml per onc. 2 Hours later, bloodsamples were obtained ancl serum were separated immedi-ately. Total lipids were extracted according to the method ofFolch et al. and saponifled with EtOH-KOH. Nonsaponifl- ..ablc lipicls were extractcd with pctroleum ether and radio "-

activity incorporatecf into nonsaponifiable lipicls wascounted.

Inhibitory activily was indicated as percent decrease ofcounts in testing groups (DPMI? ml serum/2 hours) fiom 6sthat in control group.

With respect to the compouncls of the present invention,the inhibitory activities against the cholesterol biosynthesisin which HMG-CoA reductase serves as a rate limitingeîzyme, were measured by the above Test A and B. The es

results are shown in Tables, 2, 2-2,3 and 3-2. Further, theresults of the measurements by Test C are also presented.

Inhibitorv activitiæ bv TÞs¡ A

I.o (molar cotrcentration)

t4

TAßLE.2

Conpound

(Compounds of thep¡esent inrrention)

I-13I-51t-52t-53

1.25 x 10-71.0 x 10-e7.1 x1081.9 x 1O-7

(Reference compounds)

Mevinolincs-514

.1.4 x 10-e9.0 x :10-e

In Table 2-2,the relative activities are shown based on theactivities of CS-514 being evaluated to be 1.

TABLE2-2

Relativc activitics bv Test A

Compound Relative activities

(Compounds of thepresetrt invention)

I-16t-116l-1"17

l-120I-522

Structures of reference compounds:

(1) Mevinolin

1.152.25o.37

o.76

OH

o

o H

Ho

CH:

(2) CS-s14

OH

o

oH

CH:

f¡hibitorv activities bv Test B-1

Iro (molar concentration)

5,856,33616

Examplc 1-b4-(4'-fl uorophenyl)-3-hycf roxymethyl-2-(1'-methylethyl)-quinoline (compound VI-l)

5.4 g (0.01ó mol) of compouncl VII-1 was dissolved in drys toluene uncler a nitrogen atmosphere and coolecl in ice bath

to 0" C. To this solution, 40 ml of a 16 wt 7a diisohutyla-luminium hyclricle-toluene solution was dropwise adcled, andthe mixture was stirred at 0" C. for two hours. Atìerconflrming the complete disappearance of compound VII-I

to by thin layer chromatogaphy, a s¿rturated ammonium chlo-ride solution was added thereto al 0o C. to terminate thereaction. Ethyl elher was added to the rcaction mixture, andthe organic layer was separated. A gelled product wasdissolved by an addition of an aqucous sodium hydroxide

rs solution ancl extracted anew with ethyl ether. The ethyl etherextracts were put together, dried over anhydrous magnesiumsulfate ancl filtered. The solvent was distilled off. Thercsidual oil undcrwent crystallization when left to stand. Itwas recrystallized from ethyl acetate-n-hexane to obtain 3.3

20 g of white crystals. Yield: 7OVo. Meltngpoint: 136o-137o C.

15

TARI,E 3

Compound

(CoÌnpound of thep¡cscnt invention)I-51(Referelce cornpound)cs-514

1 x 10 7

3.5 x 10-7

In'Iable 3-2, the rclativc activitics are shown base d on theactivities of CS-514 being evaluated to be 1.

.I'AtsLE 3-2

Relative acLivities bv Test B-1

Conpound Relative activities

l-116 79.4t-520 zo.oII-20 20.8

Results of the measurement of the inhibitory activities by'l'est C 2s

The pcrccnt decrease of counts after the oral administra-tion of 0.0-5 mg/kg of compound I-520 was 55Vo reTative tothe measured value of the conlrol group. The percentdecrease of counts after the orai administration of L0 mg,lkgof CS-514 was 55o/o uncler the same condition. The com- -r0

pounds of the present invention exhibited activities suireriorto the reference compouncl such as CS-514 or Mevinolin inTest A, ancl exhibited activities superior to CS-514 in TestsB and C.

Example 1-c4-(4'-fl uorophenyl)-2-( 1'-methylethyl)-quinolin-3-yl-carboxyaldchydc (compound V-1)

2.O g(9.3 mmol) of pyriclinium chlorochromate and 0.4 gof anhydrous sodium acctatc was suspended in 1"0 ml of drydichloromethane. To this suspension, a solution ol'rtainecl bydissolving 1 g (3.4 mmol) of compound VI-l in 10 ml of drydichloromethane, was inructliatcly atldctl a[ room lemera-ture. The mixture was stirrecl for one hour. Then, 100 ml ofethyl ether was added thereto, and the mixture was throughlymixed. The reaction mixture was flltered under suctionthrough a silica gel layer. The filtrate was dried underreclucecl pressure. The residue was dissolved in the isopropylether, and insoluble substances were flltered off. The filtratewas again clried under reclucecl pressure, ancl the residue wasrecrystallizcd from diisopropyl ether to obtain 0.7 g (Yield:70%) of slightly yellow prism crystals. Melting point:124"-t26" C.

Example 1-d3 -(3'-ethoxy- 1'-hydroxy-2'-propenyl)-4-(4'-fl uorophenyl)-2-(1'-methylethyl)-quinoline (compound IV-1)

1.13 g (3.13 mmoi) of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene was dissolved in 8 ml of clry tetrahydrofuran, an<l

the solution was coolecl to -78o C. in a nitrogen stream. Tothis solution, 2 ml (3.2 mmol) of a 15 wL Vo n-butyllithium-n-hexane solution was dropwise added. The mixture wasstirred for 45 minutes. Then, a solution prepared by clissolv-ing 0.76 g (2.6 mmol) of compound V-1 in 10 ml of drytetrahydrofuran was dropwise acided thereto. The reactionmixture was stirred at -78" C. for two hours. 'fhen, 2 ml ofa saturated ammonium chloride solution was aclded theretoto terminate thc reaction. 'l'he organic layer was extractcdwith diethyl ether, and the diethyl ether extract was washedwith a saturated sodium chloride aqueous solution and drieclover anhyclrous magnesium sulfate. The solvent was dis-tilled off uncler reclucecl pressure. The resiclue was separateclwith n-hexane and acetonitrile. The solvent was distilled offunder reduced pressure from the acetonitrile layer, ancl anoily substance thereby obtained was purified by silica ge1

column chromatography (eluent: 2.57o meÍh'¿nol-chlorof'orm) to obtain 0.91 g of the desired compound in apurifiecl oily form.

Test D: Acute toxicityAO.57o CMC suspension of a test compound was orally

administered to ICR malc micc (group of three mice). Theacute toxicity was cletermined basecl on the mortality afterseven days. With compound I-57, I-58, l-59,1-5L1, l-5L2,I-513, I-514, l-5ß,1-517 and I-523 of the present invention,the mortality was 07a even when they were orally adminis-tered in an amount of 1ffiO mg/kg.

Example 1

Ethyl (E)-3,5-dihyclroxy-7-[4'-(4" -fl uorophenyl)-2'-(1 "-methylethyl)-qrr¡no1i¡-3iyl]-hept-6-enoate (compound I-11)(preparecl by steps of Example 1-a through Example I-q)

Example l-aEthyl 4-(4'-fluorophenyl)-2-(1'-methylethyl)-quinolin-3-yl-carboxylate (compouncl VII-1)

The synthesis was conclucted in accordance with themethod disclosed in J. Org. Chcm., 2899 (19ó6).

6.45 g (0.03 mol) of 2-amino-4'-fluorobenzophenone,5.53 g (0.035 mol) of ethyl isobutyrylacetate and 0.1 ml ofconc. sulfuric acid were dissolved in 30 m1 of glacial accticacid, and the mixture was heated at 100o C. for about 10hours. Aftcr confirming the substantial disappcarancc of2-amino-4'-fluorobenzophenone by thin layerchromatography, the reaction solution was cooled to roomtemperature, and a mixture of 45 ml of conc. aqueousammonia and 120 ml of water coolecl with ice, was gracluallyadded thereto. A separatecl oily substance was solidified

35

40

45

50

55

60

when left to stand overnight in a refrigerator. This solid was os H-MNR (CDCI3) ò ppm: l,l(t,3H,7Hz) 1.37(d,6HJ=recrystallized from a small amount of ethanol to obtain 6.47 1lb) 3.7(m,1II); 3.7(q,2II,J=7117) 4.75(t,lH,7ÍIz) 5.7(m,g(55%) of white powcler. Melting point: 68o-70.5o C. 1H) 5.95(m,1H) 7.05-8.2(m,8H)

5,856,33617 18

Examplc l-c aqucous solution was dropwisc addcd thereto, 'lhc mixture(L)-3-[a'-(a"-fluorophcnyl)-2'-(1"-mcthylcthyl)-quinolin-3'- was stirred at room temperature for further one hour, anclyl]propenaldehyde (compound III-1) erhÀnol was clistilled offuncler recluced pressure. Then, 5 ml

0.91 g of compound IV-l wa,s dissolved in 20 ml of of water was aclcled thereto, and the mixture was extractedtetrahydrofu_ra!, oqq 5 ml of water and l0O mg of 5 with ethyl elher. The aqucous layer was freeze-clriecl 1op-toluenesulfonic acid were addecl therelo. The mixture was obtain 4ó mg 67Vo) of hygroscopit white powder. Meltingstirred at room temperature for 24 bours. The reaction poínt: 2o7"jò0" i qa""oäporø¡.solution was extractcd with dicthyl ether a few times. Thcextracts were washed with a saturated sodium chloricle Example 3aqueous solution ancl clried over anhydrous magnesium 10 (E)-3,-5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-su11àte. Then, the solvent was distilled off. The residue was methylethyl)-quinolin-3'-yl]-hept-6-enoic acid (compoundpurified by silica gel column chromatography (eluent: I-2I)chloroform) to obtain the desired product as white prism ll0mg(0.244mmo1)of compoundl-11 wasdissolveclincrystals. 0.a g 6A%). Melting poín|: 127"-1.28" C. 10 ml of ethanol. Then, 0.79 ml of a 0.5N sodium hydroxide

Example l-f 1s aqueous solution was clropwise added thereto. The mixture

Ethyl (E)-7-[4'-(4',-fluorophenyl)-2'-(1"-rnethylerhyl)- was stirrcd il i:9- temperature for furthcr one hour, and

quinoriì-:1-yrl-5-hydroxy-3-òxohépío-ó-ènoat, ¡"ó-páílo :,rtiX.Jru:|';|,åff iriåT:::l"jä:*åîfî3!T;#,îjrr-l)5ô mg of 60% sodium hydride was washed with dry with elhyl.ether.,The aqueous layer was weakly acidifiecl

petroleuñ ether ancl clriecl under a nitrogen stream, anótheá ,o þg 4) )'l:th a rlilute hydrochloric aqucous solution antl

suspenclecl in 5 ml of dry tetrahydrofuian. The suspension extractecl three.times with ethyl ether. The ethyl ether la¡rers

waicooleclto-l5oC.inanitrogenatmosphere.Then, 120 *?:".pu:,t"S"|hcr ancl <lried over anhyclrous magnesium

mg (0.92 mmol) of ethyl acetoaõctate was dropwise aclded sulfate' Then, the solvent was distilled off uncler reduced

thãrêto, ancl the mixturã was stirred for 1-5 minutes. Then, p.:T:-|"-lo 9l!,l 90 mg of slightly yellow crily substance.

0.6 ml (0.92 mmol) of a 15 wt % n-butyllithiu*-n-h"*un" ., ^ ji-NYl (^C?i13) ò ppm: 1'36(d'61:l,l=7[Iz) 2'4(m'2lI)

solurìonwas dropwise addecl rhereto, and rhe -i*tr." *u, J:1(-:tHl.3:ajlq'1H)t 3.8-46(m,ZH) 5.40(dd,1H,J1=

stirrecl for 30 minutes. Then, a rclution preparecl by clissolv- 1'9llzJ":8llz) 6'55 (d'1H'J=19IIz) 7'0-8'3(m'8FI)

ing 160 mg (0.5 mmol) of compound III-1 in dry Example 4tetrahydrofuran, was dropwise added thereto, and the mix- (E)-6-[a'-(a"-ltuorophenyl)-2'-i1"-methylerhyl)-quinolin-3'-ture was stirred ftrr one hour. To the reaction mixture, 1 ml 30 yfétt"nyfj-+-fryctroiy-3,4, 5,6-tetrahyúro-2H-pyran-2-.neof a saturated ammonium chloride aqueous solution.was ("ornpouna t_:,t¡added at -15o C. f'hen, the mixture was extracted three times 90 mg of compound I-21 was dissolved in 10 ml of clrywith diethyl ether. The cliethyl ether solution was washecl tolueneJnd the iolution was refluxed under heating for 3with a saturated sodium chloridc aquoous solution and dried hours by means of a Dean Stark apparatus.over anhydrous magnesium sulfate. The solution was evapo- Js lbluene was distilled off under rèàuced pressure, and therated to dryness under reduced pressure. The residue was resiclual solicl was recrystallizecl tiom clüàpropyl ether torecrystailized from cliisopropyl ether to obtain 130 ^mg obrain 40 mg of coloilcss prism crystals.

-trl"ìiing point,

(yíel<J,: 597o) of white crystals. Melting point: 99'-101" C. 182.-184 . ð.Example 1-g By silica gel thin chromatography, the product gave two

Ethyl (E)-3,5-dihydroxy-7-[+'-(4-"-fluorophenyl)-2'-(1"- au absorption spots close to each other attritrutable to the

methylethyl)-quinolin-3 '-yl]-hept-6-enoate (compound diastereomers. (Developping solvent: 3Va meLhanol-I-11) chloroform)

110 mg (0.245 mmol) of compound II-1 was dissolved in These diasteromers were separated and isolated by silica5 ml of ethanol in a nitrogen atmosphere, and the solutioú ,. ge1 thin layer chromatography. fDevelopping solvent:was cooled 0" C. I'hen, 10 mg (0.2ó3 mmol) of sodium -' t-BuOMe/hexanelaceto¡e=7/2/l (vlv), Rf=0.6 ancl 0.7borohycJricle was aclclecl, and the mixturer was stirred for one (obtained weight ratio: 1/2)]hour. 'l'hcn, 1 ml of a l\Vo hydrochloric acid aqueous Rf=0.7: trans lactonesolution was aclcled rherero, ancl rhe mixture was exrracted H-NMI{ (CDC13) ò ppm: 1.40(d,6H)=7Hz) 1.6(m,2H)three times with ethyl ether. The ethyl ether solution ry¿5 --^ 2 65(m,2H) 3.48(m,1H); a.20(m,1H) 5.15(m,1H) 5.37(c1d,

washed with a saturated soclium chloride aqueous solution '" 1IIJ'=18FIz,J==1Ílz) 6.68(c1,1II, J=19[Iz) 7.1-8.2(m,8II)and driecl over anhydrous magnesium sulfate. Then, the Rf=0.6: cis laclonesolution was evaporated to dryness under reduced pressure. H-NMiì (CDC13) ô ppm: 1.4(d,6HJ=7Hz) 1.6(m,2H)The resi<lual oil was purifìe<J by silica gel column chroma- 2'65(m,2H) 3.48(m,1H); 4.20(m,1H) a.65(m,1H) 5.40(dd'tography (eluent: SVa methanol-chlorof'orm) to obtain the .. lHJt=18H2,J.=7Hz\ 6.ó6(m,1H) 7.0-4.2(m,8H)clesirecl product as a pure colorless oily substance. 70 mg "-(yíeld:647o) . f Àt t.t, â-.^-^..1

Example 5

H-NMR (CDCI3) ô ppm: 1.30(r,3H,J=8Hz) 13e(cl,6HJ= 9;li':f1..;rul',:ophenvl)-2'-(1"-mcthvlethvl)-quinolin-3'-BHz) 1.4-1.S(m,2H); 2.42(d,2H,I:7Hz):.0-:.S t.,âirj llll:.|lt,'ilvtlroxv-3',4',5',6-tetrahvclro-2H-pvran-2-one3.s0(m,1H) t.o-+.e(n,zu¡'+.za(c,z[J=aHz) 5.:s(m,tHi ,.,

t""riïËTr'u?*u." of diasrereomers of compounct r_316'59(m'1r! 7'1Ga'18(m'8II) was dissolved in 5 ml of ethanol, and ro mg ot 5vo

Example 2 pallaclium-carbon was aclclecl thereto. The mixture wasSoclium salt of (E)-3,5-clihyrlroxy-7-[4'-(4"-fluorophenyl)- stirrecl under a hydrogen atmosphere. After conflrming the2'-(1 "-methylethyl)-quinolin-3 '-yl]-hept-6-enoic acid disappearance of the starting substance and the appearance(compound I-51) 6s of a new spot by thin layer chromalography, the palladium-

60 mg (0. 133 mmol) of compound I-1 I was dissolved in carbon was liltered o11, and ethanol was distilled off to obtain3 m1 of ethanol. Then, 0.26 ml of a 0.5N soclium hydroxicle colorless oil.

