Free Complaint - District Court of Delaware - Delaware

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Andrew T. Berry Jonathan M.H. Short McCARTER & ENGLISH, LLP Four Gateway Center 100 Mulberry Street Newark, NJ 07102 Telephone: (973) 622-4444 Facsimile: (973) 624-7070 Attorneys for Plaintiffs AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, IPR Pharmaceuticals, Inc., and Shionogi Seiyaku Kabushiki Kaisha

Of Counsel: Ford F. Farabow, Jr. Charles E. Lipsey York M. Faulkner FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P. 901 New York Avenue, N.W. Washington, DC 20001 Telephone: (202) 408-4000 Facsimile: (202) 408-4400 Henry J. Renk FITZPATRlCK, CELLA, HARPER & SCINTO 30 Rockefeller Plaza New York, NY 10112 Telephone: (212) 218-2100 Facsimile: (212) 218-2200

UNITED STATES DISTRICT COURT FOR THE DISTRICT OF NEW JERSEY NEWARK DIVISION : : : : : : : : : : : : : : : :

ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., and SHIONOGI SEIYAKU KABUSHIKI KAISHA, Plaintiffs, vs. AUROBINDO PHARMA LIMITED, and AUROBINDO PHARMA USA INC. Defendants.

Civil Action No. __________

COMPLAINT FOR PATENT INFRINGEMENT AND CERTIFICATION PURSUANT TO LOCAL RULE 11.2

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Plaintiffs, AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, IPR Pharmaceuticals, Inc., and Shionogi Seiyaku Kabushiki Kaisha, for their Complaint against Aurobindo Pharma Limited and Aurobindo Pharma USA Inc., hereby state as follows: Nature of the Action 1. This is a civil action for patent infringement arising under the patent laws of the

United States, 35 U.S.C. § 100 et seq., and in particular under 35 U.S.C. §§ 271(e) and (a). This action relates to an Abbreviated New Drug Application ("ANDA") filed by and/or for the benefit of Aurobindo Pharma Limited and Aurobindo Pharma USA Inc. ("the Aurobindo ANDA") with the United States Food and Drug Administration ("FDA") for approval to market generic versions of Plaintiffs' highly successful Crestor® pharmaceutical products that are sold in the United States. Parties 2. Plaintiff AstraZeneca Pharmaceuticals LP ("AstraZeneca") is a corporation

operating and existing under the laws of Delaware with its principal place of business at 1800 Concord Pike, Wilmington, Delaware 19803 USA. 3. Plaintiff AstraZeneca UK Limited is a corporation operating and existing under

the laws of the United Kingdom with its principal place of business at 15 Stanhope Gate, London W1K 1LN, England. 4. Plaintiff IPR Pharmaceuticals, Inc. ("IPR") is a corporation operating and existing

under the laws of Puerto Rico with its principal place of business at Carr 188 Lote 17, San Isidro Industrial Park, Canovanas, Puerto Rico 00729. 5. Plaintiff Shionogi Seiyaku Kabushiki Kaisha is a corporation operating and

existing under the laws of Japan with its principal place of business at 1-8, Doshomachi 3-

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chome, Chuo-ku, Osaka 541-0045 Japan. 6. On information and belief, Defendant Aurobindo Pharma Limited ("Aurobindo

Pharma") is a corporation operating and existing under the laws of India with its principal place of business at Plot # 2, Maitri Vihar, Ameerpet, Hyderabad - 500 038, Andhra Pradesh, India. 7. On information and belief, Defendant Aurobindo Pharma USA Inc. ("Aurobindo

USA") is a wholly owned subsidiary of Aurobindo Pharma, and is a corporation operating and existing under the laws of Delaware with its principal place of business at 2400 Route 130 North, Dayton, New Jersey 08810 USA (Middlesex County). Background 8. IPR is the holder of approved New Drug Application ("NDA") No. 021366 for

Crestor® Tablets, in 5 mg, 10 mg, 20 mg, and 40 mg dosage forms, containing rosuvastatin calcium. AstraZeneca is IPR's authorized agent for matters related to NDA No. 021366. 9. Crestor® (rosuvastatin calcium) is a prescription drug belonging to a group of

medicines (called statins) that are used to treat high cholesterol. Crestor® is one of the most effective lipid-lowering statins available. Over 11 million patients have been prescribed Crestor®, and over 110 million prescriptions have been written worldwide for Crestor®. 10. Plaintiffs, among other things, manufacture, market, promote, educate the public

and physicians about, and conduct research and development on existing and new indications for Crestor® Tablets. Plaintiffs financially benefit from sales of Crestor® Tablets in the United States. 11. On information and belief, Aurobindo Pharma and/or Aurobindo USA filed with

the FDA, in Rockville, Maryland, ANDA No. 79-170 under 21 U.S.C. § 355(j) to obtain FDA approval for the commercial manufacture, use, importation, offer for sale, and sale in the United

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States of rosuvastatin calcium tablets in 5 mg, 10 mg, 20 mg, and 40 mg dosage strengths, which are generic versions of Plaintiffs' Crestor® Tablets in 5 mg, 10 mg, 20 mg, and 40 mg dosage strengths, respectively. 12. By letter dated October 31, 2007, Aurobindo Pharma notified Plaintiffs that it had

filed an ANDA seeking FDA approval to market rosuvastatin calcium tablets in 5 mg, 10 mg, 20 mg, and 40 mg dosage strengths (hereinafter referred to as "the Aurobindo Rosuvastatin Calcium Tablets"), and that it was providing information to Plaintiffs pursuant to 21 U.S.C. § 355(j)(2)(B)(ii) and 21 C.F.R. § 314.95. 13. On information and belief, Aurobindo Pharma is in the business of developing

and manufacturing generic pharmaceutical products. On information and belief, Aurobindo Pharma sells and delivers its pharmaceutical products to Aurobindo USA in New Jersey. On information and belief Aurobindo USA is the agent, affiliate, representative, and/or alter ego of, and/or acts in concert with, Aurobindo Pharma for the purposes of marketing, distributing, and selling generic pharmaceutical products within the United States, including the State of New Jersey. 14. On information and belief, Aurobindo USA, as the authorized agent of Aurobindo

Pharma and/or in its own capacity, participated in the preparation and filing with the FDA of the Aurobindo ANDA for approval to market generic rosuvastatin calcium in the United States. Jurisdiction and Venue 15. 2202. 16. On information and belief, Aurobindo Pharma has developed a complete Subject matter jurisdiction is proper under 28 U.S.C. §§ 1331, 1338(a), 2201, and

infrastructure in terms of marketing, sales, administration, finance and distribution in the United

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States. On information and belief, that infrastructure includes Aurobindo USA. On information and belief, Aurobindo Pharma develops and manufactures generic drugs and, directly or indirectly through Aurobindo USA, markets, distributes, and sells its generic drugs throughout the United States, including the State of New Jersey. 17. Personal jurisdiction over Aurobindo Pharma is proper because it purposefully

avails itself of the privilege of selling its generic products in the state of New Jersey and can therefore reasonably expect to be subject to jurisdiction in Courts in New Jersey. Among other things, upon information and belief, Aurobindo Pharma, directly or through its subsidiary Aurobindo USA, places goods into the stream of commerce for distribution throughout the United States, including the State of New Jersey. In addition, Aurobindo Pharma maintains continuous and systematic contacts with its wholly owned subsidiary, Aurobindo USA, in the State of New Jersey. 18. Personal jurisdiction over Aurobindo USA is proper because Aurobindo USA's

principal place of business is in this judicial district and, thus, Aurobindo USA has purposely availed itself of the privilege of doing business in the State of New Jersey. Further, Aurobindo USA maintains continuous and systematic contacts with the State of New Jersey so as to reasonably allow jurisdiction to be exercised over it. 19. Venue is proper in this judicial district under 28 U.S.C. §§ 1391(c) and 1400(b). Count I Infringement of United States Patent No. RE37,314 Under 35 U.S.C. § 271(e)(2) 20. Plaintiffs incorporate by reference paragraphs 1-19 of this Complaint as if fully

set forth herein. 21. United States Patent No. RE37,314 ("the '314 patent"), entitled "Pyrimidine