5,856,336l9

'Ihis oil was purilìed by preparative thin layer chroma-tography to obtain 16 mg of the clesired product as purecolorless oil.

MS(m/e): 408(M*+H), 407(M), 366, 292, 278In the same manner as in Example 1-a, compounds VII-2 s

to YII-27 were prepared. The physical properties of thesecompounds are shown in Table 4. (In the Tab1e, Rl, R2, R3,Ra, Rs ancl R21 correspond to the substitients of compoundvrr.)

TABLE 5

(Compounds in this Table are compounds of theformula \4 whc¡ein R6 is hvdrosen.)

20

Cìompouncl R1 R2 Rr R4 R5 ðt8i

1ABLE 4

(Conpoun<ls in this Täble are compounds of theformula VII wherein R6 is hvdroscn-l

Com- m.p.pound R1 R2 R3 R4 R5 R21 Cc.)

VII-2vIt-3VII-4VII-5VII-6VTT-7

VII-8VIT-9vII-10VTT-11

vII-12vIt-13VII-14VII.15VII.16vlr-17vIf-18vII-19VII.20wt-21vl[-22vII-23vIt-24vrr-2s

4-FHHHH2-FH4-Cl4-OMe4-Me2-Cl4-CF33-Me3-Me4-F4-F4-F4-F4-F4-OPh

121-122102-ro2.585-A5.5100.5-101.5105.5-106.s101.0-102.0oil134.0-136.588.0-€9.0108.5-109.5101_0-103.011,',7.5-119.O

oiloil96.0-98.0139.0-139.5oil94.5-r5.5113.5-11ó.5oil96.0-98.0118.8-119.597.0-98.5oil

vr-2vI-3

10 vI-4vf-5VT-6vI-7vI-8vI-9

15 vt-10vI-11vr-72vI-13vt-14vI-]5

,n vl-l6'" vL1,7

VI-18VI-19vr-20vî-21vt-22

25 vt-zzw-24vt-25vÍ-26vr-27

p-FTIHHH2-FH4-Cl4-OMe4-Me2-Cl4-CF33-Me3-Me4-F4-F4-F4-F4-F4-OPh4-FHH4-F4-F4-F

5-Me i-Pr

149-151130-130.51,39-141168-169140.5-142.O155.0-r57.0192.O-195.O186.0-188,5161,.O-164.O

122.0-124.O183.0-186.0161.O-162.5137.0-138.0164.0-16-s.01,41,.5-743.5146.5-148.5177.O-J,72.O120-12615-3.0-154.098.5-103'i11.5-172.5

84.0-86.0119.O-J,2t.Oi60.0-161.5'162.0-163_0

HH[IHHH6-Cl H6-C1 HHH7-!le IIHHHHHH6-CI HHHHHHHó-Me -7-OMe

HHHH6-CI HHIIHH6-Cl s-Cl

H CI{.H CH3H i-P¡H CH3H i-PrH i-P¡FI i-PrH i-PrH i-PrH i-PrH i-P¡H i-Pr+F i-Pr

HHHÉI

HHHHHHHH

HLIH6-Cl6-ClH7-MeHHH6-ClHHH6-OMeHH6-ClHH

HIIHHHHHHHHHHHH

HHHHHHHHHHHH¿l-F

5-MeHHHHHHHHHH

HH

CHtcH3i-PrCH.i-Pri-Pri-Pri-P¡i-Pri-P¡i-P¡i-Pri-Pri-Pr

C.Htc2IIsCrH.CrHtC.HsCrHtc,H.C.HtC.HtCtHuCr14C"HtCrHsc2Hs

6-Cl6-ClH6-Me6-OMe

HHHH7-OMe

i-PrcrHtn-Pri-Prc-Pri-Pri-P¡Ph

c-Prsec-Bui-Prc-Pr7-OMe i-P¡ C¿Hs

c2Hs cH3HHHHH

30

-15

6-Cl 8-Cl 4-F6-Cl H H6-CI H HHH4-F

n-Pri-Prc-Pri-P¡i-P¡Phc-Prsec-Bui-Prc-Pr

CtHtCrH'cH.CrHtCtH-CrHtcH.CH,

In thc same manner as in Example 1-c, compounds V-2 toY-27 were prepared. (In Table 6, R1, R2, R3, Ra and Rscorrespond to the substituents of compound of V.)

TABLE 6

(Compounds in this Iàble are cornpounds of theformula V whe¡ein R6 is hvdrogen.)

VIT.26vil-27

6-Me H 4-F6-OMe 7-OMe 4-F

c2H5 109.0-:t11.0cH, 153.0-153.5

40 co*pound R' R2 R3 R4 Rs ä3;VII.8H-NMR (in CDCI.) ò ppm: O.92 (r,3HJ=7Hz), 1..41

(d, 6H,J= 6 Hz) ; 2.47 (s,3H), 3.27 (Hept aplet,rH J =6Hz) 3.9 6(q,2H,I =7 Hz), 7.0-7.8(m, 8H)vII-14

H-NMR (in CDCI.) ô ppm: 1.01 (t,3HJ=7Hz), 1.42(d,6H,J :6Hz); 2.38 (s,3HJ=3Hz), 3.25(Heptaplet, lHJ=6Hz) 4.04 (q,2H,J=7Hz), 6.9 -a.1(m,7Hz)

45

v-2v-3Y-4v-5v-6v-7v-8v-9v-10

HHH6-Cl6-ClH7-MeHHH6-ClHHH6-OMeHH6-CtHH6-Cl6-Cló-clH6-Ve6-OMe

HHHHHHHHTIHHHHH7-OMeHTIHHH8-C1

HHHH7-OMe

p-FHI.IHH2-FH4-Cl4-OMe4-Me2-Cl4-CF33-Me3-Me4-F4-F4-F4-F4-F4-OPh4-FHH4-F4-F4-F

H CH3H CH3H i-PrH CH.H i-P¡H i-PrH i-PrH i-PrH i-PrH i-PrH i-PrH i-Pr4-F i-Pr

i-P¡i-PrC.Htn-P¡i-P¡c-Pri-Pri-PrPh

c-Prsec-Bui-Prc-Pr

1,25-1241,43-14692-93

140-140.5121.5-124.0105.1-109.23,47.D-147.4135.6-136.8119.4;120.4105.8-106.9163.7-164.2161.1*108.1720.8-1?2.3164.4-165.2'143.1-144.2

150.2-155.3164.5-165.3150.1-151.6106.9-107.7135.0-135.71'14.8-175.3157.5-t58.01,25.0-126.5155.0-157.0200.0-200.5

UI-15 v-11

H-NMR(in CDC13) ò ppm: 0.9(t,3H,J-7Hz),1,.43 (d,6H, so Yl1

J :6Ílz); 2.29 (s,6Ll) 3.25 (Ileptaplet, ltI,J =6Ílz) 4.OO (q,ztl, v I 4I=7Hz), ó.8-3.0(m,7H) v-rsVII_18 v-16

H-NMR (in CDCI,) ò ppm: 0.98 (I,3HJ=7H"), r.o2 ,, Y;-itr(t,3H,J =7 Hz); I.6-2.3(m,2H), 2.8-3. 1 (m,2H) 4.03 (q,2H J='- v- r o

7Hz), ó.9-8.1(m,8H) v-20

vrr 2l v-21v-22

II-NMR (in CDCI.) ô ppm: 1.03 (t,3I{J=7tIz), I.41. v-23(c1,6H,J=6Hz); 3.25(Heptapet, lH,J =6Hz), 4.O5(q,2H,J= uo

uza7Hz), 6.&-8.1(m, 13H)

v_26VII-25 v-2l

5-McHHHHHHHHHHHH

II-NMR (in CDC1.) ò ppm: 0.97 (d,6IIJ=6Hz), 2.0-2.6(m,1H); 2.8s (d,2H,J=7Hz), 3.51(s,3H), 6.8-8.1 (m,8H)

In the same manner as in Example 1-b, compounds VI-2 65 In the same manner as in Exampie 1-d, compouncls IV-21o Yl-27 were prepared. (In Table 5, Rl, R2, R3, R'r and Rs to IV-6 were preparecl. (In Table 7, R1, R2, R3, Ra and R5correspond to the substituents in compouncl VL) correspond to the substituents of compound IV.)

5,856,3362t

TAI}LE 7

))

TABLE, 9-continued

(Compounds in this Table are compounds of lhefomula IV whc¡cin R6 is hydrogen.)

(Compoundsformula

in this Table are compounds of theof II whercin R6 is hvd¡osen. )

Compound R1 R2 R3 R4 Rs m.p. ("C.) Com- Ãr.P.

cc.)pouml R1 R2 Rr R4 Rs R12rv-zIV-3rv-4IV-5IV-6

HHHó-cló-cl

+FHHHH

HHHHH

HHHHH

CH.cH.i-PrCH.i-Pr

177-179

In the same manner as in Example 1--e, compounds III-2fo lll-27 were prepared. (In Table 8, Rl, R2, R3, Ra and Rscorrespond to the substituents of compouncl III.)

TABLE 8

(Compounds in this Täble are compounds of lheformula III wherein R6 is hvd¡oeen,)

m.p.

II-1110 tr-12

II-13II.14II-15II.I 6Ít- 17

15 Il-13IT.19il-20ft-21rf-22tr-23

4-OMc4-OMe2-Cl4-CF33-Me3-Me4-F4-F4-F4-F4-F4-OPh

78.0-78.575.O-18.Ooil78.0-83.066.W71.Ooil83.0-90.094.0-97.Ooil111.0-113.591.0-93.0121.0-125.Ooiloil69.0-71.0oil

HH6-ClHHH

II-_10

HH6-CtHH6-Cl s-Cl 4-F6-Cl H H6.CI H HHH4.F

T1.24'¿u l-zs

7-OMe6-OMe

HHHHHH

HHHHH

oilorl

H i-Pr CrH,H i-Pr CrH,H i-Pr CrH,H i-Pr CrHt+F i-Pr CrH,5-Mc i-Pr CtHtFI i-Pr C2HsH C2H5 C2H5H n-Pr CrH,H i-Pr CrHtH c-Pr CrH,H i-P¡ CrH.H i-Pr CrH,H Ph C,H.H c-Pr CrH,H sec- CrH,

BuH i-Pr C2II5II c-Pr C2ËIs

ttuzIII-3tn-4III--5III-6ITT.7III-8III-9IIT-10IIt-11tIr-12III-13III-14IIt-15ITI.16Ítr-17TIT-18

III.19IIt-20ÍlJ-21frr-22trr-23ilr-24f[-25tft-261rr,27

+FHHHH,2-FH+cl,l.oMe4.Me2-Cl4-CF33-Me3-Me+F4-F+F+F+F4-OPh

HTI

+F4-I,'+F

5-Me i-Pr

194-196170-1,71.5:107-108.5192-194125.5-72780.1-€0.2121,.1,-12?.3

148.0-149.1737.4-140.1111.6-113.183.8-84.5'126.2-128.8

124.8-126.4117.6-120.3147.8-150.9124.1728.5117.&-121.5135.2-135.91,41,.3-1,44.1,oil11,7-122142.8-144.3161.0-161.578.0-41.0137.0-137.5139.5-191.0

Compound R1 R2 R3 R4 Rs Cc.) fi-26I-27

6-Me II 4-F6-OMe 7-OMe 4-F

2s ll-7II-NMR(in CDCL) ô ppm: 1.21(t,3ÍrJ=7¡1r¡, 1..32(d'61r,

J =6Hz) ; 2.2-2,. a{m,zH), 2.5 -2.7 (m,IH) 3. 28(s, 1 H), 3. 34(Heptaplet, rH,J-6Hz) 4.O8(q,2H,J =lHz), a s4.6(m,IH)5.28(dd,1H,J=óHz,I= ISHz), ó.53(dd,1HJ:1 .5HzJ=15H2),

:o 6.9-4.0(m,8H)TI-T2

H-NMR(in CDCI3) ò ppm: 1.25(t,3HJ=7Hz), 1.33(d,6H,J = 6Hz) ; 2.2-2.4(m,2H), 2. 5 -2.8(m,7H) ; 3. 32(s,2H), 3. 38(Heptaplet, IH, J=6Hz); 4.I3(q,2H)=7Hz), 4.24.6(m,IH);

3s 5.34(dd, 1H,I = 6Hz, J =ríHz), 6.53(dd, 1 HJ= 1 .SHz J =ríHz),7.0-4.0(m,7H)il-15

H-NMR (in CDCI.) ô ppm: 1.23(t,3H ) =7llz), 1.35(d,6I I,t =6Hz); 2.2-2.4(m,2H), 2.31(s,6H); 2.6-2.8(m,IH), 3.32(s,

+o 2I'l) ; 3.35(He pt aplet,lll,J = 6[lz), a.l4q,2H J =7 tlz) ; 4.3 4.7(m,1H), s.30(dd,1HJ-6Hz)=16¡1r¡t 6.s1(dd,1HJ-1Hz"I-l6Hz), 6.7-8.o(m,7H)II-18

II-NMR (in CDCI.) ò ppm: 1.00 (t,31'l,J=7Ílz), L26(t,4s 3H J =7 Hz) ; I .6 -2.3(m,2H), 2.42 (d, 2H J = 6Hz); 2. 6 -3.2(m,

3 H), 3. 3s(s, 2H) a.fl @,?H,I =7 Hz), 4.34.7 (m,IH) 5 .27 (dd,1H,J=6Hz,J=16H2) 6.a6(dcl,1H,J= 1.5Hz,J= 16Hz), 6.9-4.0(m,8H)

55

TT22

H-NMR(in CDCI3) ò ppm: 1.2ó(r,3HJ=7Hz), 1.33(d,6H,J =6Hz) ; 2. 43(d,2H,J = 6H z), 2.6-2..9 (m,1H) 3. 36(s, 2H), 3. 44(Hep taplet,1 H, J =6Hz) a.ß (t ZH I -7Hz), 4.3 4.7 (m,LH)5 3qdd, 1 H,J=6Hz.,J =76H2), 6.53(dd, 1 H,I= 1 .5Hz J =16H2),7.0-7.6(m,6H)l-23

H-NMR(in CDCI3) ð ppm: 1. 23(t,3H,J =7Hz), 2.2 I(d,2H,l = 6Hz) ; 2. 4-2. 6 (m,LH), 3.25 (s,zH) 4.o9 (q,ZH,J =7 Hz),a. Ia.a(m,rH) 5.08(dd,1H,J=6Hz,J= t6Hz), 6.26(dd,tRJ =1.5Hz,J=I6Hz), 7.0-8.0 (m,13H)

60 ll25H-NMR(in CDCI3) ò ppm: 0. 96(d,óH,J = 6Hz), I.26(t,3H,

J =7Hz), 1.8-2.a(m,lH), 2.43 ((l,2H,J=6Hz), 2.6-2.9(m,1H),2.88(d,2H J =7 Hz), 3 .3 6(s,2H), 4.M{q,ZH,I -7 Hz), 4.3 4.7(m, 1 H), s.O-s.s(m, 1 H), 6.3-6.(m, I H), 6.9-8. 1(m,3H)

6s Il-26I I-NMR(in CDC13) ò ppm : 1 .25(t,3ll, I :7 ÍIz), 1,.34d,61t,

J =6Hz), 2.32(s,3H), 2.39(d,2H, J =7Hz), 2.6*3.1(m,r}]),

HHH6-Cl6-CtH7-MeHHH6-ClHHH6-OMeEH6-CtHH

HHHHHHHHHHHHHH

H CH3H CHIH i-PrH CH3H i-PrH i-PrH i-PrH i-PrH i-PrH i-PrII i-PrH i-Pr+F i-Pr

HHHHHHHHHHHH

6-Cl6-CtHó-Me6-OMe

HHHH7-OMe

i-PrC.Hun-P¡i-Prc-Pri-Pri-PrPhc-Prsec-Bui-Prc-Pr

7-OMeHHHHH

6-Cl 8-Cl 4-F

It-22H-NMR(in CDCL) ò ppm: 1.40(d6H,J=7Hz), 3.44

(Heptaplet,lHJ =7Hz); 5.93(dd,IHJ =8Hz,J=I6Hz), 6.8-4. 1

(m,1 4H) 9.3 (d,IH J =8Hz)In the same manner as in Example 1--f, compounds ll-2 to so

ll-27 were prepared. (tn Table 9, Rt, R2, R3, R't and Rscorrespond to the substituents of compound II.)

TABLE 9

(Compounds in this Täble are compounds of theformula of II whe¡ein Rd is hvdrosen-)

Com-pound Rr R2 R3 R4 Rs R12

m.P.

cc)ïf-2II-3tÍ-4II-5II.6il-7tI-8II-9

HHH6-Cl6-CIH7-MeH

CH,CH.i-PrCH,i-Pri-Pri-Pri-P¡

c.HtC.HtCtHtCrH'crHtC.HtC¿HtCrHt

HHHHHHHH

p-FHHHH2-FH4-Cl

HHHHHHHH

oil105-10688.5--90.577,4296-98oil68.5-74.091.0-94.0

233. 3 6 (s,2H), 3. 4 1(Hep t ap let,lH,I : 6Hz), a, U,(q,?H,J =7 Hz),4 3-a.7 (m,1,H), s.0-s. s(m, 1 H), 6.3-6.7 (m,1.H), ó.8-7. 9(m,7H)il-27

H-NMR (in CDCIr) ò ppm: 0.8-1.5(m,aQ, 1.26(t,3HJ=7 Hz), 2.0-2. 9 (m,4H), 3. 42(s,2H), 3.7 t (s,3H), a. 00(s,3H),a.20(q,2HJ=7Hz), 4.44.8(m,1H), s.3-s.8(m, 1H), 6.4-6.9(m,1H), ó.sS(s,1H), 7.G-7.5(m,5H)

In the same manner as in Example 1-g, compounds I-12to l-127 were prepared.

TABLE 10

5,856,33624

3.49(Heptaplet,lH,I =6Hz) 3. 6-3.8( m,l H), 3.9 a.z(m,IH)a.zo(q,zH ) =7 Hz), 4.34.5(m,tH) s.2-s. 5(m, 1 H), ó.s-6.8(m,lH) 7.0-8.2(m,8H)I-110

s H-NMR (in CDCI.) ò ppm: 1.29(t,3H,J=7Hz),1.40(cl,6H,J =6Hz); 1.s-1.6(m,2H), 2.3-2.5(m,2H) 2.8-3.0(m, 1H),3.4-3.ó(m,1H) 3.52(Heptaplet,lH,J=6Hz), 3.88(s,3H)3. 9-4. 1(m,1 H), 4.20(q,2H,J =7 Hz) 4.34. 5 (m,tH), 5.3-5.5(m,1FI) 6.5-ó.7(m,1H), 6.9-8.1(m,8H)

FI-NMR (in CDCI.) ò ppm: 1.30(t,3tl)=7Ílz),1.3-1.s(m,' " 2H) ; 1 . 3 e(d,6H J=6H z), 2.3-2. s(m,2H) 2.a3(s,3H), 2.s-3.0

(m,1H) 3.50(Heptapiet,lHJ=6Hz), 3.51.7 (m,IH) 394.2(m,1 H), 4.19 (q,zH J -7 Hz) 4.2-4. S(1,LH), 5.2-5.6(m, 1 H)6.,f-6.8(m,1H), 6.9-8.{m,8H)t-t121s H-NMR (in CDC13) ô ppm: L.30(r'3H'l=7Hz),1.3-1.ó(m,2H); 1,.37 (d,6H,I =6Hz), 23-25(m)H) 2.9-3.2(m,1H), 3.47(Heptaplet, 1 H J =6Hz) 3.-5-3.8(m, 1H), 3.9-4. 1(m,1 H) 4. 19(q,zH,I =7Hz), 4.24.5 (m, IH) s.3*s.7(m, 1H), 6.5-6.8(m,1H) 7.1-8.1(m,7H)

2û l-1L3H-NMR(in CDC13) ô ppm: J-.G-1.3(n,2H), 1.30(t,3HJ-

7 Hz) ; 1,. 40(d,6H,J=6FIz), 2.3--2. 4(m,2H) 3.3-3.s(m, 1 H),3.49 (Heptaple t,rH J = 6Hz) 3.61.7 (m,IH), 3. 9-4. 1(m, 1 H)a.ß(q,zH,J =7 Hz), 424. S(n,IH) s. l-s.s(m, 1H), ó.s-ó.8

zs (m,lH) 7.2-8.2(m,8H)l-tl4

H-NMR (in CDCIr) ô ppm: 1.2-1.4(m,2H), 1.30(t,3HJ=7 Hz) ; 1.39(d,6H,t = 6Hz), 2.32(b s,3H) 2.3-2. s (m,zH),

I-1R3 R4 OH

-rÐ OH

N Rs

R

n.p.("c.)Com- Masspound Rr R2 R3 R4 R5 R12 spectrum

Í-1,2

I-13Í:14I-15I-16r-1,7f-18I-19I-110I-111r-1,3,2

I-113I-114I-115I-11 61-11,7

I-118I-11Sr-120r.-D1Í-222t-1,23f-124I-125T-126r-127

H

HFI6-Cl6-ClH7-MeHHHó-ctHHH6-OMeHH6-CtHH6-Ct6-Cl6-ClH6-Me6-OMe

HIIHHHHHHHHHHÉI7-OMeHHHHH8-ClHHHH7-OMe

4-F

HIIHH2-FH4-Cl4-OMe4-Me2-CI4-c,F33-Me3-Me4-F4-F4-F4-F4-F4-OPh4-FHH4-F

H

HÉI

HHHHHHHHH+F5-MeHHHHHHHHHH

CH,

CHti-PrCH.i-P¡iP¡i-Pri-Pri-P¡i-P¡i-P¡i-Pri-PriP¡i-Pr

QHrn-Pri-Prc-Pri-Pri-P¡Phc-Prsec-Bu

CtHtM/e

CrHtCrHtC.HtcrHtC.HtC.H.CtH¡CrHtCrHtC.HtCtHtCrHtC.II,C.H.crHtCzHsC"H'C.HtCrHtCrHtC.HtCrHtCrH-,

oil423,292264,24992-70597-100oiloiloil'oil98-10494-9879-€5oil117*12885-97oilgumoiloiì79-42100-104oil133-143gumoiloil

H

4-F H i-Pr C"H. oil4-F H c-Pr C?II5 gum

3.{}-3.3(m,1H) 3.50(Heptaplet,lHJ=6¡1r5, 3.6-3.8(m,1H)3. 8-4. 1 (m, 1 H), 4.2o(q,2H,J =7 Hz) 4.3 - 4. 6 (m,IH), 5 .2-s . 6(m,1 H) 6.s-6.8(m, 1H), 7.0-.8.2(m,7H)I-115

H-NMR (in CDCI") ò ppm: 1.1-1.4(m,2H),1.30(ÉHJ=7 Hz) ; t.4o(d,6H,I - 6Hz), 2.2-2. 5 (m,2}{) 2. 3s(s,6H),2.7 -3.\(m,IH) 3.5 1 (Heptaplet, IH ) =6Hz), 3. ó-3.7(m, 1 H)3.8-4. 1 (m, 1 H), a.z8 (q,zH ) -7 Hz) 4.24.6(m,IH), s.z-s . 6(m,lI-I) 6.4-6.8(m,1H), 6.8-8.2(m,7LI)I-116

H-NMIì (in CDCI.) ò ppm: 1.30(t,3H,I=7Hz),1..37(d,6H,J = 6Hz); 1.5-1. 8(m,2H), 2.3-2. 5 (m,2}l) 2.9 -3.2(m,IH),3.46 (Heptapl et,1,H,J =6Hz) 3.ó-3:8(m,1H), 3.75(s,3H)3.e-a. 1(m,1 H), 4.07(s,3H) 4.20(q,2H,r =7Hz), 4.245(m,1H) 5. 1-5.5(m, 1H), 6.4-6.8(m,2H) 7. 1-7.5(m,5H)t-117

H-NMR(in CDCI3) ò ppm: 1.30(t,3H,I=7Hz), L.37(t,3H,J =7 Hz); 1.4-1.7 (m,2H), 2.2-2.6(m,2H) 2.8a.2(m,3H),3.6-3.e(m,1 H) 3.9 4.7 (m,4H), s.2-s.7(m,1 H) 6.3-6.7 (m,1FI) 7.0-8.2(m,8ÉI)I-118

H-NMR (in CDCI.) ô ppm: 1.01(t,31'lJ=7Ílz), r.27(t,3H,t =7 Hz); t. a-2. r(m,aH), 2.3-2. 6(m,2H) ; 2.8-3. 3(m,3H),3. 6-3.3(m,1 H) ; 3.94.I(n,LH), a. 18(q,2H,J= 7Hz); 4.24.5(m,1H), s.2-s.6(m,1H); 6.4-6.1(m,IH). 7.0-8. 1(m,8H);I-119

H-NMR (in CDCI,) ô ppm: 1.2-1.5(m,2H), 1.31(t,3HJ=7 Hz) ; 1.37 (d,6H,I :7 Hz), 2.31.6(m,2H); 3.G-3.4(m, 1 H),3.49(Heptaplet,tH,J=6Hz); 3.6-3.8(m,1H), 3.8-4.2(m,1H);4.2o(q,2H,I =7Hz), 4.34.5(m,IH); s.2-5.6(m,1H), 6.4-6.8(m,1H); 7.0-€.1(m,7H);r-t20

H-NMR (in CDCI3) ò ppm: 0.8-1.8(m,6I'I), 1.30(t,3UJ=7 Hz) ; 2.1-2.6(m,3H), 2.e-3.3(m, 1 H) ; 3.4-3.7 (m,t}]),3.8-a.6(m,2H) : 4.2O(q,2H,I =7 Hz), -5.4-5.8(m,1.H); 6.44.3(m,1H), 6.8-8.0(m,8H);I-L2L

H-NMR (in CDCI.) ò ppm: 1.29(t,3HJ=7Hz),1.39(d,6H,J : 6Hz) ; l. a-I . 9 (m,zH), 2. 3 -2. 5 (m,2H) ; 2.7 -3 .2(m,t[),

30

35

40

45

.50

r-17H-NMR (in CDCI.) ð ppm: 1.29(t,3H,J=7Hz),1.40(d,6H,

I =6Hz); I .4-1.7 (m,2H), 2.3-2.5(m,2H) 2.9-4.z(m,lH), ss

3.49(Heptaplet,IH J =6lfz) 3.5-3.8(m,1 H), 3.9 4. 5(m,2H)a.2o(q,21'I,J =7 | Iz), 5 .2-5.7 {m, 1 ÉI) 6. 5-6. e (m,trr), 7 .o -a.2(m,8H)I-1B

H-NMR (in CDCI.) ò ppm: 1.0-1.4(m,2H), 1.31(t,3HJ= oo

7 H z) ; 1., 39 (d,6H, I : 6Hz), 2.3 -2. 5 (m,2H) 2. 5 2(s,3H),3.r-3.4 (m,lH) 3.48@eptap1et,1H J6Hz),3.5-3.8(m,1H)3.8-4. 1(m,i H), 4.2o(q,2Ír,I =7 Ítz) 4.24.5 (m,rrD, 5.2-5 . 6(m,1$ 6.a-6.8(m,1H), 7.G{.0(m,8H)I-19 6s

H-NMR (in CDCI.) ò ppm: 1.29(t,3H,J=7Hz),1.38(d,6H,J =6Hz): 1.a-1.8(m,2H), 2.3-2.5(m,2H) 3.24.a@,IH),

5,856,3362s 26

3.5 1(Hcptapict,lH,l :6Hz); 3.ó-3.8(m,1H), 3.9-4.2(m,IH); l-I25a.r9(q,2H,J=7Hz),4.34.6(m,LH); 5.2-5.6(m,1H), 6.4-6.8 NMR (in cDCl3) ò ppm: 0.94(d,6lrJ=6wz), 1.G-1.7(m,(m,lH); 6.9-8.2(m,t3H); ¡H), t.27(t,3H,J=7Hù,1.9-2.5(m,3H), 2.90(d,z4,r-7qz),t-122 334.4(m,3H), 4.r2(9,2nf,=7Hz), 5.È5.5(m,1H), 6.2-6.7

H-MNR (in CDCI3) ð ppm: 1.1--1.8(m,2H),,1.31(t,3HJ= 5 (m,1H), 6.9-8.0(m,8H),7Hz); 1.41(d,6H,J-6Hz), 2.3-2.5(m,2H); 2.94.a(m,1H), br263.50(Heptaplet,lHJ=6Hz);3.6-3.8(m,1H), 3.9-4.5(m,2H); H_NMR (in CDCI ) ò ppm: 1.0_1.6(m,3H), r.2r(t,3H,J=a.20\9]H."t=|H2),5.2-5.6(m,1H); 6.4-6.8 (m,1H), 7.1-7.3 zuil, l.à+ìä,arU =øø"f,' z.z+1"5'): ní@,z*,r=7Hz),(m,5H); 7 .7 2(d,tH ) =6Iì2):r_rz3 .^ 2.9-3.7(m,2H), 3.8-4.5(m,2H), 4.1'5(q,2H"l=7Hz),5.û-5.5

H-NMR (in cDCl.) ò ppm: 0.8-1.5(m,2H), t.2e(t,3HJ='" ÍÏ']i)'6'3-6'7(m'1H)' 6'e-8'0(m'7H)'

7Hz); 2.2-2.4(m,2H), 2.6-2.9(mjH); 3.2-3.6(m,t[), "_1'-___ .. ^_z.l-+.1(m,Zlj);'+.|tçq2lHS=løz), 5.a_5.4{m,IH);'6.1_6.1 __-H.