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Derivatives," was duly and legally reissued by the United States Patent and Trademark Office on August 7, 2001. Plaintiffs hold all substantial rights in the '314 patent and have the right to sue for infringement thereof. A true and correct copy of the '314 patent is attached as Exhibit A. 22. On information and belief, Aurobindo Pharma and Aurobindo USA filed ANDA

No. 79-170 in order to obtain approval to market the Aurobindo Rosuvastatin Calcium Tablets in the United States before the expiration of the '314 patent. On information and belief, Aurobindo Pharma and Aurobindo USA also filed with the FDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) and 21 C.F.R. § 314.94(a)(12)(i)(A)(4), a certification alleging that the claims of the '314 patent are invalid. 23. On information and belief, Aurobindo Pharma and Aurobindo USA do not assert

that Aurobindo Rosuvastatin Calcium Tablets are not covered by one or more claims of the '314 patent. 24. Under 35 U.S.C. § 271(e)(2)(A), the submission by Aurobindo Pharma and/or

Aurobindo USA to the FDA of ANDA No. 79-170 to obtain approval for the commercial manufacture, use, or sale of the Aurobindo Rosuvastatin Calcium Tablets before the expiration date of the '314 patent constitutes infringement of one or more claims of the '314 patent, either literally or under the doctrine of equivalents. 25. Plaintiffs will be substantially and irreparably harmed by the infringing activities

described above unless those activities are precluded by this Court. Plaintiffs have no adequate remedy at law. Count II Declaratory Judgment of Infringement of United States Patent No. RE37,314 Under 35 U.S.C. § 271(a) 26. Plaintiffs incorporate by reference paragraphs 1-25 of this Complaint as if fully

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set forth herein. 27. Upon information and belief, Aurobindo Pharma and Aurobindo USA have made

substantial preparations to sell Aurobindo Rosuvastatin Calcium Tablets labeled for the same dosages as the Crestor® products. 28. Upon information and belief, Aurobindo Pharma and Aurobindo USA intend to

commence sale of Aurobindo Rosuvastatin Calcium Tablets immediately upon receiving approval from the FDA. 29. The manufacture, importation, sale, and offer for sale of Aurobindo Rosuvastatin

Calcium Tablets, once approved by the FDA, will directly infringe, induce and/or contribute to the infringement of one or more claims of the '314 patent under 35 U.S.C. § 271(a). 30. Plaintiffs will be substantially and irreparably harmed by the infringing activities

described above unless those activities are enjoined by this Court. Plaintiffs have no adequate remedy at law. 31. An actual controversy exists relating to Aurobindo Pharma and Aurobindo USA's

threatened infringement of the '314 patent. PRAYER FOR RELIEF WHEREFORE, Plaintiffs respectfully request that this Court enter judgment in its favor as follows: (1) (2) holding that the claims of the '314 patent are valid and enforceable; holding that the submission of ANDA No. 79-170 by Aurobindo Pharma and/or

Aurobindo USA infringes one or more claims of the '314 patent under 35 U.S.C. § 271(e)(2); (3) declaring that the manufacture, use, offering for sale, or sale of the Aurobindo

Rosuvastatin Calcium Tablets within the United States or importing the Aurobindo Rosuvastatin

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Calcium Tablets into the United States before expiration of the '314 patent will infringe one or more claims of the '314 patent; (4) ordering, pursuant to 35 U.S.C. § 271(e)(4)(A), that the effective date of any FDA

approval of the Aurobindo Rosuvastatin Calcium Tablets shall be no earlier than the expiration date of the '314 patent; (5) enjoining Aurobindo Pharma, Aurobindo USA, and all persons acting in concert

with them, from commercially manufacturing, using, offering for sale, or selling the Aurobindo Rosuvastatin Calcium Tablets within the United States or importing into the United States the Aurobindo Rosuvastatin Calcium Tablets, prior to the expiration of the '314 patent; (6) declaring this to be an exceptional case and awarding Plaintiffs their attorney fees

under 35 U.S.C. § 285; (7) (8) proper. Respectfully Submitted, awarding Plaintiffs their costs and expenses in this action; and awarding Plaintiffs any further and additional relief as this Court deems just and

Dated: December 18, 2007

S/Andrew T. Berry Andrew T. Berry Jonathan M.H. Short McCARTER & ENGLISH, LLP Four Gateway Center 100 Mulberry Street Newark, NJ 07102 Telephone: (973) 622-4444 Facsimile: (973) 624-7070 Of Counsel: Ford F. Farabow, Jr. Charles E. Lipsey

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York M. Faulkner FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P. 901 New York Avenue, N.W. Washington, DC 20001 Telephone: (202) 408-4000 Facsimile: (202) 408-4400 Henry J. Renk FITZPATRlCK, CELLA, HARPER & SCINTO 30 Rockefeller Plaza New York, NY 10112 Telephone: (212) 218-2100 Facsimile: (212) 218-2200 Attorneys for Plaintiffs AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, IPR Pharmaceuticals, Inc., and Shionogi Seiyaku Kabushiki Kaisha

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CERTIFICATION PURSUANT TO L. CIV. R. 11.2 Pursuant to Local Civil Rule 11.2, I hereby certify that the matter in controversy is the subject of other actions: ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. MYLAN PHARMACEUTICALS INC., 1:07-cv-00805 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. SUN PHARMACEUTICAL INDUSTRIES LTD., SUN PHARMACEUTICAL INDUSTRIES INC., CARACO PHARMACEUTICAL LABORATORIES LTD., 1:07-cv-00806 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. SANDOZ INC., 1:07-cv-00807 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. PAR PHARMACEUTICAL, INC., 1:07-cv-00808 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. APOTEX INC. AND APOTEX CORP., 1:07-cv-00809 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. AUROBINDO PHARMA LIMITED, AUROBINDO PHARMA USA INC., 1:07-cv-00810 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. COBALT PHARMACEUTICALS INC. AND COBALT LABORATORIES INC., 1:07-cv-00811 (Dist. Delaware) ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., SHIONOGI SEIYAKU KABUSHIKI KAISHA vs. COBALT PHARMACEUTICALS INC. AND COBALT LABORATORIES INC., 2:07-cv-00815 (Middle Dist. Florida)

Dated: December 18, 2007

S/Andrew T. Berry Andrew T. Berry Jonathan M.H. Short McCARTER & ENGLISH, LLP

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Four Gateway Center 100 Mulberry Street Newark, NJ 07102 Telephone: (973) 622-4444 Facsimile: (973) 624-7070 Of Counsel: Ford F. Farabow, Jr. Charles E. Lipsey York M. Faulkner FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P. 901 New York Avenue, N.W. Washington, DC 20001 Telephone: (202) 408-4000 Facsimile: (202) 408-4400 Henry J. Renk FITZPATRlCK, CELLA, HARPER & SCINTO 30 Rockefeller Plaza New York, NY 10112 Telephone: (212) 218-2100 Facsimile: (212) 218-2200 Attorneys for Plaintiffs AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, IPR Pharmaceuticals, Inc., and Shionogi Seiyaku Kabushiki Kaisha

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EXHIBIT A

1111111111111111111111111111111111111111111111111111111111111111111111
(19) (12)

United States Reissued Patent
Hirai et al.