WR (in CDCI.) ô ppm: 0.8-1.9(m,8H), L.29(I,3HJ=(m,1H),'7.G{í.2(m,1àü); 7Ítz)'r-tzç 1s 2.1-2.6(m,3H), 2.8-3.2(m,tH), 3.72G,3H), a.02(s,3H),

H-NMR (in CDCI.) ô ppm: 0.8-1,.8(m,óH), 1..29(t,3HJ= 4.1'9(q,2H)=7Hz), 4.34.6(m,IH), s.+-s.8(m,1H), 6.44.87Hz), 2.2-2.6(m,3H), 2.s-3.2(m,tlH), 3.3-3.7(m,1H), (m,lH),6.56(s,1H),7.a-7.4(m,s}])3.94.5(m,2H), 4.19(q,2H,J=7Hz), 5..+-5.8(m,1H), 6.5-6.8 In the same manner as in Exmpie 2, compounds I-52 to(m,lH), 7.1-€.i(m,8H), I-52i7 were prepared.

TABLE 11

=Ð

R3 R4 OH

OH

R4 R5

15 (Rr2 = Na)

R12

Rl

RsN

Compound R1 R2 R3m.p.

cc)Í-52

f-53

r-54

f-55

r-56

r-57

I-58

I-59

I-510

I-5:11

f-512

t-513

I-514

I-515

f-516

r-517

I-518

H

H

H

6-Cl

6-Cl

H

7-Me

H

H

H

6-Cl

H

H

H

6-OMe

H

H

TI

H

H

H

H

[I

H

H

H

H

H

H

H

H

7-OMo

H

H

+F

H

H

H

H

2-î

H

+cl

+OMe

4-Me

+cFÌ

3-Mc

3-Mc

+F

+F

4-F

H

H

H

H

H

H

H

H

H

H

H

H

4-F

5-Me

H

H

H

CH,

CH,

i-P¡

CH.

i-P¡

i-P¡

i-Pr

i-P¡

i-Pr

i-Pr

i-Pr

i-P¡

i-Pr

i-Pr

i-Pr

CrIf

n-Pr

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

Na

138-142(decomposed)

130-1-?2(decomposed)

196-197(decomposed)

2111ß(decomposed)

19s-l98(deconposed)

793-207(decomposed)

170-7'75(decomposed)

193-202(deconposed)

778-193(decomposed)

187-200(decomposed)

203-209(decomposed)

20È212(decornposed)

195-200(decornposed)

192-797(decomposed)

239-245(deconrposed)

230-237(deconposed)

193-200(decomposed)

5,856,33627

'IABLE 11-continued

28

R3 R4

N Rs

Rt Rs

I-5 (Rr2 = Na)

R12

OH

t2

(Ró- ÐRl

OH

Compound Rl R2 R3m.p.

cc.)

t-519

ts2a

l-521

r-522

I-523

t-524

r-525t-s26

t-527

ó-cl

H

H

ó.CI

6-Cl

H6-Me

6-OMe

4-F

+F

4-OPh

+F

H

H

iPr

c-Pr

i-Pr

i-Pr

Ph

c-Pr

sec-Bui-Pr

c-P¡

H

H

H

Na

Na

Na

Na

Na

Na

NaNa

Na

H

H

H

H

H

H

HH

I.I

193-1,98(decomposed)

197-799(decomposed)

180-:t89(decomposed)

183_187(decomposed)

190-196(decomposed)

204-21A(decomposed)

204-204(deco mposed)

234-238

8-Cl

H

H

HH

4-F+F

7-OMe 4-F(decomposed)

l-57 3s H-NMR (in DMSO-d6) ò ppm: 0.9-1.3(m,2 H), 1.35(d,H:\YR. (in DMso-d) È pp-, 0.e-1,.2(m,2[), L.37(d,

-- 6HJ-7Hz); I.7-2.r(m,zF.),2so6,ztt¡=zÈz¡; :.0-:.a1à,

6\J=7Hz);1.6-2.L(m,2H),3.48(Heptaplet,LH,J=6Hz); 3H),3.51(Heptrple¡,IHJ=i:7Hz);3.9-4.3(m,1H),5.3-5.6(m,3.743(m,4H), 5.3-5.6(m,1H);6.a-6.7(m,IH), 7.1-8.1(m, 1H); 6.3-6.ó(m,1H), 6.9-3.1(m,7H);8H), il-s t"sI-58

^^ FI-NMR (in DMSO-d6) ð ppm: 1.G-1.2(m,2fQ, 1.35(d,

F!-NMR (in DMSO-d6) ò ppm: 0.9-1.2(m,2Ít),1.31(d, '" 6ÍtJ:7tIz); r.6-Z.Z(m,iH), -2.:S1s,An;;

à.0-:S1rn,:t!,Q\J17Hz); .t.7-22(m,2H), 2.s0(s,3H); 3.3-4.s(m,5H), 3.51(Heptaplet,lH,J=7Hz); 4.o4.3(m,IH), 5.3--5.6(m,1H);s.2-s.6(m,1H); 6.3-6.6(m,1H),7.I1.9(m,8H)) 6.3-6.6(m,1H), 6.s-s.0(m,7H);r-59 I-516

H-ryMR (in DMSO-d6) ò ppm: 0.9-1.3(m,2H), 1.33(d, _ H-NMR (in DMSO-<16) ò ppm: 0.9-1.3(m,2H), 1.31(rt,6\J=7Hz); L.6-2.2(m,2H), 3.48(Heptaplet,I[,J=7Hz); as 6[''¡=711t¡t 1.7-2.o(m,2[), 3.2-4.7(m,4H); 3.62(s,3rÐ,3.s-4.6(m,aH), 5.2-5.6(m,2rt); 6.3-ó.ó(m,1FI), 7.1-8.1(m, 394.2(m,11'r);3.e4(s,3H), s.1-s.s(m,lH); 6.2-6.6(m,t1),8H)t 7.0-7.5(m,6H);I-510 t-5I7

H-NMR (in DMSO-d6) ò ppm: 1,.0-1.3(m,2H), r.32(1, H-NMR(inDMSO-d6)òppm:0.9-1.5(m,2H), t.34(t,3n,6H,J=7Hz); 1.Á-22(m,2H), 3.0-3.8(m,4H); 3.8ó(s,3H), so J=7Hz); 1.6-2.2(m,2H), 2.7-3.4(m,4H); 3.64.3(m,ZH),4.0-4.3(m,1H); 5.3-5.6(m,1H), 6.3-6.6(m,1H); 6.9-8.1(m, 5.2-s.7(m,IH);6.1-6.6(m,1H), 6.e-8.1(m,sH);8u); I-s18I-511 H-NMR (in DMSo-d6) ò ppm: 0.8_1.3(m,2H), 1.01(r,3H,

H-NMR (in DMSO-d6) ò ppm: 0.9-L.3(m,2H),1.33(d, J=7Hz); 1.6-2.1(m,4H), 2.7-3.8(m,5H); :.S-a.:(rn,tH),6H,I=7Hz); L.7--21(m,2H), 2.41(s,3H); 3.2-4.3(m,sH). ss 5.2-5.7(m,1H); 6.3-6.6(m,1H),7.1-s.1(m,sH);5.3-s.6(m,1H); 6.3-6.6(m,1H), 7.0-8.3(m,8H); I-519t-s12 II-NMR (in DMSo-d6) ô ppm: 0.9-1.3(m,2FI), 1.33(d,

H-NMR (in DMSo-d6) ò ppm: 0.9-1.3(m,2H), 1.33(d, 6H)=7Hz);r.6-2.2(m,2H),2.9*3.e(m,3[);3.49(Heptaplet,6IlJ=1Hz); L6-2.2(m,2ll),3.1-3.8(mjr!; 3.48(Fleptaplet, lllJ=7Ílz), 4.0-4.3(m,1H); 5.3-5.6(m,1H), 6.3-6.6(m,1H);IH,J =7 Hz),3.94.2(m, 1 H) ; 5.3-5.(m,1 H), 6.3-6.7 (m,l}Ì) ; so 7 .Z-a.I(m,7H) ;7.0-4.1(m,7H); l-52oI-513 H-NMR (in DMSo-d6) ò ppm: 0.8-1.5(m,6H), r.7-2.2H-NMR (in DMSO-d6) ô ppm: 0.8-1.3(m,2r!, I.34(d,6Í1, (m,2tl); 2.3-2.7(m,ttl), 3.0-3.9(m,3H); 4.0-4.3(m,1[Ð,J=7Hz); L6-2.2(m,2H),2.7-3.9(m,3H);3.49(Heptap1et,1H, 5.5-5.s(m,lH); 6.4-6.1(m,tE),7.2-8.O(m,sH);J=7Hz), 3.94.3(m,rH); s.2-5.6(m,1H), 6.3-6.7(m,1H); 65 I-52L7.1*8.1(m,8H); H-NMR (in DMSo-dl ò ppm: 0.9-1.5(m,2H), r.36(d,t-s14 6H,J=7Hz);1.71.3(m,2H),3.0-3.9(m,3H); 3.50(Heptaplet,

5,856,33629

LH):6Hz), 4.0-4.3(m,lH); 5.2-5.ó(m,1H) 6.4-6.7 (m,LH);7.G-8.1 (m,13H);

I-522

I'I-NMR (in DMSO-dd) ô ppm: 0.8-1.3(m,2ÍI), 1..37(d, s

6H,I =1Hz); t.6-2.2(m,2H), 3. 1-3.9(m,3H); 3.51(Heptaplet,IHJ=7Hz),4.o-4.3(m,1H); s.3-s.7(m,1H), 6.3-ó.7(m,1H);7.1-8.0(m,6H);

t-523 10

H-NMR (in DMS0-d6) ò ppm: 0.8-1.4(m,2H), I.6-2.1(m,2H); 2.e3.7 (m,3H), 3.7 4. I(n,IH); s. 1-s.a(m,1 H),6. 1-6.4(m,1 H); 7 .t-8.2(m,1.3[);

r-524

H-NMR (in DMSO-d6) ô ppm: 0.8-1,.5(m,5H), I.6*2.2(m,zH); 2.31.7 (m,zÉ), 3.0-3.8(m,3H); 3.9-4.3(m,1H),s.4-s.8(m,1H); 6.3-6.6(m,1H), 7.0-8.0(m,8H);

r-525

H-NMR (in DMSO-dó) ò ppm: 0.9-1.6(m,2rf 0.96(d,óFI,J = 6Hz) ; 1.7 -2. 6(m,3H), 2.89 (d,zH,J =7 Hz); 3. 0-3.8(m, 3H),3.94.?\m,1Ét); -s.2-s.6(m, 1 H), 6.2-6.6(m,1 rf ; 7. 1 -8. 1(m, zs8H)t

t-526

30

TABLN 13

t-3Rl R4

N R5

OH

(R6- ÐRr

o o

Compound R1 R2 R3 R4 R5

r-32I-33I-34I-35r-36

HHH6-Cl6-Cl

HHHHH

4-FHHHH

HHHHH

CH.CH.i-P¡CH3i-P¡

FORMULATÏON EXAMPLE 1

'Iàblels

DMSO-d6) ò ppm: 1.30(d,6H,J=7Hz), ,^2.34(s,3H), 2.a-2.6(n,tH), 3.0-3.3(m,2H), - "3.9-4.2(m,lFI), 5.2-5.6(m,1rf; 6.3-6.6(m,7H);

Compoutrd I-51IjctoseCrystal cellulose powderCorn starchHydroxypropylCMC-C¿

cellulose

Magncsium stearate

Total 20.0 g

:1.0

5.08.03.01.01.5

H-NMR (in1.7-2.\n,2H),3.3-3.B(mjrf;1H),7.0-8.0(m,

t-527

H-NMR (in DMSO-d6) ò ppm: 0.7-1.-5(m,5H), 1.3-2.2(m,2H), 2.2-2.6(m,2H), 3.1-3.3(m,2H), 3.59(s,3H), 3.94.2(m,2H), 3.9 1(s,3I-I), s.4-s.7(m, 1FI), 6.3-6.6(m, 1 tQ, 6.s2(s,1,H),7.o-7.a{m,SH);

In the same manner as in Examplc 3, compounds I-22 tol-26 can be preparecl.

,IAtsLE 12

The above components were mixed by a usual methodand then tabletted to procluce 100 tablets each containing 10mg of tbe active ingredient.

FORMULATTON EXAMPLE 2

35

40

60

Capsules

Compound I-51láctoseCrystal cellulose powderMagnesium stearate

To tal 15.0 g

The above components were mix cd by a usual mcthodand then packed in No. 4 gelatin capsules to obtain 100capsules each containing 10 mg of the active ingredient.

FORMULATTON EXAMPLE 3

Soft øpsules

:1.0

3.510.00.5

=Ð

R3 R4

N R5

OH

OH

R2 R3 R{ Rs

l-2

50

Rl

55

Compound R1Compourd I-51PEG (polyethylene glycol) 4O0Saturated fatty acid triglycèridePeppermint oilPolysorbate 80

'fotal

1.00 g3.89 g

15.00 g0.01 g0.10 g

20.00 I

Í-22r-2-1

t-?4t-25r-26

4-FHHHH

HHHHH

HHHHH

HHH6-C16-Ct

CH.CH.i-PrcH.i-Pr

In thc same manner as in Examplc 4, compounds I-32 toI-36 can be prepared.

65 The above components were mixed and packed in No. 3soft gelatin capsules by a usual method to obtain 1.00 soflcapsules each containing 10 mg of the active ingredient.

5,856,33631

FORMULAIÏON EXAMI'LE 41t

I'OIIMULAIION EXAMI'LE 7

Oitrtnetrt Gra¡ules

Compound I-51Liquid paraffinCetarolWhile vaselineEthylparabenl.-menthol

Total

1.0 g (10.0 g)10.0 g (10.0 g)20.0 g (20.0 g)68.a g (se.4 g)0.1 g (0.1 g)0.s g (0.5 g)

100.0 g

Compound I-51IåctoseCrystal cellulose powderCorn slarchHvdroxypropyl celhloseMagnesium stcaratc

Total

1.06.06.55.01.0

cs

cs

10

2O.O g

The above components were mixed by a usual method toobtain a LVa (IOVo) ointment.

FORMUI-ATION EXAMPLE 5

Suppository

15 The above components were granulated by a usualmethod and packaged to obtain 100 packages each contain-ing 200 mg of the granules so that each package contains 10mg of the activc ingredient.

We claim:1. A compound of the tbrmula,

l^l

N^

35

Z=-CH(OH)-CH2-CH(OH) -CHr-Co O.VzCa.

2. A method for reducing hyperlipidemia, hyperlipopro-teinemia or athcrosclerosis, which comprises administeringan elfective amount of the compound of formula A as

ao definecl in claim 1.

Compound I-51Wirepsol H15*Witcpsol W35*Polysorbate 80

1.0 g46.9 g52.O g0.1 g

100.0 g

,t1

25

F'Ibtâ I

*T¡ademark for triglyceride compound

The above componenls were melt-mixed by a usualmethod and poured into suppository containers, followed bycooling for solicliûcation to obtain 100 suppositories of 1 g 30

each containing 1.0 mg of the active component.

FOI{MULÄIION EXAMPLE 6

Injection fonnulation

Compound I-51Distilled waùer forinjection formulation

The formulation is prepared by dissolving the compoundin the distilled water whenever it is required.

z

7

5mgml

EXHIBIT B

I lllll illlllll ill ililt illl llllt ]llt llilt ll]t llilt llllt ililll llll illl lltrus00855799382

(r2) UnÍted States PatentVan der Schaaf et al.

qro; Patent No.:

1+s; Date of Patent:us 8,557,993 B2

Oct. 15,2013

(s4)

(71)

(72)

(73) Assignee: Nissan Chemical Industries Ltd.,Toþo (JP)

( * ) Notice: Subject to any disclairner, theterm ofthispatent is extended or adjusted under 35U.S.C. 154(b) by 0 days.

Appl. No.: 131664,498

Filed: Oct.3l,2012Prior Pu̡lication Data

US2013/005341341 Feb.28.2013

Related U.S. Application Data

Continuation ofapplication No. l31280,431, filed onOct.25,201 l, row abandoned, which is a continuationof application No. I 2/33 I ,086, filed on Dec. 9, 2008,now abandoned, which is a continuation ofapplicationNo. 10/544,752, filed âs application No.PCT/8P2004/050066 on Feb. 2, 2004, nowabandoned.

(30) Foreign Application Priority Data

Feb,12,2003 (EP) 03405080

0 304 063 2/19890 520 406 12/t992I 099 694 5DOOI1472227 n/2004I 472228 11t2004I 697 326 912006

6l-t71460 8/1986o5-t48237 5/1993

6-92970 4/19948-12674 1^996

2005-500382 t/20052005-516064 6/20052005-520814 7/20052007-s16952 612007

o3iot6317 2/200303i064382 8/2003

wo o3i064392 812003wo 031070717 8/2003

03/087091 10/2003wo2004107204a 812004

OTHER PUBLICAIIONS

CRYS'IALLINE FORMS OF PIIAVAS'IAIINCALCIUMApplicant: Nissan Chemical Industries, Ltd,

Toþo (JP)

Inventors: P¿ul Adriaan Van der Schaaf.HagenthalJe-Haut (FR); Fritz Blatter,Reinach (CH); Martin Szelagiewicz.Muenchenstein (CH); Kai-UweSchoening, Oberwil (CH)

Int. Cl.c07D 2ts/38 (2006.01)u.s. cl.usPC ............ 546n01.Field of Classification SearchUSPC 546/101See application file for complete search history

References Cited

U.S. PAIENT DOCUMENTS

F OREIGN PAT'F,NT DOCUMtsNT S

EPEPEPEPEPEPJPJPJPJPJPJPJPJPwowowowowowo(21)

(22)(6s)

(63)

Ian. 21,201O Submission of Refe¡ences in JP 2006-501997 (JPcounterpad to present application) with English trarslation.Mar. 3, 2010 Submission of References in JP 2006-501997 (JP cou-terya¡t to present application) with English üanslation.Ma¡. 26, 2010 Submission of References in JP 2006-501997 (JPcounterpart to present application) with English translation.Jun. 29,2OlO Office Action in JP 2006-501997 (JP counterpart toprcsont âpplication) with English translation.Aug. 23, 2010 Submission of Refe¡ences in JP 2006-501997 (JPcounterpart to present application) with English translation.Dec.27,2OlO Submission of References in JP 2006-501997 (JPcounterpart to present application) with English trmslation.Ian. 21,2OlO Submission of References in JP 2006-520594 (JPcounterpad to lelated U.S. AFpl. No. 13 /487,289) withBnglish trans-lation.Mar. 3,2010 Submission ofReferences in JP 2006-520594 (JP coun-terpart to related U.S. Appl. No. 13i487,289) with English transla-tion.Ma¡, 26, 2010 Submission of References in JP 2006-520594 (JPcounterpilt to relaled U.S. Appl, No. 131487,289) with English trans-lation.Apr. 12,20ll Office Action in JP 2006-520594 (JP counte¡part torelated U.S. Appl. No, l3l487,289) with English translation.Akibaetal., "Six-MontÏ Repeated Orâl Toxicity StudyofNK-104 inRats," The Journal ofToxicological Sciences, vol. 23, SupplementV,7 t3-720, 1998.Aug. 26, 2004 lnternational Seuch Report in EP 2004:707232 (EPcounterpart to prcsent application),Mar. 14,2006 Office Action inEP 20t)4-707232 (EP counterpa.rt topresent application).Dec. 14, 2006 Third Paty Submission in EP 2004-707232 (EP coun-terpat to pr€sent application).

(Continued)

Primary E-taniner -D M Seaman(74) Altorney, Agent, or Fínn - Oblon, Spivak,McClelland, Maier & Neustadt, L.L.P.

(57) ABSTRACTThe present invention is directed to new crystalline f'onns ofPitavastatin hemicalcium sa1t, refered to hereinafter as poly-morphic Forms A, B. C, D. E and F, as well as the âmorphousfomr. Furthennore, the present inve[tion is directed to pro-cesses for tlìe preparation of these crystalline fonus and theanorphous fbnn and pharmaceutical compositions compris-ing these crystalline fonns or the amorphous fonns.

39 Claims,9 Drawing Sheets

(s1)

(s2)

(s8)

(s6)

5,514,804 A5,856,336 A *5,872,130 A *5,939,552 A6,335,449 Bl6,528,661 B26,835,838 827,37t,865 B2

2002/0099224 A.l2003/0105359 Al2003/0233001 Al2004/0063961 AI2005/0130978 Al2012/0245200 Lt

3,t7s,9445,011,9305.2U,9535,407,9295,473,015

A 3/1965A * 4/t991A 2/1994

^ 4n995

A t2il995

81t999t/20023t2003

t2120045i 20087120026t2003

t2t20034/20046120059t2012

546/IOI

-5,'1996 Ohara et al.li 1999 Fujikawaet al.2/1999 Fujikawaet al.

Hoekse¡naFujikawaet al, ......Ohara et al.T¿kahashi et al.Oha¡a et al.

Ikeda et al.Ohua et al.Niddam et al.Chen et ¿1.

Acemoglu et al.Niddm et al.Va¡ Der Schaafet al.StorzVan De¡ Schmf et al.Yuda et al.Ohara et al.

........51413lt

........514/3lt

us 8,557,993 82Page2

(56) References Cited

OTHER PUBLICATIONSAug. 11, 2008 Third Party Submission in EP 2004-707232 (EPcounterpart to present application).Feb. 17. 2010 Office Action inEP 2004-707232 (EP counterpa¡t topresent application).Sep. 29, 2010'Ihird Party Subrnission in ËP 2004-707232(EP coun-telpart to present application).Jan. 25,2011 Office Action inEP 2004-707232 (EP counterpart topresenl application).Jul. 15, 2005 Intemationa.l Semch Report in EP 2004-807807 (EPcounterpart to related U.S. Appl. No. 131487,289).Sorbera et al., "NK-104: Hy'polipidernic HMG-CoA Reduct¿seInhibitor," Dnrgs ofthe Fuhrre 1998,23(8), pp. 847-859.Nov. 14. 2005 Intemational Preliminary Report on Patentability inEP 2004-807807 (EP counterpart to related U.S. Appl. No.t3t487,289).Jn. 19,200'7 Office Action in EP 2004-807807 (EP counterpart torelated U.S. Appl. No. 13i487,289).Apr. 4, 2008 Office Action in EP 2004-807807 (EP counterpart torelated U,S. Appl. No. 13i487,289).Aug. 2, 20lO Office Action in EP 2004-807807 (EP counterpart torelated U.S. Appl. No. 13i487,289).Sç. 29, 2010 Third Pa¡ty Submission ir EP 2004-807807 (EP coun-terpad to relâted U.S. Appl No. 13/487,289).Feb. 8, 2011 Office Action in EP 2004-807807 (EP counterpart torelated U.S. Appl. No. 13i487,289).Apr. I l, 201 I Third Pa¡fy Submission ir EP 2004-807807 (EP coun-terpari to relâted U.S. Appl. No. l3/487,289).tsyrn et al., Solid State Chernistry of Dmgs. 2d a1., SSCI, I¡c., 1998,pp.59-64.The UniterlStates Pharmacopeia 201 l, The Nafional Formul¿ry, USP34 NF 29, vol. l.Brittain, Polymorphism in Pharmaceutical Solids, 2cl ed., InfonnaHealtlrcare USA, 1999, 2009.Berge et al., "Pharmaceutical Salts," Journal of Pha¡maceutical Sciences, vol. 66, No. l, Jan. 1977, pp. I to 18.Takahashi et al., "Syntlesis of an Afificial HMG-CoA ReductaseInhibitor NK-l(X via a Hydrosilylation-Cross-Coupling Reaction,"Bull. Chem. Soc. Jpn., 68,2649-2656 (1995).Miyachi et al., 'A Novel Synthetic Methotl of HMG-CoA ReductæeInhibito¡ NK-104 Via a HytJroboration-C¡oss Coupling Sequence,"Tet¡¿hedron Letters, vol. 34, No. 51. pp. 8267-8270,1993.Bhattacharya, et al., "Theunoanalytical and Crystallographic Meth-ods," Polymorphism in Pharmaceutical Solids, Bdttain H. ed,, 2d ed.,Informa Healthcale USA, Inc., 2009, pp.3l8-335.Ivmisevic, et al., "Uses of X-Ray Powder Diffraction in the Pharma-ceutical Industry." Ph¿nn. Fonn. Qual., 201 I, pp. 30-33.Ev¿luation Reports for Approval ltrr Prescription Drug: PitavastâtinCalciurn, LIVALO tablet I mg, LIVALO tablet 2 mg, http:liwww.info.pm<la.gojpi, rnarle public Sep. 10, 2003. with partial Englishtranslation,Feb. 5, 2013 Office Action in JP 2011-260984 (JP counteryart torelatedU.S, Appl. No. l31487,289), with partial English translation.

Ogata, How to Op€rate Chemical Experiment, vol. l, 1963, pp.I 54- I 55, I 85-1 99 (Feb. 5, 20 l3 O1üce Action in JP 20 I l -260984).Dec. 10, 2012 Subrrission of References in JP 2006-501997 (JPcounterpart to present application) with English t¡anslation.Nov. 6, 2012 Submission ofReferences in JP 2006-520594 (JP coun-terpart to related U.S. Appl. No, l31487,289), with English transl¿-tion."Medical Supplies Interuiew Form: HMG-CoA redlct¿se inhibito¡designated dmgs LMALO Tablet I rng and LIVÀLO Tablet 2 mg,"Japaaese Society ofHospiial Phannacists, Sep. 2003, with Ënglishtranslation.Aug. 19, 2010 Submission of References in JP 2006-501997 (JPcounterpalt to pÌesent application) with partial English translaiion.Ma¡. 8, 2011 Office Action in JP 2006-501997 (JP counterpart topresent applicalion) with English translation.Apr. 26,20ll Submission of References in JP 2006-501997 (JPcounterpåf to present application).Sep. 30, 2010 Submission of References in JP 2006-520594 (JPcounterpart to related U,S. Appl. No. 13/487,289), with partialEnglish translation.Introrluctory Chemistry Course 2, Physical Chemistry, pp.32I-341,Aug. 28, 1997 (Sep. 30, 20ll Submission ofReferences in JP 2006-s20s94).Apr. 26,2?ll Subrnission of References in JP 2006-520594 (JPcounterp¿rt to related U.S. Appl. No. 131487,289), with partialEnglish translation.Japanese Pharmacopoeia, Fourteenth Edition, pp. 49-51 Mr.30,20 1 I (Apr, 26, 20 I I Submission of References in JP 2006 -520 59 4).Mat,27,2Ol2 Office Action in JP 2006-520594 (JP counterpart torelated U.S. Appl. No. 131487,289), with English trmslation.Information Offer Form dispalched Apr 6, 20 l0 in Japanese PatentApplication No. 2006-5001997 (with Ënglish-language trmslation).Info¡mation Offer Form dispatched Feb. 23, 2010 in Japanese PatentApplication No. 2006-501997 (with English-language translation).Infomation Offer Foln dispatched Apl27 ,2010 in Japanese PatentApplication No. 2006-501997 (with English-language tra.nslation).Official Action dispatched Jun. 29,2010 in Japanese Patent Applica-tion No. 2006-501997 (with English-lmguage translation).M. Suzuki et ¿1, Fi¡st Systematic Chiral Syntheses of Two Pai¡s ofEnmtiomers with 3,5-Dihydroxyheptenoic Acid Chain, Associatedwith a Potent Synthetic Statin NK-104, Biorganic &. MedicinalChemistrl, I-¿¡¿¡'5, 9, (1999), 2977-2982.Third Palty Observation Submifted on Aug. 21, 2010 in JP 2006-50 I 977 (including excerpt liom JP-A-2005 -520814).English Language Translation ofAug. 21, 2010 Third Party Obser-vation Submitted in JP 2006-501977 (including excerpt frorn WO03/064932. which is a counterpad to JP-A-2005-5208 14).Suzuki, Mikio, Developlnent Workfor HMG-CoA Reductase Inhibi-tor NK-104, (2001), (partial English translation attachexl).Ce¡tificate for Library Material stored in the National Diet Library,Developrnent Wolk for HMG-CoA Rednct¿se Inhibitor NK-104,Published (2001) Volume Heisei-l3, Chief Lib¡arian of Kmsai-ka¡ofNational Diet l-ibrary KazuyukiYamaguchi (parlial English trms-lation attached).

* cited by exarniner

us 80557,993 B2

\

U.S. Patent oct. t5,2ot3 sheet I of 9

o<r

fr¡Ët(9-r{

RgrtlEtHG¡

r¡ì.VI

ofrl

rf,t<\l

rr¡Fl

oF{

¡¡-t

=$|.\

oo¡rlGI

ooúl

(Ðrfl

FHsavt æ,=e.EãH

oaoctrf¡G¡

oorr'e

us 8,557,993 82IJ.S. Patent ocr. 15,2013 sheer 2 or9

o-1.

r¡l(vt

f¡ltsl(9=É

RÉfrlH|ñ'

Õofl

a-f1GI

rfl

e

\

'$\¡-r'

oc¡o€'(Þc>oo(Ðo<. tlr, (\¡ r-l

eoú)qaH==>o<-)

-HHaît=r{E-r

=¡-t

oocroÕeooc¡¡ cE¡ ri._ (f,

us 80557,993B.2

FÈ¡JC,=é

ofCY EiF.'ñ¡

o.rt

rrlcrl

oa.¡

r-r!6t

tr¡FI

rr.l

Õ

€rl

{îl

'$\oo<\

oo o-1.

oo<\lFI

LJ.S. Patent oct. 15,2013 sheet 3 of 9

oe(..ooo@

oQo

eo-1.

Þ{

Ðâf-l

=tsì5

us 8,557,993 B2[LS. Patent oct. r5o 2013 sheer 4 of 9

r{C-D

=éoÍGr ËË

F.cf

Õ=

rrlc/¡

oc.¡

ar'G¡

rrt

o

3/rt

eFl

Fel

,$\

G'oooaO

Ie@

ecte

ËeËs

IGI

ooqqt

oo<.€toGIFl

orfD(\lFI

êoQ

oIJì

Õ¡¡l<\l

o

U.S. Patent ocL L5,2or3 sheet 5 of 9

eõr.f,

us 8,557,993 B2

o-i

¡rì(vt

o(rD

rr¡GI

¡r¡r-l

orl

EÊlÉ<9=oo<rr éHrIE:HGI

r.rl\

=$\Q

ÐeËs

us 8,557,993 B2IJ.S. Patent ocL 15,2013 sheet 6 of 9

Erl)¡LÐ=r4

RgËlFrGI

e-l.