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USOORE37314E Filed 12/18/2007

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Patent Number: US RE37,314 E Date of Reissued Patent: Aug. 7,2001
4,925,852 5,026,708 5/1990 Kesseler et al. .. 6/1991 Fujikawa et al. 514/256 514/256

(54) (75)

PYRIMIDINE DERIVATIVES Inventors: Kentaro Hirai, Kyoto; Teruyuki Ishiba, Osaka; Haruo Koike, Kyoto; Masamichi Watanabe, Shiga, all of

FOREIGN PATENT DOCUMENTS
0330057 0367895 8/1989 (EP). 5/1990 (EP).

(lP)
(73) Assignee: Shionogi Seiyaku Kabushiki Kaisha, Osaka (lP) Appl. No.: 09/141,731 Filed: Aug. 27, 1998 Related U.S. Patent Documents Reissue of: (64) Patent No.: Issued: Appl. No.: Filed: (30) 5,260,440 Nov. 9, 1993 07/897,793 Jun. 12, 1992

OTHER PUBLICATIONS Moore et al, 1. Am. Chern. Soc., vol. 107, pp. 3694-3701, 1985.* G. Beck et al., J. Med. Chem., 33, 52-60 (1990). B. Roth et al., J. Med. Chem., 34, 463-466 (1991). * cited by examiner Primary Exarniner-Richard L. Raymond (74) Attorney, Agent, or Firrn-Pillsbury Madison & Sutro, LLP Intellectual Property Group (57) ABSTRACT

(21) (22)

Foreign Application Priority Data
(JP) 3-188015

Jul. 1, 1991 (51) (52) (58) (56) Int. CI?

U.S. Cl. Field of Search

A61K 31/505; C07D 239/34; C07D 239/38; C07D 239/42 514/316; 544/318; 544/322 514/756; 544/297

References Cited U.S. PATENT DOCUMENTS
4,868,185 9/1989 Chucholowski et al. 514/256

The compounds of the present invention inhibit the HMGCoA reductase, and subsequently suppress the biosynthesis of cholesterol. And they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. 3 Claims, No Drawings

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PYRIMIDINE DERIVATIVES

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Matter enclosed in heavy brackets [ ] appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue. This application is a reissue of u.s. Pat. No. 5,260,440, issued Nov. 8, 1993.
BACKGROUND OF THE INVENTION

5

10

1. Field of the Invention The present invention relates to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. 2. Prior Art 15 As the first generation of drugs for the treatment of atherosclerosis by inhibiting the activity of HMG-CoA reductase, there are known Mevinolin (U.S. Pat. No. 4,231, 938), pravastatin sodium (U.S. Pat No. 4,346,227), and, simvastatin (U.S. Pat. No. 4,444,784), which are fungal 20 metabolites or of the chemical modifications. Recently, synthetic inhibitors of HMG-CoA reductase such as fluvastatin (F. G. Kathawala et al., 8th Int'l Symp. on Atherosclerosis, Abstract Papers, p. 445, Rome (1988)) and BMY 22089 (GB Pat. No. 2,202,846) are developed as the 25 second generation drugs.

SUMMARY OF THE INVENTION The compounds of the present invention inhibit the HMGCoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. DETAILED DESCRIPTION The present invention relates to compounds of the formula (I):
OH OH
40 30

35

45

isohexyl and the like. Further, the lower alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano. Halogen means fluorine, chlorine, bromine and iodine. The term "aryl" refers to C 6 to C 12 aromatic group including phenyl, tolyl, xylyl, biphenyl, naphthyl, and the like. The aryl may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano. Preferred aryl is phenyl substituted by 1 to 3 halogens. The term "aralkyl" refers to C 1 to C 6 lower alkyl substituted by C 6 to C 12 aromatic aryl group defined above. Examples of them are benzyl, phenethyl, phenylpropyl and the like, each of which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl halogen, amino, cyano, and the like. The term "a cation capable of forming a non-toxic pharmaceutically acceptable salt" refers to alkali metal ion, alkaline earth metal ion, and ammonium ion. Examples of alkali metal are lithium, sodium, potassium, and cesium, and examples of alkaline earth metal are beryllium, magnesium, and calcium. Especially, sodium and calcium are preferred. Examples of "acyl" are formyl acetyl, propionyl, butyryl, isobutyryl, valeryl, and isovaleryl. In the term "imino which may have a substituent", preferred substituents are acyl, optionally substituted amino, and substituted sulfonyl. The term "substituted amino as substituent" means amino group substituted by sulfonyl and alkylsulfonyl. Examples of them are sulfonyl amino and methanesulfonyl amino. The term "substituted sulfonyl as substituent" means sulfonyl group substituted by alkyl, amino, or alkylamino. Examples of them are methanesulfonyl, sulfamoyl, methylsulfamoyl, and N-methylsulfamoyl. The compounds of the present invention can be prepared by the following method. (1) The carboxylate group of the compound a is converted into the alcohol group by the reduction in an appropriate inactive solvent such as THF, ether, and toluene in the presence of the reductant such as LiAlH and DIBAL-H. The reaction is performed at _70° to 50° c., preferably at near room temperature, for 10 minutes to 10 hours, preferably for 30 minutes to 3 hours. Then the obtained alcohol is subjected to oxidation in an appropriate solvent such as methylene chloride in the presence of the oxidizing agent such as TPAP/4-methylmorpholin-N-oxide or pyridium chlorochromate to give aldehyde compound b. The reaction is performed at 0°_60° c., preferably at near room temperature, for 10 minutes to 10 hours, preferably 30 minutes to 3 hours.

50

wherein R 1 is lower alkyl, aryl or aralkyl, each of which may have one or more substituents: R 2 and R 3 each is independently hydrogen, lower alkyl, or aryl, and each of said lower alkyl and aryl may have one or more substituents; R 4 is hydrogen, lower alkyl, or a cation capable of forming a non-toxic pharmaceutically acceptable salt; X is sulfur, oxygen, or sulfonyl, or imino which may have a stubstituent; the dotted line represents the presence or absence of a double bond, or the corresponding ring-closed lactone. This invention also provides a pharmaceutical composition comprising the same. In the specification, the term "lower alkyl" refers to a straight, branched, or cyclic C 1 to C 6 alkyl, including methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, and

60

~JXcno
R1-X N R3

b

65

wherein R\ R 2 , and R 3 each has the same meaning as defined above, and Alkyl means lower alkyl.

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3
(2) The obtained compound b is subjected to reaction with (3R)-or (35)-3-(tert-buty ldimethyIsilyloxy-5 -oxo-6triphenylphosphoranylidene hexanoic acid derivatives in an appropriate solvent such as acetonitrile, diethylether, tetrahydrofuran, and dimethylformamide to give the compound c. The reaction is performed for 1-30 hours, preferably for 10-15 hours under heating.