ú)(v¡

ct(Y¡

¡,rtñt

¡-flFl

oFl

ìe

,$\

rrD

o€o<\l

ee.<1.

ool-t

eoæeoeFl

-tscâ=-4.Ës

Þ

us 8,557,993 B2U.S. Patent oct. 15,2013 sheet 7 of 9

o.€.

r.rD(Y¡

ÉllåCl'=é

RÉEIFr<\¡

ocrt

rft(\l

¡.fìFl

ctFl

\è

.$\

rrt

eee<\l

ee<teÕ@ (Gt

xÊ. -^â#EiÉEìJ

oeorl

oeG¡rl

o

us 8,557,993 B2

o-ll

rf,(fl

e6rD

f-lFÍt9=éRgf¡IH6¡

GI

o

N

'$\oóFl

oeGI

ôeoo< cÉlHHev¡-zÉ.3r¡ =tsÈ5H

LJ.S. Patent ocr. 15,2013 sheet I of 9

ooeôoo\¡Ct rrt

us 8,557,993B.2

e-1.

É)cFl

otYD

r¡ìd

oH

l.ltGI

fr¡F¡(-t=éRgEr¡E{GI

Rs\

rfl

oooe(:>

G¡

oo(i/¡

ãeËs

o

LJ.S. Patent ocr. 15,2013 sheer 9 of 9

eo.tl.€tor¡)

oo\o

us 8,557,993 82l2

CRYSTALLINE FORJUS OF PITAVASTÄTIN polymorphism. Polyrnorphism is conmonly defined as theCALCIUM ability of any substance to lìave two or more different crystal

strucnres. Dmg substances may also cncâpsulatc solvcntCROSS REFERENCES TO RELAIED molecules when crystallized. These solvates or hydrates are

APPLICATIONS 5 refêrred to as pseudopolymorphs. It is also possible that theamorphous fonn is encountered. Different polymorplß,

This application is a continuation of U.S. patent applica- pseudopolymorphs or the amorphous l-onn diflèr in theirtion Ser. No. 131280,431. filed Oct. 25, 2011, which is a physical properties such as melting poht, solubility etc.continuation ofU.S. patent application Ser. No. 12/331,086, These can appreciably influence pharmaceutical propertiesfiledonDec.9,2008,nowabandoned:whichisacontinuation l0 suchasdissojutionrateandbioavailability.Itisalsoeconomi-of U.S. patent application Ser. No. 101544,7 52, filed on Aug. cally ¿esirable that the product is stable ior exten¿ecl periods8' 2005' now abandoned; whicl.r was a 37I of International oftime without the need for specialized storage conditions. ItPatent Application No. PCT/EP2004/050066, filed on Feb. 2. :.. ¡,-.._.. ¡. _ . :__ ^r^. ,. ^ , _ ^ ls rnererore lmponanr ro evaruare porymorpnrsm or orug siln-2004.andclaimsnrioritvtoEuroneanPatentAnnlicationNo. --.-------'--.;-'---'-

03405080.7.fiIedonFcÛ. n,20ö3.all ofwhiJdarcincorpo- 't ttu|il

l*-lerrnore'tneolscoveryolnewcrystaltlnepoly-rated herein by reference in their entiretier. '" morphic foflns of a drug enlarge the repertoire ofmaterials

The present irvention is directed to new crystalline forms that a frluþtion scientist has witir which to design a phar-

and the amorphous fo¡m of Pitavastatin calcium, p.o."rr", lnaceutical.dosage. form of a drug with a targeted release

lor the preparãtion thereofan<1 pharmaceutical corn-positions profile^or other desired characteristics' We now have srtrpris-

comprising these forrns. 2u ingly for¡nd novel crystalline lirrms of Pitavastatin calcium,

Thepresentinventionrelatestonewcrystallineformsand herein.designated¿s form A' B' c' D, E and F, and the

the amòrphotrs form of pitavastatin calciurn. pitavastatin is atnorphous form,of Pitavastatin calcium'

also known by the narnes NK-104. Itavastatin and Nisvasia- Accordingly' the present invention is directed to the poly-

tin. Pitavastaûn calcirun is known by the chemical ou-., morFhic Fil"t ^; P'c' D' E and F" and the amorphous lorm

(3R,5s)-7-[2-cyclopropyl-4-(4-fluoroihenyl)quinolin-3-ylj- "5 ofPitavastatincalcirunsalt(2:1)'

ì.s-ainyato*y-o(E)lh"pt"ooi" acid hémicálcium salt. piiav- ,^P:::lj::t of the inve'tion is a crystalli'e poly'rorph ofastatin òalciurn has t¡e following formula: (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-

yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalciurn salt,

oHo

herein designated as FonnA, which exhibits a characteristic

3¡ X-ray powder dilïraction pattern with characteristic pcaksexpressed in d-values (,Ä.) and in 20 as given in Table I(vs:very strong intensity, s=strong intensity, m:mediumintensity, w:weak intensity, vlry'-very weak intensity).

35 TABLE I

d-sDacings md 20 ægles for Fo¡m A.

d-spachg [Å] Argte [20] Rel. lùtersÌry

40I'1.613.0

8.88.48.t6.76.5

6.3

ó.05.575.255.174.824.644.274.204.1t)3.873.143.673.533.293.022.952.61

5.06.8

9.t10.01().5

I 1.0

13.3

13.'1

14.0

14.715.916.9

1,7.1,

18.4l9.l20.821.1

21.622.923.724.225.227.t29.630.234.()

s

s

s

ntm

s

m

mntmms

m

9.7

Pitavastatilì calcium has recently been tlevelope<l as a newchemically synthesized and powerful statin by Kowa Com-pany Ltd, Japan. On the basis ofreported data, the potency ofPitavastatin is dose-dependent and appears to be equivalent tothat of Atorvastatin. This new statin is safe and well toleratedin the treatnrent of patients with hypercholesterolaemia. Sig-nificant interactions with a number of other comrnonly useddrugs can be considered to be extremely low.

Processes for the preparation of Pitavastatin a¡e describedin EP-A-0304063 and EP-A-1099694 and in the publicationsby N. Miyachi et al. in'l'etrahedron Letters (1993) vol. 34,pages 8267-8270 and by K. Takahashi et al. in Bull. Chem.Soc. Jpn. (1995) vol. 68,2649-2656. These publicationsdescribe the synthesis ofPitavastatin in great detail but do notdescribe the hemicalcium salt of Pitavastatin. The publica-tions by L. A. Sorbera et al. in Dnrgs of the Future (1998) vol.23, pagcs 847-859 and by M. Suzrki et al. in Bioorganic &Medicinal Chemistry Letters ( 1 9 99 ) vol. 9. p ages 297 7 -29 82describe Pitavastatin calciun, howeve¡ a precise procedurefor its preparation is not given. A full synthetic procedure forthe preparation ofPilavastatin oalciurn is described in EP-A-0520406. ln the proccss dcscribed ûr this patent Pitavastatincalciun is obtainedby precipitation from an aqueous solutionas a wlúte crystallinematerial witha rneltingpoint of 190-192C. It is known that phannaceutical substances can exhibit

,furother object ofthe invention is a crystalline polyrnorphof (3 R,5S)-7-[2-cyclopropyl-4-(4-fluor<rphenyl)quinolin-3-yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt,irerein designated as Fo¡m B. wlúch exhibits a characteristicX-ray powder diffraction pattern with characteristic peaksexpressed in d-values (^Â.) and in 29 as given in Table 2.

45

50

55

60

65

us 8,557,993 B23

TABLE 2

4TABLE 4

d-soæines md 20 ursle for Fom B. / ..."^¡--- "-¡ 1A ¡noles fôr Fôm n

d-spacing lÅl Arglc [20] Rel. lntensitv d-spacing [Å] Anglc [20] Rel. Intens¡ty

19.0t6.614.2

11.5

9.69.28.5

7.8'1.6

7.0o.ð6.46.0s.945.665.435.225.104.924.744.594.43

4.264.t94.133.97

3.'73

3.643.533.423.373.303. l93.09

4.65.36.2

9.29.6

10.3

1 1.3

tl.712.613.013.914.'7

14.91.5.6

16.317.0l7.418.018.719.3

20.020.520.821.221.522.423.223.624.425.226.026.427.O

27.928.9

7.1

mnts

mmmm

nls

m

m

mm

YS

s

mtìl

m

10

20

vss

s

II¡

m

m

m

m

shouldçr

5.0

6.5

ó.8

8;710.010.2

10.8

13.I13.5

14.3

15.3

16.1

16.8

18.2

18.5

19.0

19.9

20.5

21-t)

21.'t22.3

23.424.025.6

26.2

I 7.5

13.5

13.0

10.1

8.88.6

8.26.86.55

6.20

-5.78

5.52

5.284.874.80

4.664.464.34

4.234.O9

3.99

3.803.703.4't

3.4n

Another object of the invention is a crystalline polymorphof (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt,herein designated as Form C, which exhibits a characteristic

d-soæinss md 2O mslæ for Fom C.

15

25

Another object ofthe invention is a crystalline polymorph30 of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-

yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalciurn salt,hcrein designated as Form E, which exhibits a characteristicX-ray powder diffraction pattern with characteristic peaksexpressed in d-valrres (.Â.) and in 20 as given in Table 5.

l5

TABLE 5

¡l-cn¡cinoc ¡nrl fA ugles for Form E.

d-spachg [Å] Angle [20] Rel. lntensityX-ray powder diffraction pattern with clmracteristic peaks 40

expressed in d-values (,Å) alld in 20 as given in Table 5.

TABLE 3

mms

m

mms

rì

b¡oad

21.615.9

tt.410.68.67.'l5.064.954.744.554.314.134.06

3;71

3.58

+.1

5.67.88.3

10.3I 1.617.5

t7.918.719.520.62r.52t.923.1

24.O

24.8

20.0r7.'713.4l3.l10.08.88.68.26.66.56.35.845.565.395.244.994.U4.694.394.344.304.244.21

4.124.083.993.',17

3.73

3.ó91.603.503.35

4.45.06.66.88.9

10.010.3

10.8

13.3

13.6

14.0

15.2

15.9

16.4t6.91 7.8

18.3

18.9

20.220.420.72û.921.1

21.621.722.323.523.824.1

24.725.426.6

s

s

s

s

ms

ms

ms

m

vsIII

mtrì

\rs

mutmmm

trt

50

55

60

ms

mmtn

ms

m

mm

45

d-spachg lÅl Argle l20l R€1. Intçnsity

Another object of the invention is a crystalline polymorphof (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt,herein designated as Form D, which edribits a characteristic os

X-ray powder diff¡action pattern with characteristic peaksexpressd in d-values (.&) and in 20 as given in Table 4.

d-spæinss ud 20 msles fo¡ Fo¡m E.

us 8,557,993 B26

Furthermore, the present invention is directed to processesfor the preparation of Form A, B, C, D. E and 4 and thcanorphons fonn of Pitavastatin calcium.

Form A can be generally prepared fron Pitavastatinsodium upon reaction with CaCl, in an aqueous reactionrnedium. Altematively. Form ,A of the invention may also beobtained in situ lrcm the free acid ((3R,55)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3 -y1l -3,5 -dihydroxy- 6(E)-hep-tenoic acicl) or the corresponding lactone with Ca(OH)r,advantageously also in an aqueous reaction rnedium. Theaqueous reactio[ mediun usually contains at least 80% b.w.of water; preferably it is water or water containirig minoraruounts of solvents and/or reactants frorn previous steps.Form A may contain up to I 57o wate¡ preferably about 3 to127o, nore preferably 9 to llvo ofwater.15 Form B can be generally prepâredby suspending formA inethanol containing water as a co solvent. The amount ofwateris preferably about 1 to 50%.

Form C can be generally prepared by suspending formA inisopropanol containing wâter âs a co solvcnt. The amount of

20 r¡r'ater is preferably about 1 to 50%, especially 7 to 2OVo andmore preferably about 5%. Form C can also be prepared froma mixtu¡e of isopropanol and a ketone solvent, containingwater as a co solvent. Preferably, the ketone solvent isacetone, and the amount ofketone solvent are aboutl to30Vo,

25 more preferably about 107o. The amount ofwater is prefer-ably about I lo 20yq more preferâbly about 5%o.

Form D can be generally preparedby suspending fomrA inabsolute ethanol.

Fonn E can be generally prepared by suspending formA in:o 1,4-dioxane containing watcr as a co solvent. The amount of

water is preferably about I to SOVI.

Fonn F can be generally prepared by suspending fomrA inmethanol containing water as a co solvent. The arnount ofwater is preferably about I to 50%.

35 In the above mentioned processes small amormts of seed-ing crystals of the desired crystalline fomr may be added tothe reaction mixture. Preferably srnall amou¡ts are about I to20 weight %o. more preferably about 5 weight %. Seedingcrystals may be added bef'ore or, where appropriate, after the

40 step initiating the crystallization (e. g. cooling. addition ofnon-solvent etc. as described above). Addition before initiat-ing the crystallization is of specific technical interest.

The arnorphous 1-orm can be generally prepare<lby aiklitionof a non-solvent to a concentrated solution of Pitavastatin

+s calcium in an organic solvent. As non-solvent may be takenfor example heptane or methyl tert-butyl ether, whereasexamples forthe organic solvent are 1,4-dioxane, tetrahydro-luran an<l ethyl methyl ketone. It is preferable that lhe non-solvent and solvent are miscible. The amorphous form can

so also be prepared by lyophilization ofan aqneous solution ofPitavastatin calcium.

Preparations ofpolymorphic fomrsÀ, B, C, D, E, F as wellas the amorphous fon¡ are usually done in substantially purereaction systems, essentially consisting ofthe edÙct specified,preferably in substantially crystalline form, and solvents and/or non-solvents as given above.

Another object ofthe present invention are processes forthe preparation of crystalliue forms of Pitavastatin calciumessentially free ofrcsidual organic solvent.

Particularly, the present invention is ¡elated to processesfor the preparation of crystalline forms of Pitavastatin cal-cium essentially f¡ee ofresidual organic solvent by exposingthe crystalline f'orm olPitavastatin calcium lo an atmospherewith a defined relative air hrunidity. Morc particularly, thepresent invention is directedto aprocess forthe preparationofany crystalline fomr or amorphous form of Pitavastatin cal-cium which is essentially free of residual organic solvent.

5TABLE 5-continued

d-spacing [Å] A¡glc [20] Rel. Intensity

Another object of the invention is a crystalline polyrnorphof (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- to

yll-3,5-dihydroxy-6(E)-heptenoic acid hernicalcium salt,herein designated as Form F, which exhibits a characteristicX-ray powder diffraction pattern with characteristic peaks

expressed in d-values (Å) and in 20 as given in Table 6.

TABLE ó

d-so¿cine ard 20 mples for Fon¡ F.

d-spacing [Ä] Angle [20j Rel. Intensity

30.234.0

2.962.64

17.2i 5.812.610.09.28.78.1

7.8'7.4

7.1

6.86.56.28.045.'.79

5.705.285.f13

4.854,614.514.304.184.083.903.M3.743.693.593.463.403.353.313.143.023.002.89

5.15.67.08.89.6

10.210.911.3

11.912.5

13.0

t3.7r4.4t4.715.3

15.5

16.81,7.6

18.3

19.3

t9.'I20.62r.22 1.8

22.823.1

23.824.124.825.726.226.6

28.429.529.830.9

m

s

ms

nt

Ìnms

ms

III

m

mmmmvss

s

s

s

m

fIl

m

shoulde¡

Small changes in the experimental details can canse snalldeviation in the d-values and 20 ofcharacteristic peaks in theX-ray powder <lifftaction pattems.

Another object of the invention is the arnorphou* fo.m of 55

(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt whichexhibits characteristic X-ray powder diffracti<u pattems as

depicted in FIG. 7. 60Powder X-ray diffraction is performed on a Philips I710

powder X-ray diffractometer nsing Cu k (ctl) radiation(1.54060 ,Å.); 2B angles are recorded with an experimentalerror of t0. l-0.2".4 discnssion ofthe theory of X-ray powdcrdiffraction patterns can be found in "X-ray diffraction proce- os

dures" by H. P. Klug and L. E. Alexander, J. Wiley, NewYork(1e74).

us 8,557,993 827

These can, for example, be prepared by exposing the crystal-line form or amorphous lonù to an atmosphere with a relativeair hrunidity of 5 to 100%. Prcferably. thcse are prcparcd byexposr.ìre to an inert gas stream with a defined relative airhurnidity to exchange residual organic solvent with water. In s

general, a relative air hunridity of 5 to 1007o, especially 40 to8096, is used.

Arother object ofthe present invention are phamraceuticalcompositions comprising an ellèctive arnount of crystallinepolyrnorphic FonnA, B, C, D, E or F orthe amorphous for- 10

ofPitavastatirr caloium, and a pharmaceutical acceptable car-rier.

'lhese polymorphic lbrms may be used as single compo-lìent or ås mixtures rvith other crystalline forms or the amor- ,,phous fonn.

As to the novel polymorphic fcrnns and amorphous fomr ofPitavastatin calciurn it is preferred that these corrtain25-1ffi% by weight. cspecially 50-100% by wcight, of atleast one of the novel forms, based on the total amount of 26

Pitavastatin calcium. Pretèrably, snch an arnount ofthe novelpolyrnorphic forms or amorphous form of Pitavastatin cal-ciunr is 75-100%oby wei-gJlt, especially 90-100% by weiglrt.Hi¡fily preferred is an amour.rt ol95-lü)% by weight.

The cornpositions ofthe invention incltrde powders, granu- 25

lates, aggregates and other solid compositions comprising atleast one of the novel fonns. In addition, the compositiorsthat are contemplated by the present invention rnay fi-rrtherinclude diluents, such as cellulose-derived materials likepowdered cellnlose, microcrystalline cellulose, nricrofine ¡ocellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cel-lulose, hydroxypropyl cellulose, hydroxypropylmethyl cellu-1ose, carboxyrnethyl, cellulose salts and other substinrted andunsubstituted celluloses; starch; pregelatinized starch; inor-ganic dilucnts like calcium carbonate and calcium diphos- :sphate and other diluents known to the pharmaceutical indus-try. Yet other suitable diluents include waxes, sngars andsugar alcohols like maruútol and sorbitol, acrylate polyrnersand copolymers, as well as pectin, dextrin and gelatin.

Furthcr cxcipicnts that arc within thc contcmplation of thc ¿o

present invention inchlde binders, such as acacia gutrr, prege-latinized starch, sodium alginate, glucose and other bindersrtsecl in wet and dry granulation and direct cotnpressiontablcting processes. Excipients that also rnay be present in thesolid compositions ftrrther include disintegrants like sodirun ¿s

starch glycolat, crospovidone. low-substituted hydroxypro-pyl cellulose and others. In addition, excipients may includetableting lubricants like magnesium and calcium stearate an<lsodium stearyl firmarate; flavorings; sweeteners; preserva-tives; phannaceutically acceptable dyes and glidants such as 50

silicon dioxide.The dosages include dosages suitable for oral, buccal, rec-

tal, parenteml (inclu<ling subcutaneous, intrarnuscular, andintravenous). inlialant and ophthalmic adrninistration.Although the most suitable route in any given case will ;sdepend on the nature and severity of the condition beingtreated, the most preferred route of the present ilention isoral. The dosages may be conveniently presented in ruritdosage form and prcpared by any ofthc methods wcll-knownin the art of phamracy.

Dosage forms include solid dosage fornm, like tablets,powders, capsu.les, suppositories, sachets. troches and losen-ges as well as liquid suspensions and elixirc. While thedescription is not intended to be limiting, the invcntion is alsouot intended to pertain to tnte solutions of Pilavastatin cal-cium lvhereupon the properties that distinguish the solidforms of Pitavastatin calcirun are lost. However. the use of the

Inovel fonns to prepare snch solntions is considered to bewithin the conternplation of the invention.

Capsulc dosages, ofcourse, will contain the solid cornpo-sition within a capsule which nay be made of gelatin or otherconventional encapsulating material. Tablets and powdersrnay be coated. Tablets and powders may be coated with aneuteric coating. The enteric coated powder f'orms rnay havecoatings comprising phthalic acid cellulose acetate, hydrox-ypropylmethyl-cellulose phthalate, polyvinyl alcohol phtha-late, carboxyrnethylethylcellulose. a copolymer of styreneand maleic acid, a copolymer of rnethaorylic acid and methylmethacrylate, and like materials. and if desired, they rnay beernployed with suitable plastioizers an<Vor extending agents.A coated tablet nìay have a coating orì the suface ofthe tabletor may be a tablet comprising a powder or granules with anenteric-coating.

Preferred unit dosages of the pharmacentical compositionsofthis invcntion typically contain from 0.5 to 100 mg ofthenovel Pitavastatin calciuln fonns or mixtures thereof wilheach other or other f'onns of Pitavastatin calcium. More usr¡-ally, the cornbined weight of the

Pitavastatin calcium fonns ofa nrút dosage are liom 2.5 mgto 80 mg. for example 5, 10, 20 or 40 mg.

ïre f'ollowing Exanples illustrate the invention in moredetail. Temperatures a¡e given in degrees Celsius.

EXAMPLE 1

Preparation of Fomr A

4.15 gr of (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-<lihydroxy-6(E)-heptenoic acid tert-butylester (Pitavastatin tert-butyl ester) was suspended in 52 rnl ofa mixture ofrnethyl tert-butyl ether and nìetlìanol (10:3). Tothis mixtwe were added 2.17 ml of a 4M aqueous solution ofNaOH, andtheresultingyellowish solutionwas stirred for2.5hours at 50' C. The ¡caction mixture was coolcd to roomterÌrperature f'ollowed by the addition of 50 ml water andstirring fbr an additional hour. The aqueous phasc was scpa-rated and once extracted with 20 ml of metþltert-butyl ether.To this aqueous solution werc added a solution of 0.58 grCaCl, in 80 ml of water over a period of 1 hour. The resultingsuspension was stirred for about 16 hours at room tempera-ture. The suspension was filtered and the obtained solid wasclried al 40" Cl. and 50 mbar ftrr about 1 6 hours. '['he obtaine<lproduct is crystal lorm A which is characterized by an X-raypowder diflraction pattem as shown in FIG. 1. Further char-acterizatiol of the obtained Fonn A by lhennogravimetrycoupled with FT-lR spectroscopy revealed a water content ofabout l0%o. Difïerential scarning calorimetry revcalcd a

melting point of 95" C.

EXAMPLE 2

Preparation of Fonn B

100 mg Pitavastatin calcitun FonnA was suspendcd in 2 ml60 water arrd stirred at room temperatwe for 30 min. followed by

the addition of2 ml ofethanol and additional stirring for l8honrs. The suspension was filtered and dried in air, yielding36 rng ol- Fomr ts. 'lhe obtained crystzrl Form B is character-ized by an X-ray powder diffraction pâttcm as shown in FIG.

es 2. Further cluracterization of dre obtained Form B by ther-mogravirnetry coupled with FTJR spectroscopy revealed a

water content of about 1070.

9EXAMPLE 3

Preparation of Form C

62 mg Pitavastatin calcium FonnA was suspended in 2 mlisopropanol containing 5Vo waïer. This suspension washeated to 60o C., which led to almost complete dissolution ofForm A, aud again cooled to room tenperature. At tlús tern-perature the snspension was stirred 1-or 66 hours. The result-ing suspension was flltered, once washed with some isopro-panol containing SVo water, and clrie<l in air. 'lhe obtainedcrystal Form C is characterized by an X-ray powder diffrac-tion pattern as shown in þ'lG. 3. Further characterization ofthe obtained Form C by thermogravimetry coupled with FT-IR spectroscopy revealed that the sample contains about 6.37oisopropanol aud a small amotnt of water.

60

60 mg of Pitavastatin calcium FonnA was suspended in 3ml metha¡ol containing 207o water, and stirred at 40" C. for Ihour. 'fhe resulting suspensiorr was skrwly cooled to nxrmtemperaturc and stirring was continued for 4 hours. Thc sus-pension was heated again to 40o C., stirred for 30 rnin, slowly os

cooled to room ternperature ard stirred for an additionally I 5hours. The suspension was filtered and the obtained white

us 8,557,993 B210

solid dried in air. The obtainedcrystal Form F is characterizedby an X-ray powder diffraction pattem as shown in FIG. 6.

EXAMPLE 8

Preparation of theAmorphous Form

62 mg of Pitavastatin calcium FonrA was dissolved in 0.3ml 1,4-dioxane. To this stirred solution was slowly added 2.3

to ml n-hcptane at roonr tenperature, and stirred for an addi-tional 16 hours. The resulting suspension was filtered anddried in air. The obtained solid was amorphous as is shown bythe X-ray diffraction pattern given irl FIG. 7 (top).

15 EXAMPLE 9

Preparation of the,Amorphous Form

29.6 (vw), 30.2 (w),34.0 (w);B) polyrnorph B exhibits a characteristic X-ray powder

diffraction pattern with characteristic peaks expressed in2ë at 4.6 (w), 5.3 (vs), 6.2 (s), 7.7 (s), 9.2 (m),9.6 (rn),10.3 (w), ll.3 (m), ll.7 (w), 12.6 (vw), 13.0 (w), 13.9

@),1a.7 (vw), 14.9 (w), 1s.6 (w), 16.3 (m), 17.0 (vw),17.4 (vw), 18.0 (w), 18.7 (rn), 19.3 (m), 20.0 (s), 20.5(w),20.8 (m),21.2 (w, shoulder).21.5 (m),22.4 (m),

EXAMPLE 4 60 mg of Pitavastatin calcium FormA was dissolved in i.5

prepararion of Form c '' il,"l:i:,ï$'JlTliïiii;i'J,"*"',ii,îä:äfr:ï5:ffJresulting suspension was stirred at room temperature for

65 mg Pitavastatin calcitun Forn A was suspendcd in a about I 6 hours. The suspension was filtered and the obtâi-ûedrnixtrreofO.9rnlisopropanol,0.lmlacetoneand40¡rlwater. solid was dried in air. An X-ray diffraction study on theStirring this suspelsion for about I hour led to nearly com- 25 product showed it to be amorphous, see FIG. 7 (bottorn).plete dissolution. Seeding with 4 rng of Form C (from f'urthercharacterizationoftheobtainedproductbythermo-example 3) and stiring for 2 hours led to thc forrnation ofa gravirnetry coupled with FT-IR spectroscopy revcaled thatconcentrated suspension. Tlis suspensio¡ was diluted with lhg samp]e contained about 5.5%o metþl tert-butyl ether.

the same amoruriof solvent mixture as above and stirred for Differential scanning calorimetry showed the sample to have

an additional 40 hours. The suspension was filtered and the 30 a glass transitiontemperature ofabout 6So C'

obtâìned solid was dried at40" C. l-orabout 10 min. Analysi* BRJEF DESCRI.TION OF THE DRAWINGSby X-ray powderdiffraction indicates the product to be crys-

tal Form c as shown in FIG' 3' F'lG. I is a characteristic X-ray powder dilfraction pattem

EXAMPLE 5 35 for FonnA'FIG. 2 is a characteristic X-ray powder diffraction pattern

Preparation ofForm f) for Form B'FIGS. 3A and 3B are two cha¡acteristic X-ray powder

60 mg orpiravasratin catcium F'orm A was suspen<tecl in r ., utf]ä:Ïiro;HiTfåÏ:î:.ay

powder diffracrion panemml absolute ethanol and stirred at room ternperature for 20 for Forrn D.hours. 'lhe resulting suspension was filtered and dried in air. FIG. 5 is a characteristic X-ray powder diffractiol pattemThe obtained crystal Form D is characterized by an X-ray lor Form E.powder diffraction pattern as shown in FIG. 4. FIG. 6 is a characteristic X-ray powder difüaction pattem

EXAMPLE 6 4t %Tåi: Tl ,"0 ?B are two characrerisric X-ray powderdiffraction patterns for the amorphous form.

Preparation of Form E

The invention claimed is:60 rng of Pitavastatin calcium Form A was suspended in a 5¡ | A crystalline polyrnorph A, B, C, D, E, F, or the amor-

mixture of l,4-dioxane and water (1:1). and stined for 18 phous form, of (3R.5S)-7-[2-cyclopropyl-4-(4-fluo-hours at roonr tenperature. Tlre resulting suspension was rophenye)quinolin-3-y1]-3,5-dihydroxy-6(E)-heptenoic acidfiltered and dricd in air. The obtained crystal Fomr E is char- hernicalcium salt whereinacterized by an X-ray powder difraction pattem as shown in A) polymorph A exhibits a characteristic X-ray powderFIG.S. 55 diffractionpatternwithcharacteristicpeaksexpressedin

20 at 5.0 (s), 6.8 (s),9.1 (s), 10.0 (w), 10.5 (m), 1l.0 (n),EXAMPLE 7 13.3 (vw). 13.7 (s), 14.0 (w), M.7 (w), i5.9 (vw). 16.9

(w), 17.1 (vw), 18.4 (m), 19.1 (w),20.8 (vs),21.1 (m),Preparation of Form F 21.6 (m), 22.9 (m).23.7 (m),24.2(s),25.2(w\,27.1(m),

us 8,557,993 8211 t2

23.2 (s),23.8 (m), 24.4 (vw),25.2 (w, broad), 26.0 (w), 7. A process for preparing the crystalline polymorph or26.4 (vw),21 .0 (w),27 .9 (vw),28.9 (w); arnorphous fomr according to clairn 1, wherein:

C) polymorph C exhibits a characteristic X-ray powder the crystalline polymorph or amorphous fonn being pre-difÏraction pattem with characteristic peaks expressed in pared is the crystalline polymorph C; and20a14.1(m),5.6(s),7.8(m),8.3(m), 10.3(m), 11.6(w), 5 the process comprises suspending the crystalline poly-17.5 (w), 17.9 (w),18.7 (m), 19.5 G), 20.6 (m), 21.5 morphAinamixtureof isopropanol andaketonesol-(vw).21.9 (m), 23.1 (n), 24.0 (w), 24.8 (w); vent, containing water as a cosolvent.

D) polymorph D exhibits a characteristic X-ray powder 8. The process according to clain 7, wherein the ketonediffraction pattem with characteristic peaks expressed in solvent is acetone.20atS.O(n¡,0.5(m),6.8($,8.21m),iO.O1m), 10.2(m), 10 9. fte process according to claim T, wherein the ketone10.8 (m), 13.1 (w). 13.5 (m), 14.3 (s), 15.3 (vw), 16.1 solventispresentinanamounlof 1to30%byvolumeolthe(m), 16.8 (w), 18.2 (w), 18.5 (m), 19.0 (w), 19.9 (n), suspension of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyt)20.5(n),21.0(vs),21.7(s),22.3(w),23.4(m),24.0(m), quinolin-3-ylj-3,5-dihydroxy-6(E)-heptenoic aci<l hemical-25.6 (w), 26.2 (m); ,, cium salt.