(I)

5

N

R1-xAN
10

r
R2

~/ r

I

"

'"

r r

C, ~C, ~COOR H <;»: H <;»:

4

R3

wherein C*, the dotted line, R\ R 2 , R 3 , and R 4 each has the same meaning as defined above. Further, if necessary, the obtained compounds (I) are subjected to reflux under heating to give the corresponding 15 lactones. The compound of the present invention can be administered orally or parenterally. For example, the compound of wherein C* means asymmetric carbon atom, the dotted line the present invention may be orally administered in the form means the presence or absence of the double bond, R\ R 2 , of tablets, powders, capsules and granules, aqueous or oily 3 4each R , and R has the same meaning as defined above. 20 suspension, or liquid form such as syrup or elixir, and (3) The compound c is subjected to elimination of the parenterally in the form of aqueous or oily suspension. tertbutyldimethylsilyl group in an appropriate organic solThese preparations can be prepared in a conventional vent in the presence of hydrogen halogenide to give the manner by using excipients, binders, lubricants, aqueous or compound d. oily solubilizers, emulsifier, suspending agents, and the like. Every sort of halogen can be used for hydrogen halo- 25 And preservatives and stabilizers can be further used. genide. Amongst all, hydrogen fluoride is preferred. The dosages may vary with the administration route, age, The same organic solvents as used in the step (2) may be weight, condition, and the kind of disease of the patients, but employed. Acetonitrile is especially preferred. are usually 0.5-200 rug/day, preferably 1-100 mg/day The reaction is performed in a range of from 0° to 60° c., through oral route, and 0.1-100 mg/day, preferably 0.5-50 preferably at room temperature, for 0.5-10 hours, preferably 30 mg/day through parenteral route. They may be used in a for 1-2 hours. single or divided doses. The present invention is illustrated by the following d examples and reference examples, which are not to be OH considered as limiting. I The abbreviations used in examples and reference 35 C* COOR 4 examples have the following meanings. H~ Me: methyl, Et: ethyl, i-Pr: isopropyl 40 t-Bu: tert-butyl, wherein C*, the dotted line, R 1 , R 2 , R 3 , and R 4 each has the Ph: phenyl, same meaning as defined above. DMF: dimethylformamide, (4) The compound d is reacted with diethylmethoxyboTHF: tetrahydrofuran rane and NaBH 4 in an alcohol-organic solvent mixture and DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone subjected to column chromatography of silica gel to give the 45 TPAP: tetrapropylammonium perruthenate compound (I) (in case R 4 is lower alkyl). The reaction is HMPA: hexamethylphosphoramide performed at a temperature between -100° to 20° c., DIBAL-H: diisobutylaluminum hydride. preferably between _85° to -70° C. under cooling, for 10 minutes to 5 hours, preferably for 30 minutes to 2 hours. REFERENCE EXAMPLE 1 50 Here, the alcohol includes methanol, ethanol, propanol, and butanol; and the organic solvent includes the same as in Ethyl 4-(4-fluorophenyl)-6-isopropyl-2the step (3). methy lthiopyrimidine-5-carboxylate (III-1) and Further, if necessary, the obtained compound may be Ethyl 4-(4-fluorophenyl)-6-isopropyl-2subjected to saponification with the solution of metalic 55 methylsulfonylpyrimidine-5-carboxylate (III-2) 4 hydroxide (R : cation), and after the saponification, the reaction mixture is neutralized with an acid and extracted F~ with an organic solvent (R 4 : hydrogen). The saponification is performed in a popular solvent such as water, acetonitrile, dioxane, acetone, and the mixture thereof, preferably in the 60 presence of a base, by a conventional method. The reaction F is performed at 0° to 50° c., preferably at near room COOEt temperature. iPf As metalic hydroxide which may be used are sodium hydroxide, potassium hydroxide, and their analogue. 65 Acids which may be used include inorganic acids such as o hydrochloric acid, sulfuric acid and the like.

~CHO

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F(P)-"'yY~'

COOEt

HNyN
SMe
2

5

F(P)-,"yY~'

COOEt

10

equivalent) of potassium carbonic anhydride and 166 mg (1.1 equivalent) of iodine, and the mixture is stirred at room temperature for 2.5 hours. After reaction, to the mixture is added saturated sodium hydrogensulfite and extracted with ether. The organic layer is washed with water and dried. The solvent is distilled away under reduced pressure to give 166 mg (Yield: 83.6%) of the compound (III-I) as resinous substance. NMR (CDCI 3) 0: 1.10 (t, 3H, 1=7); 1.31 (d, 6H, 1=7); 2.61 (s, 3H) 3.17 (heptet, lH, 1=7); 4.18 (q, 2H, 1=7); 7.07-7.17 (m, 2H); 7.61-7.69 (m, 2H) REFERENCE EXAMPLE 3

NyN
SMe

(III-1)

Another synthetic method of the compound (I1I-2) 15 To a solution of 1.0 g (2.97 mmol) of the compound 2 in 10 ml of acetone is added 1.5 g (9.48 mmol) of potassium permanganate, and the mixture is stirred at room temperature for 15 minutes. Acetic acid 1.0 ml is added thereto, and 20 the mixture is stirred at room temperature for further 30 minutes and water is added thereto. The reaction mixture is extracted with ether, washed with saturated sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled away under 25 reduced pressure to give 1.07 g (2.94 mmol) (Yield: 99.1%) of the compound (I1I-2) as crystals.
(III-2)

REFERENCE EXAMPLE 4
30

p-Fluorobenzaldehyde 81.81 g is reacted in the same manner as disclosed in the specification of 1P Unexamed. Pat. Publn. No. 61-40272 to give 151.0 g (Yield: 86.7%) of the compound 1. Then the mixture of a solution of 44.68 g of the compound 1 in 65 ml of HMPA and 28.24 g of s-methylisourea hydrogen sulfate is stirred at 100° C. for 22 hours. Then the reaction mixture is extracted with ether, and washed with saturated sodium hydrogencarbonate and water in order. The organic layer is dried, and the solvent is distilled away. The obtained residue is subjected to column chromatography of silica gel to give 26.61 g (yield: 46.8%) of the compound 2. To a solution of the obtained compound 2 in 400 ml of benzene is added 21.64 g (0.095 mmol) or DDQ, and the mixture is stirred for 30 minutes. Then the mixture is subjected to column chromatography of silica gel to give 24.31 g (Yield: 91.9%) of the compound (III-I). NMR (CDCI 3) 0: 1.10 (t, 1=7,3H): 1.31 (d, 1=7,6 Hz); 2.61 (s, 3H); 3.18 (hept, 1=7,lH); 4.18 (q, 1=7,2H); 7.12 (m, 2H), 7.65 (m, 2H). To a solution of 13.28 g (0.04 mmol) of the compound (III-I) in chloroform is added 17.98 g of m-chloroperbenzoic acid, and the reaction mixture is stirred at room temperature. Then it is washed with sodium sulfate and saturated sodium hydrogencarbonate in order. The solution is dried, and the solvent is distilled away and washed with n-hexane to give 13.93 g (Yield 95.7%) of the compound (I1I-2). NMR (CDCI3) 0: 1.16 (t, 1=7,3H); 1.37 (d, 1=7,6H); 3.26 (hept, 1=7,lH); 3.42 (s, 3H), 4.28 (q, 2H); 7.18 (m, 2H); 7.76 (m,2H). REFERENCE EXAMPLE 2 Another synthetic method of the compound (III-I) To a solution of 200 mg (0.594 mmol) of the compound 2 in 5 ml of dichloromethane are added 0.5 g (6.10