E) polyrnorph E exhibits a characteristic X-ray powder 10.Theprocessaccordilgtoclaim7,whereinthewaterisdiffraction pattem withcharacteristic peaks expressed in present in an amount of 1 to 20yo by volume ofthe suspension2B at 4.4 (vw), 5.0 (s), 6.6 (s), 6.8 (s). 8.9 (s), 10.0 (m), of (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-10.3 (s), 10.8 (m). 13.3 (s), 13.6 (n), 14.0 (s). 15.2 (vw), yll-3,5-dihydroxy-6(E)-heptenoic acid hcmicalcium salt.15.9 (w), 16.4 (w), 16.9 (vw), 17.8 (vw), 18.3 (n), 18.9 zo 11. A process for preparing the crystalline polymorph or(w),2O.2 (vs), 20.4 (m),20.7 (m), 20.9 (m), 21.1 (vs), amorphons ftrnn according to claim 1, wherein:21.6 (m), 21.7 (n),22.3 (m),23.5 (m), 23.8 (m\ 24.1 the crystalline polymorph or amorphous form being pre-(w),24.7 (vw),25.4 (vw), 26.6 (m),3O.2 (w),3a.0 (vw); pared is the crystalline polyrnorph D; andand the process cornprises suspending the crystalline poly-

F) polyrnorph F exhibits a characteristic X-ray powder zs mo¡phAinabsoluteethanol.diffractionpattemwithcharacteristicpeaksexpressedin 12. A process for preparing the crystalline polymorph or20 at 5.1 (m), 5.6 (w), 7.0 (s), 8.8 (m), 9.6 (s), 10.2 (w), amorphous form according to claim 1, wherein:10.9(m), IL3(w). I1.9(nt), 12.5(m), 13.0(s), 13.7(m), thecrystallinepolynorphoramorphousfonnbeingpre-14.4 (s), 14.7 (m), 15.3 (vw), 15.5 (w), 16.8 (m), 17.ó pared is the crystalline polymorph E; and(w), 18.3 (n), 19.3 (m), 19.7 (m),20.6 (m),21.2 (vs), :o the process comprises suspending the crystalline poly-21.8 (s), 22.8 (s),23.1 (w), 23.8 (w, shoulder), 24.1 (s), morphA in 1,4-dioxane containing water as a cosolvent.24.8 (s), 25.7 (m),26.2(vw),26.6 (n),26.9 (w),28.4 13.Theprocessaccordingtoclairnl.2,whereinthewateris(w), 29.5 (w), 29.8 (vw), 30.9 (rn); wherein, for each of present in the amount of I to 50% by volurne of the susper.-said polymorphs, (vÐ stands f'or very strong sion of (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quino-intensity; (s) stands for strong intensity; (m) stands for rs lin-3-yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalciummedium intensityl (w) stands for weak intensity; (vw) salt.stauds for very weak intensity. 14. A process for perparing the crystalline polymorph or

2. A process for preparing the crystalline polymorph or amorphous form according to claim 1, wherein:atnorphous fcrrm according to claim 1, wherein: the crystalline polymorph or amorphons form being pre-

the crystalline polymorph or amorphous form being pre- 40 pared is the crystalline polyrnorph E; andparedisthecrystallinepolymorphA;and the process conprises suspending the crystalline poly-

the process comprises reacting (3R,5s)-7-[2-cyclopropyl- morph A in methanol containing water as a cosolvent.4-(4-fluorophenyl)quinolin-3-yll-3,5-diþdroxy-6(E)- 15. The process according to claim 14, wherein the water isheptenoic acid sodium salt with CaCl2 in an aqllcous present in an amount of 1 to 50%o by volume of the snspensionreaction medinm. 4s of (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-

3. A process for preparing the crystalline polymorph or yll-3,5-dihydroxy-6(E)fieptenoic acidhemicalcium salt.amorphous fomr according to claim l, wherein: 16. The process according to ctaim2, whereir (3R,5S)-7-

the crystalline polyrnorph or amorphous lorm being pre- [2-cyclopropyl-4-(4-tluorophenyl)quinolin-3-yl]-3,5-dihy-pared is the crystalline polymorph B;and droxy-6(E)-heptenoic acid henicalcium salt is isolated by

the process comprises suspending the crystalline poly- so filtration and dried in air or vacuum.rnorphA in ethanol containing water âs a cosolvent. 17. The process according to claim 2, wherein seeding is

4. The process according to claim 3, wherein the water is carriedoutwithcrystalsofthedesiredcrystallinepolyrnorph.presentinanamountof 1to50%byvolumeofthesuspensiorr lS.Aprocesspreparingthecrystallinepolymorphoramor-of (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- phous form according claim 1, wherein:yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalciurn salt. 55 11æ crystalline polymorph or amorphous fomr being pre-

5. A process for preparing the crystalline polymorph or pared is the amorphous formi andarnorphous form according to claim l, wherein: theprocesscornprisesaddinganon-solventto asolutionof

the crystalline polymorph or amorphous f'orm being pre- (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-pared is the crystalline polymorph C; and 3-y1l-3,5-dihydroxy-6(E)-hcptenoic acid hemicalcirun

the process cornprises suspending the crystalline poly- oo saft in an organic solvent.morph A the process cornprises suspending the crystal- 19. The process according to claim 18, wherein the non-line polymorph A in isopropanol containing water as a solvent is selected from heptane and rnethyl tert-butyl ether.cosolvent. 20.

-fhe prucess according to claim 18, wherein the organic

6.Theprocessaccordingtoclaim5.whereinthewateris solvcnt is selected from l,4-dioxane, tetrahydrofuran andpresent in an amount of 1 to 50% by volume of the srspeusion os ethyl methyl ketone.of (3R,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- 21. A process for preparing the crystalline polymorph oryll-3,5-dihydroxy-6(E)-heptenoic acid hemicalciu¡r salt. amorphous form according c.lairn 1, whe¡ein:

us 8,557,993 8213 t4

the crystalline polymorph or amorphous fbrm being pre- irtensity, (m) stands for meditun intensity, (w) stands forpared is the arnorphous fonn; and weak intensity, and (vw) stands forvery weak intensity.

the process cornprises drying an aqueous solution of (3R, 29. A crystalline polyrnorph C of (3R,5s)-7[2-cyclopro-5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3- pyl-4-(4-lìuorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(F.)-yll-3,5-dihydroxy-6(E)-heptenoic acid hernicalcium 5 heptenoic acid hemicalcium salt, having an X-ray powdersalt by lyophilization. diffraction pattem substantially as depicted in FIGS. 3A and

22.Aphannaceuticalcompositiolcomprisinganeffective 38.amount of the crystalline polymorph or amorphous fomr 30. A crystalline polyrnorph D of (3R,5s)-7[2-cyclopro-accordiug to claim l, and a pharmaceutically acceplable car- pyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-<tihydroxy-6(E)-rier. l0 heptenoic acid hemicalcium sah, which exhibits a charactcr-

23. A crystalline polymorphA, B, C. D, E, F, or the arnor- istic X-ray powder diffraction pattern with characteristicphous form, of (3 R,5 S)-7-[2-cyclopropyl-4-(4-fluorophe- peaks expressed in 20 at 5.0 (m), 6.5 (n), 6.8 (s), 8.7 (m), 10.0nyl)quinolin-3 -yll-3,5-dilrydroxy-6(E)-heptenoic acid (rn), 10.2 (m), 10.8 (m), 13.1 (w), 13.5 (m), 14.3 (s), 15.3hemicalcium salt of clairn 1, wherein polymorph A has an (vw), 16.1 (m), 16.8 (w), 18.2 (w), 18.5 (m). 19.0 (w), 19.9X-raypowderdiffractionpattcnrsubstantiallyasdepictedin rs (m),20.5(m),21.0(vs),21.7(s),22.3(w\23.4(m).24.0(rn),FIG. l,polyrnorphBhasanX-raypowderdiffractionpattern 25.6 (w), ard26.2 (m), wherein (vs) stands forvery strongsubstantiallyasdepictedinFlG.2,polymorphChasanX-ray intensity, (s) stands for strong intensity, (m) stands forpowder diffraction pattern substantially as depicted in FIGS. mediurn intensit¡ (w) stands for weak inteusity, and ('w)3A and 38, polyrnorph D has an X-ray powder dilfraction stands I'or very weak intensity.pattem substantially as depicted in FIG. 4, polymorph E has ro 31. A crystallinc polymorph D of (3R,5s)-7[2-cyclopro-an X-ray powder diffraction pattem substantially as depicted pyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)-in FIG. 5, polymorph F has a¡ X-ray powder diffraction heptenoic acid hemicalciurn salt, having an X-ray powderpattem substantially as depicted in FIG. 6, and diffraction pattern substantially as depicted in FIG. 4.

the amorphous lorm has an X-ray powder diffraction pat- 32. A crystalline polymorph E of (3R,5S)-7[2-cyclopro-tem substantially as depicted in FIGS. 7Aand7B. zs pyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)-

24. A crystalline polymorph A of (3R.5s)-7[2-cyclopro- heptenoic acid hemicalcium salr, which exhibits a character-pyl-4-(4-fluoropherry1)quinolir-3-yll-3,5-dihydroxy-6(E)- istic X-ray powder diffraction pattem with characteristicheptenoic acid hemicalcium salt, which exhibits a character- peaks expressed in 20 at a.a (wv),5.0 (s), 6.6 (s), 6.8 (s),istic X-ray powder diffraction pattern with characteristic 8.9(s), 10.0(m), 10.3 (s), 10.8 (m), 13.3 (s), 13.6(m), 14.0(s),peaksexprcssedin20at5.0(s),6.8(s),9.1 (s), 10.0(w), 10.5:o 15.2(vw), 15.9(w), 16.4(w), 16.9(vw), 17.8(vw), 18.3(m),(m), 11.0 (m), 13.3 (vw), 13.7 (s), 14.0 (w), 14.7 (w), 1s.9 18.9 (w), 20.2 (vs), 2o.a @\2o.7 (m),20.9 (m). 21.1 (vs).(vw), 16.9 (w), 17.1 (vw), 18.4 (m), l9.l (w), 20.8 (vs), 2l.1 21.6 (m), 2t.7 Qn), 22.3 (n),23.s (m),23.8 (rn), 24.1 (w),(m),21.6(m),22.9(m),23.7 (m),2a.2$),2s.2(w).27.1(m), 24.7 (vw),25.4 (vw),26.6 (m). 30.2 (w), and 34.0 (vw),29.6 (rw), 30.2 (w), and34.0 (w), wherein (vs) stands lòrvery whe¡ein (vs) stands for very strong intensity, (s) stands forstrong intensity, (s) stands for strong intensity, (m) stands for :s strong intensity, (m) stands for medium intensity. (w) standsmedinm interuity, (w) stands for weali intensity, and (vw) for weatri intensity, and (vw) stands for very weak intensity.stands for very weak intensity. 33. A crystalline polymorph E, of (3R.5s)-7-[2-cyclopro-

25. A crystalline polyrnorph A of (3R,5s)-7[2-cyclopro- pyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-py1-4-(4-fluorophenyl)quinolin-3-yll-3.5-dilrydroxy-6(E)- heptenoic acid hemicalciurn salt, having an X-ray powderheptenoic acid hemicalcium sa1t, having an X-ray powder +o diffraction pattern substantially as depicted in FIG. 5.diffraction pattern substantially as depicted in FIG. l. 34. A crystalline polymorph F of (3R,5s)-7[2-cyclopropyl-

26. A crystalline polymorph B of(3R,5s)-7-[2-cyclopro- 4-(4-fluorophenyl)quinolin-3-yl]-3,5-dilrydroxy-6(E)-hep-pyl-4-(4-lìuorophenyl)quinolin-3-yll-3,5-ttihydroxy-6(E)- tenoic acid hemicalcium salt, which exhibits a characteristicheptenoic acid hemicalcium salt, which exhibits a character- X-ray powder diffraction pattern with characteristic pcaksistic X-ray powder diffraction pattern with characteristic +s expressed in 20 at 5.1 (m), 5.6 (w), 7.0 (s), 8.8 (m), 9.6 (Ð,peaksexpressedin20at4.6(w),5.3(vs),6.2(s),7.7(s),9.2 10.2(w), 10.9(m), 11.3(w). I1.9(m), 12.5(m). 13.0(s), 13.7

Gn),9.6(n),10.3(w),11.3(n),11.7(w),12.6(vw),13.0(w), (m), 14.4 (s), 14.7 (rn),1s.3 (vw), l5.s (w),16.8 (rn),17.613.9(rn), 14.7(vw), la.9(w). 15.6(w), 16.3(m), 17.0(vw), (w), 18.3(m), 19.3(m),19.7(m),20.6(m),21.2(vs),21.8(s),17.4(vw), 18.0(w), 18.7(m), 19.3(m),20.0(s),20.5(w), 22.8(s),23.1 (w),23.8(w,shoulder),24.1 (Ð,24.8(s),25.720.8(m),21.2(w.shoulder),21.5(n),22.4(m).23.2(s),23.8 so Qn),26.2(vw),26.6(n),26.9(w),28.4(w),29.5(w).29.8(m),24.4 (vw),25.2 (q broad). 26.0 (w), 26.4 (vw), 27.0 (w), (vw), and 30.9 (m), wherein (vs) stands for very strong inten-27 .9 (wv), and 28.9 (w), wherein (vs) stands for very strong sity, (s) stands for strong intensity, (rn) stands for rnediumintensity, (s) stands lor slrong intensit¡ (m) stands lor intensity. (w) stands ft.lr weak intensity, and (vw) stands lormedium intensity, (w) stands fbr weak intensil-v, and (vw) \,ery weak intensity.stands for very weak intensity. s5 35.'A crystallinepolymorph F of (3R,5s)-7[2-cyclopropyl-

27. A crystalline polymorph B of(3R,5S)-7-[2-cyclopro- 4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-hep-pyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)- tenoic acid hemicalcium salt. having an X-ray powder dif-heptenoic acid hemicalcium salt, having an X-ray powder fiaction pattem substantially as depicted in FIG. 6.diffraction pattern substantially as depicted in FIG. 2. 36. The amorphous form of (3R,5S)-7[2-cyclopropyl-4-(4-

28. A crystalline polymorph C of (3R,5s)-7[2-cyclopro- oo fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoicpyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)- acid hemicalciurn sall.heptenoic acid hernicalcium salt, which exhibits a characte¡- 37. The amorphous form of(3R,5s)-7[2-cyclopropyl-4-(4-istic X-ray powder diflraction pattem wilh characteristic fìuorophenyl)quinolin-3-yll-3,5-<tihydroxy-6(F))-heptenoicpeaks expressed in20 at 4.I (m), 5.6 (s), 7.8 (m), 8.3 (m), 10.3 acid hemicalcium salt. having an X-ray powder diffraction(m), 11.6(w), 17.5(w), 17.9(w), 18.7(m). 19.5(s).20.6(m),6s pâttemsubstantiallyasdepictedinFIGS.TAandTB.21.5(vw),21.9(m),23.1(m),24.0(w),and24.8(w),wherein 38. A process for preparing the crystalline polymorph or(vs) stands for very strong intelsity, (s) stands for strong amorphons forn according to claim 1., wherein:

us 8,557,993B.215

the crystalline polymorph or amorphous fonn being pre-pared is the crystalline polymorph F; and

the process comprises suspending the crystalline poly-morph A in methanol containing water as a cosolvent.

39. The process according to claim 38, wherein the water ispresent in anamount of I to 5fflo by volume ofthe suspensionof (3R,5S)-7[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yll-3,5-dihydroxy-6(E)-heptenoic acid hemicalcium salt.

*!F,t¡t*

t6