Ethyl 4-(4-fiuorophenyl)-6-isopropyl-2-(N-methylN-methyl-sulfonylamino)pyrimidine-5-carboxylate (I1I-3) and Ethyl 4-(4-fiuorophenyl)-6-isopropyl-2(N-methyl-N-dimethylsulfamoylamino)pyrimidine5-carboxylate (I1I-4)

35
(III-2) -

F(P)-Ph~iPr
NyN NHMe3

COOEt

40

\
45

(III-3)

50

55

60

65

To a solution of 52.7 g (144 mmol) of the compound (I1I-2) in 500 ml of absolute ethanol is added gradually a solution of 71.9 ml of 5N methylamine in ethanol under ice-cooling. The reaction mixture is warmed to room temperature, stirred for 1 hour and evaporated under reduced pressure. To the residue is added water, and the mixture is extracted with ether, dried and evaporated under reduced pressure to give 46.9 g (Yield: 100%) of the compound 3. mp. 85°-86° C. Anal Calcd. (%) for C17H2oN3F02: C,64.34; H,6.35; N,13.24: F,5.99. Found: C,64.42, H,6.46: N,13.30; F,6.14. To a solution of 370 mg (1.213 mmol) of the compound 3 in 5 ml of DMF is added 60 mg of 60% NaH under ice-cooling, and the reaction mixture is stirred for 30 min-

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utes. Methanesulfonyl chloride 208 mg is added thereto, and To a solution of 2.50 g (6.77 mmol) of the compound the mixture is warmed to room temperature and stirred for (I1I-2) in 50 ml of absolute ethanol is added 0.80 g (16.93 2 hours further. To the mixture is added ice-water, and the mmol) of methyl hydrazine under ice-cooling. The reaction mixture is extracted with ether. The organic layer is washed mixture is warmed to room temperature and stirred for 2 with water and dried. The solvent is evaporated under 5 hours and extracted with ether. The organic layer is washed reduced pressure, and the resulting residue is washed with with saturated brine and dried to distill the solvent. To a ether-n-pentane to give 322 mg (Yield: 57.6%) of the mixture of 2.37 g of the thus obtained compound and a compound (I1I-3). mixture of anhydrous THF and anhydrous pyridine is added 1.03 g (7.84 mmol) of methanesulfonyl chloride under NMR (CDCI3 ) 0: 1.10 (t, J=7,3H); 1.32 (d, J=7,6H); 3.24 (hept,J=7,lH); 3.52 (s,3H); 3.60 (s, 3H); 4.19 (q, J=7,2H); 10 testing. The reaction mixture is warmed to room temperature and stirred for 1.5 hours. To the mixture are added 3 ml of 7.14 (m, 2H); 7.68 (m, 2H). anhydrous pyridine and 1.53 g (11.65 mmol) of methaneTo a solution of 4.13 g (13.0 mmol) of the compound 3 in sulfonyl chloride, and the mixture is stirred for 2 hours. To 40 ml of DMF is added 0.57 g of 60% NaH under icethe reaction mixture is added ice-water and extracted with cooling, and the mixture is warmed to room temperature and 15 ether. The organic layer is washed with water and the stirred for 1 hours. After cooling again, dimethylsulfamoyl resulting oily residue is subjected to column chromatograchloride 2.43 g (16.9 mmol) is dropwise added thereto, and phy of silica gel to give 2.75 g (Yield: 94.0%) of the the mixture is stirred for 2.5 hours. To the mixture is added compound (I1I6). icewater, and the mixture is extracted with ether washed NMR (CDCI3 ) 0: 1.08 (t, J=7,3H); 1.29 (d, J=7,6H); 2.96 with water, dried and evaporated under reduced pressure to distill ether. The resulting residue is washed with ether- 20 (s, 3H); 3.24 (hept, J=7,lH); 3.59 (s, 3H); 4.16 (q, J=7,2H); 7.14 (m, 2H), 7.63 (m, 2H). hexane to give 4.10 g (Yield: 74.2%) of the compound (I1I-4). mp. 114°-116° C. REFERENCE EXAMPLE 6 Anal Calcd. (%) for C19H2SN4SF04: C,53.76; H,5.94; N,13.20; F,4.48. Found: C,53.74: H,5.96; N,13.19; F,4.78. 25 Methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6triphenylphosphoranylidene hexanate REFERENCE EXAMPLE 5 (1) (3R)-3-(tert-butyldimethylsilyloxy)glutaric acid-1((R)-(- )mandelic acid ester*l 65 g (164 mmol) is dissolved Ethyl 4-(4-fiuorophenyl)-6-isopropyl-2into 60 ml of methanol, a solution of sodium methoxide in methoxypyrimidine-5-carboxylate (111-5) and Ethyl 30 methanol (28% methanol 310 ml, 1.6 mol) is added drop4-(4- fiuorophenyl)-6- isopropyl-2-(N-methyl-Nwise thereto under nitrogen atmosphere at 0° C. for 45 methylsulfonylhydrazino)pyrimidine-5-carboxylate minutes at internal temperature under 7° C. The reaction (I1I-6) mixture is stirred at 0° C. for 30 minutes and poured into a mixture of 150 ml of conc.HCI, 300 ml of water, and 500 ml 35 of methylene chloride being stirred under ice-cooling and the organic layer is collected. The aqueous layer is extracted with 200 ml of methylene chloride, and each organic layer is washed with dil.IICl and brine in order. Each organic layer (III-2) are collected and dried over anhydrous magnesium sulfate 40 and evaporated to distill the solvent to give half ester compound.

-:

\

(III-5)

This compound can be prepared by the method described at page 10 in the specification of KOKAI 2-250852. 45

*"

lHNMR(CDCI3 ) 0: 0.08 (s, 3H); 0.09 (s, 3H); 0.86 (s, 9H); 2.52-2.73 (m, 4H); 3.08 (s, 3H); 4.55 (quint, lH, J=6Hz). IR (CHCI3 ) : 2880, 1734, 1712, 1438, 1305, 1096,836 cm- 1 . [u]D=-5.0±0.4° (C=1.04, 23S c., CHCI 3 ) . 50 Rf 0.32 (CHCI3/MeOH=9/1). (2) To a solution of the thus obtained half ester compound (III-6) in 10 ml of ether are added dropwise triethylamine and ethyl chlorocarboxylate in order under nitrogen atmosphere at _78° C. The resulting white suspension is stirred at 0° C. for To a solution of 1.39 g (3.8 mmol) of the compound 55 1 hour and cooled to _78° C. The resulting precipitate is (I1I-2) in 60 ml of absolute methanol is added a solution of filtered under nitrogen atmosphere and the filtrate is washed 0.41 g (7.6 mmol) of sodium methoxide under ice-cooling. with 15 ml of ether. To a suspension of 1.29 g ( 3.6 mmol) The reaction mixture is warmed to room temperature graduof methyl bromide triphenylphosphonium in 5 ml of THF is ally and stirred for 1 hour. The mixture is neutralized with added dropwise butyllithium (1.6M hexane, 2.25 ml, 3.6 acetic acid and extracted with ether. The organic layer is 60 mmol) under nitrogen atmosphere at _78° C. The reaction washed with sodium bicarbonate and water in order, dried mixture is stirred at 0° C. for 1 hour and cooled to _78° C. and evaporated under reduced pressure to distill ether. The and added dropwise to the solution of thus obtained active residue is subjected to column chromatography of silica gel ester compound in ether. The reaction mixture is washed to give 1.17 g (Yield: 96.7%) of the compound (111-5). with 5 ml of THF and stirred at 0° C. for 1 hour, and 10 ml NMR (CDCI3 ) 0: 1.10 (t, 3H, J=7 Hz); 1.32 (d, 6H, J=6.6 65 of 5% sodium hydrogencarbonate is added thereto. The reaction mixture is stirred for 5 minutes and extracted with Hz); 3.21 (m, lH); 4.08 (s, 3H); 4.18 (q, 2H, J=7 Hz); ethyl acetate and the organic layer is separated and the 7.07-7.74 (m, 4H).

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remammg aqueous layer is extracted with ethyl acetate. Each organic layer is collected and washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue is subjected to column chromatography of silica gel eluting with ether-ethyl acetate and crystallized from ether-hexane to give objective compound. 1HNMR (CDC13)o: 0.04 (s, 3H); 0.06 (s, 3H); 0.83 (s, 9H); 2.4-2.9 (m, 4H); 3.64 (s, 3H); 3.74 (d, lH); 4.5-4.7 (m, lH); 7.4-7.8 (m, ISH). IR (CHC13): 2380, 1730, 1528, 1437, 1250, 1106,835 em
-1

5

10

triphenylphosphoranylidene hexanate (Reference Example 6), and 5 ml of acetonitrile is refiuxed under heating for 14 hours and evaporated under reduced pressure to distill acetonitrile. The resulting residue is subjected to column chromatography of silica gel eluting with methylene chloride to give 233 mg (Yield: 71.3%) of methyl 7-[4-(4fiuorophenyl)-6-isopropyl-2-(N -methyl-Nmethylsulfonylamino )pyrimidin -5 -y1]-(3R)-3-( tertbutyldimethylsilyloxy)-5-oxo-(E)-6-heptenate 6 as syrup.

[a]D=-6.2° (C=1.27, 22.0° c., CHC13). mp.:77.5°-78.5° c., Rf=0.48 (CHC13/MeOH=9/1). Anal Calcd. (%) for C31H3904PS: C, 69.63; H,7.35; P,5.79. Found: C, 69.35; H,7.35; P,6.09. 15 EXAMPLE 1 Sodium (+)-7-[4-(4-fiuorophenyl)-6-isopropyl-2-(Nmethyl-N-methylsulfonylaminopyrimidin)-5-yl](3R,5S)-dihydroxy-(E)-6-heptenate (I a-I) (1) To a solution of 322 mg of the compound (III-3) obtained in Reference Example 2 in 7 ml of anhydrous toluene is added dropwise 1.4 ml of DIBAL-H in l.5M toluene at -74°C., and the reaction mixture is stirred for 1 hour and acetic acid is added thereto. The mixture is extracted with ether, and the organic layer is washed with sodium bicarbonate and water, dried and evaporated under reduced pressure to distil ether. The obtained residue is subjected to column chromatography of silica gel eluting with methylene chloride/ether (20/1) to give 277 mg (Yield: 96.1%) of [4-(4-fiuorophenyl)-6-isopropyl-2-(N-methyl-Nmethylsulfonylamino)pyrimidin-5-yl]methanol 4.
4

Ph-P(p)

o
COOMe

20

25

30

35

(4) To a solution of 16 g of the compound 6 in 100 ml of acetonitrile is added dropwise a solution of 48% hydrogen fiouride in 400 ml of acetonitrile (1:19) under ice-cooling, and the mixture is warmed to room temperature and stirred for 1.5 hours. The reaction mixture is neutralized with sodium bicarbonate and extracted with ether. The organic layer is washed with sodium chloride, dried and evaporated under reduced pressure to distil ether to give 13 g (Yield: 100%) of methyl 7-[4-( 4-fiuorophenyl)-6-isopropyl-2-(Nmethy1-N-methylsulfonylamino)pyrimidin-5-y1]-(3R)-3hydroxy-5-oxo-(E)-6-heptenate 7 as syrup.
7

Ph-P(p)
40

o

OH
COOMe

(2) A suspension of 277 mg of the thus obtained compound 4, 190 mg of 4-methylmorpholin-N-oxide, 6 mg of TPAP, 1.0 g of powder molecular sieve 4A, and 10 ml of methylene chloride is stirred for 2 hours. The insoluble matter is filtered off and the two-thirds of the filtrate is distilled away under reduced pressure. The resulting residue is subjected to column chromatography of silica gel eluting with methylene chloride to give 196 mg (Yield: 71.2%) of 4 - ( 4 - fiuo rop he n y 1)- 6 -isop rop y 1-2 -(N - me th y 1-N methylsulfonylamino)-5-pyrimidinecarbardehyde as crystals.
5

45

50

55

60

65

(3) A solution of 190 mg of the compound 5, 450 mg of methyl (3R)-3-( tert-butyldimethylsily10xy)-5 -oxo-6-

(5) To a solution of 13 g of the compound 7 in 350 ml of anhydrous THF and 90 ml of methanol is added a solution of 29.7 ml of 1M diethylmethoxyborane-THF at _78° c., and the mixture is stirred at the same temperature for 30 minutes. To the mixture is added 1.3 g of NaBH 4, and the mixture is stirred for 3 hours. Acetic acid 16 ml is added thereto, and the mixture is adjusted to pH 8 with saturated sodium bicarbonate and extracted with ether. The organic layer is washed with water, dried and evaporated ether under reduced pressure. To the resulting residue is added methanol and the mixture is evaporated under reduced pressure for three times. The resulting residue is subjected to column chromatography of silica gel eluting with methylene chloride/ether (3/1) to give 11.4 g (Yield: 85.2%) of methyl 7 -[ 4 -( 4- fiuorophe n y1)- 6 -iso -propy 1-2 -m e th y1-N meth ylsulfonylamino )pyrimidin-5-y1]-(3R,5S )-dih ydroxy(E)-6-heptenate as syrup.

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(Ib-1)

3.58 (brs, lH); 3.74 (s, 3H): 4.21 (m, lH); 4.48 (m, lH); 5.50 (dd, 1=5,16, lH); 6.66 (dd, 1=2,16); 7.11 (m, 2H); 7.61 (m, 2H).
5

COOMe

(3) The thus obtained compound (I b-2) is reacted in the same manner as Example 1 (6) to give the objective compound (I a-2).
(Ia-2) Ph-P(p)

10

OH

OH COONa

NMR (CDC13 ) 0: 1.27 (d, 1=7,6H); 1.53 (m, 2H); 2.47 (d, 1=6,2H); 3.36 (hept, 1=2H); 3.52 (s, 3H); 3.57 (s, 3H); 3.73 (s, 3H); 4.20 (m, lH); 4.43 (m, lH); 5.45 (dd, 1=5,16, lH); 6.64 (dd, 1=2,16, lH); 7.09 (m, 2H); 7.64 (m, 2H). (6) To a solution of 11.4 g of the compound (I b-1) in 160 ml of ethanol is added 223 ml of O.lN sodium hydroxide under ice-cooling. The reaction mixture is warmed to room temperature and stirred for 1 hour. The solvent is distilled away under reduced pressure, and ether is added to the resulting residue and the mixture is stirred to give 11.0 g (Yield: 95.0%) of the objective compound (I a-I) as powdery crystals.
(Ia-1) Ph-P(P) OH OH COONa

15

20

NMR (CDC13)0: 1.27 (d, 1=7,6H); 1.57 (m, 2H): 2.17 (s, 3H); 2.27 (d, 1=6,2H); 3.72 (s, 3H); 3.50 (hept, 1=7, lH); 3.70 (m, lH); 4.35 (q, 1=6,lH); 5.59 (dd, 1=5,16, lH); 6.54 (d, 1=16, lH); 7.24 (m, 2H): 7.59 (m, 2H). EXAMPLE 3-6

25

As a starting material, each pyrimidine carboxylate (III) obtained in Reference Example 1-3 is reacted in the same manner as Example 1 or 2 to give the compound (I b) and (I a). Their physical constants are shown in Table 1-3.

30

{(mOB
Ph-P(p) Me-X N iPr

[ub=+18.9±0.6° (C=1.012, 25.0° c., H 2 0 ). NMR (CDC13 ) 0: 1.24 (d, 1=7,6H); 1.48 (m, lH); 1.65 (m, lH); 2.27 (dd,1=2,6.2H); 3.41 (hept, 1=7,lH); 3.48 (s, 3H); 3.59 (s, 3H); 3.73 (m, lH); 4.32 (m lH); 5.49 (dd, 1=7,16 lH); 6.62 (d, 1=16,lH); 7.19 (m, 2H); 7.56 (m, 2H). EXAMPLE 2 Sodium (+)-7-[4-(4-fiuorophenyl)-6-isopropyl-2-(Nacetyl- N-methylamino)pyrimidin-5-yl]-(3R,5S)dihydroxy-(E)-6-heptenate (I a-2)

35

(III)
Ph-P(p) 40 OH OH COOMe -

45

(Ib)

(1) Ethyl 4-( 4-fiuorophenyl-6-isopropyl-2methylaminopyrimidine-5-carboxylate 3 838 mg obtained in Reference Example 4 is allowed to react in the same manner as in Example 1 (1) and (2) to give 157 mg of 4-(4- 50 fiuorophenyl)-6-isopropyl-2-methylaminopyrimidine-5carbaldehyde. (2) A solution of 157 mg of thus obtained aldehyde compound in 4 ml of anhydrous DMF is reacted with 25 mg of 60% NaH under ice-cooling for 30 minutes, 0.05 ml of 55 acetylchloride is added thereto and the mixture is stirred for 1 hour. The mixture is added with ice and extracted with ether. The organic layer is washed with water and dried and concentrated to distill the solvent to give 167 mg (Yield: 93.4%) of 4-(4-fiuorophenyl)-6-isopropyl-2-(N-acetyl-N- 60 methylamino)pyrimidine-5-carbardehyde. Thus obtained aldehyde compound is reacted in the same manner as in Example 1 (3)-(5) to give methyl 7-[4-(4-fiuorophenyl)-6isopropy1-2-(N-acety1-N-me thylaminopyrimidin)-5 -y1](3R,5S)-dihydroxy-(E)-6-heptenate (I b-2). 65 NMR (CDC13)0: 1.27 (d, 1=7,6H); 1.54 (m, 2H); 2.48 (d, 1=6,2H); 2.52 (s, 3H); 3.39 (hept, 1=7, lH); 3.60 (s, 3H);

COONa

(Ia)

TABLE 1
Ex. No.

Startup material

Product NMRo 1b-3(X: S)Yield 96.0% (CDel 3 , 1.26(d, J ~ 7.6H): 1.52(m, 2H): 2.47(d, J ~ 6, 2H): 2.60(8, 3H): 3.33(hept, J ~ 7, lH): 3.73 (8, 3H): 4.18(m, lH): 4.44(m, lH): 5.44(dd, J ~ 5, 16, LH): 6.60(dd, J ~ 2, 16, LH), 7.07(m, 2H): 7.58(m, 2H) 1a-3(X: S)Yield 87.3% (0 20) 1.20(d, J ~ 7, 6H): 1.47(m, 1H): 1.61(m, lH): 2.26(m, 2H), 2.54(8, 3H): 3.36(hept, J ~ 7, 1H):

3

(Ill-1)

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TABLE 1-continued
3.71(m, lH): 4.29(m, lH): 5.43(dd, J ~ 6, 16, LH): 6.55(d, J ~ 16, LH): 7.16(m, 2H), 7.47 (m,2H) lb-4(X: S02): Yield 93.7% (CDCI 3 ) 1.31(d, J ~ 7, 6H): 1.52(m, 2H): 2.48(d, J ~ 6, 2H): 3.40(s, 3H); 3.47(hept, J ~ 7, lH); 3.74 (s, 3H): 3.87(brs, lH): 4.23(m, lH): 4.49 (m, .l H); 5.59(dd, J ~ 5, 16H, .l H); 6.74(d, d, J ~ 2, 16, lH); 7.12(m, 2H): 7.69(m, 2H) la-4(X: S02): Yield 70.9% (0 20 ) 1.27(d, d, J ~ 7, 2, 6H); 1.60(m, 2H); 2.25(J ~ 6, d, 2H): 3.44(s, 3H): 3.51(hept, J ~ 7, LH): 3.70(m, .l H): 4.33(q, J ~ 6, LH): 5.65(d, d, J ~ 5, 16, lH): 6.71(d, J ~ 16, lH): 7.23(m, 2H); 7.60 7.60(m,2H)

water and dried to give 1.32 g of calcium salt as powdery. This compound started to melt at a temperature of 155° c., but the definitive melting point is ambiguous.
5

[a]D=+6.3° ±0.2° (C=2.011, 25.0°

c., MeOH).

4

(Ill-2)

Anal Calcd. (%) for C22H27N306SF . O.5Ca . 0.5H 20: C,51.85; H,5.53; N,8.25; F,3.73; Ca,3.93. Found: C,51.65; H,5.51; N,8.47; F,3.74; Ca,4.07.
10

Biological Activity Experiment The HMG-CoA reductase inhibitory effect

15

(1) Preparation of rat liver microsome TABLE 2
Ex. No.

Starting material

Product NMRo lb-5(X: 0): (CDCI 3 ) 1.27(d, 6H, J ~ 6.6 Hz): 1.35-1.68(m, 2H): 2.47 (m, 2H): 3.34(m, lH): 3.78(s, 3H): 4.03(s, 3H): 4.19(m, lH); 4.43(m, lH): 5.43(dd, lH, J ~ 5.6, 16 Hz): 6.59(dd, lH, J ~ 1.4, 16 Hz): 7.037.64(m,4H) la-5(X: 0) Yield 57.7% (CDel 3 , CD 30D) 1.27(d, 6H, J ~ 6.6 Hz): 1.35-1.68(m, 2H): 2.172.43(m, 2H): 3.36(m, 2H), 4.05(s, 3H): 4.37 (m, 2H): 5.48(dd, lH, J ~ 5.6, 16 Hz): 6.54(dd, lH, J ~ 1.4, 16 Hz): 7.06-7.65(m, 4H) lb-6(X: N-S0 2NMe2): (CDCI 3 ) 1.26(d, 6H, J ~ 6.6 Hz); 1.38-1.62(m, 2H): 2.47 (d, 2H, J ~ 5.8); 2.84(s, 6H), 3.35(m, lH): 3.64(s, 3H); 3.74(s, 3H); 4.20(m, lH): 4.44 (m, lH); 5.42(dd, lH, J ~ 5.4, 16 Hz): 6.60 (dd, lH, J ~ 1.2, 16 Hz): 7.03-7.64(m, 4H) la-6: Yield: 91.2% (CDel 3 , CD 30D) 1.26(d, 6H, J ~ 6.6 Hz); 1.36-1.69(m, 2H): 2.152.50(m, 2H); 2.85 (s, 6H); 3.41(m, 2H): 3.64 (s, 3H): 4.04(m, lH): 4.37(m, lH); 5.48 (dd, lH, J-5.6, 16 Hz): 6.54(dd, lH, J-l, 16 Hz): 7.05-7.66(m, 4H)

20

5

(Ill-5)

25

Sprague-Dawley rats, which were in free access to ordinary dietes containing 2% cholestyramine and water for 2 weeks, were used for the preparation of rat liver microsome. The thus obtained microsome was the purified according to the manner by Juroda et al., Biochem. Biophys. Act, 486, 70 (1977). The microsomal fraction obtained by centrifugation at 105,000xg was washed once with a buffered solution containing 15 mM nicotinamide and 2 mM magnesium chloride (in a 100 mM potassium phosphate buffer, pH 7.4). It was homogenized with a buffer containing nicotinamide and magnesium chloride at the same weight as the liver employed. The thus obtained homogenate was cooled down and kept at _80° C. (2) Measurement of the HMG-CoA reductase inhibitory activities

30

(Ill-4)

TABLE 3
Ex. No.

Starting material

Product NMRo lb-7(X: N-NHS0 2Me): Yield: 87.8% (CDCI 3 ) 1.24(d, J ~ 7, 6H): l.5l(m, 2H): 2.47(d, J ~ 6, 2H); 2.95(s, 3H); 3.35(hept, J ~ 7, lH); 3.46 (d, J ~ 2, lH): 3.55(s, 3H); 3.66(d, J ~ 2, lH): 3.74 (s, 3H): 4.18(m, lH): 4.44(m, lH): 5.41 (dd, J ~ 5, 16, LH); 6.58(dd, J ~ 2, 16, LH); 7.09(m, 2H); 7.58(m, 2H), 7.70(s, lH) la-7(X: N-NHS0 2Me): Yield: 74.7% (0 2° ) 1.23(d, J ~ 7, 6H): l.5l(m, 2H): 2.26(d, J ~ 6, 2H) 3.10(s, 3H); 3.37(hept, J ~ 7, LH): 3.44 (s, 3H): 3.70(m, lH). 4.29(q, J ~ 6, lH): 5.39 (dd, J ~ 5, 16, .l H): 6.58(d, J ~ 16, LH): 7.19(m, 2H):7.52(m, 2H)

7

(Ill-6)

EXAMPLE 7 Calcium salt of the compound (I a-1) (sodium salt) 1.50 g (3.00 mmol) is dissolved in 15 ml of water and stirred at room temperature under nitrogen atmosphere, successively 3.00 ml (3.00 mmol) of 1 mol/L calcium chloride 3.00 ml (3.00 mmol) is added dropwise thereto over 3 minutes. The reaction mixture is stirred at the same temperature for 2 hours, and the resulting precipitate is collected, washed with

The rat liver microsome sample (100 ,ul), which was preserved at _80° c., was fused at 0° C. and diluted with 0.7 35 ml of a cold potassium phosphate buffer (100 mM, pH7.4). This was mixed with 0.8 ml of 50 mM EDTA(buffered with the aforementioned potassium phosphate buffer) and 0.4 ml of 100 mM dithiothreitol solution (buffered with the aforementioned potassium phosphate buffer), and the mixture 40 was kept at 0° C. The microsome solution (1.675 ml) was mixed with 670 ,ul of 25 mM NADPH (buffered with the aformentioned potassium phosphate buffer), and the solution was added to the solution of 0.5 mM [3- 1 4](HMG-CoA (3mCi/mmol). A solution (5 ,ul) of sodium salt of the test 45 compound dissolved in potassium phosphate buffer is added to 45,u1 of the mixture. The resulting mixture was incubated at 37° C. for 30 minutes and cooled. After termination of the reaction by addition of 10 ,ul of 2N·HCI, the mixture was incubated again at 37° C. for 15 minutes and then 30,u1 of 50 this mixture was applied to thin-layer chromatography of silica gel of 0.5 mm in thickness (MerckAG,Art 5744). The chromatograms were developed in toluene/acetone (1/1) and the spot, whose Rf value was between 0.45 to 0.60, were scraped. The obtained products were put into a vial contain55 ing 10 ml of scintillator to measure specific radio-activity with scintillation counter. The activities of the present compounds are shown in Table 4 as comparative ones based on the assumption that the activity of Mevinolin (sodium salt) as reference drug is 100.
60

TABLE 4
Test Compound HMG-CoA reductase inhibitory activities 442 385 279

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la-l la-3 la-5

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consisting of halogen, amino, and cyano, or (3) C 6 to Cn aromatic group which may have 1 to 3 substituents TABLE 4-continued independently selected from the group consisting of Test Compound HMG-CoA reductase inhibitory activities lower alkyl, halogen, amino, and cyano; R 4 is (1) 5 la-7 260 hydro-gen, (2) lower alkyl, or a cation capable of Mevinolin Na 100 forming a non-toxic pharmaceutically acceptable salt; X is sulfur, oxygen, or sulfonyl, or imino which may be substituted by formyl, acetyl, propionyl, butyryl, From the test data, the compounds of the present invention exhibit HMG-CoA reductase inhibition activities supeisobutyryl, vale-ryl, isovaleryl, amino substituted by rior to Mevinolin. 10 sulfonyl or alkyl-sulfonyl, and sulfonyl substituted by What is claimed is: alkyl, amino or alkylamino, the dotted line represents [1. A compound represented by the formula (I): the presence or absence of a double bond, or the corresponding ring -closed lactone.] OH OH [2. The compound claimed in claim 1, wherein X is imino 15 which may be substituted by formyl, acetyl, pro-pionyl, butyryl, isobutyryl, valeryl, isovaleryl, amino substituted by sulfonyl or alkylsulfonyl, or sulfonyl substituted by alkyl, amino or alkylamino.] [3. The compound claimed in claim 2, wherein X is imino 20 which may be substituted by formyl, acetyl, pro-pionyl, butyryl, isobutyryl, valeryl, isovaleryl, alkylsul-fonylamino, or alkylsulfonyl.] [4. The compound claimed in claim 1 having the (3R, 25 5S)-dihydroxy configuration.] wherein [5. A pharmaceutical composition comprising an R1 is (1) lower alkyl which may have 1 to 3 substitutents ef-fective amount of the compound claimed in claim 1 as an independently selected from the group consisting of active ingredient, in combination with a pharmaceu-tical halogen, amino, and cyano, (2) C 6 to Cn aromatic group which may have 1 to 3 substituents indepen- 30 excipient.] 6. The compound 7-(4-(4-jluorophenyl)-6-isopropyl-2-(Ndently selected from the group consisting of lower methyl-N-methylsulfonylamino)pyrimidin-5-yl)-(3R,5S)alkyl, halogen, amino, and cyano, or (3) C1 to C 6 lower dihydroxy-(E)-6-heptenoic acid in the form of a non-toxic alkyl substituted by C 6 to Cn aromatic group which may have 1 to 3 substituents independently sel-ected pharmaceutically acceptable salt thereof 7. The compound of claim 6 in the form of a sodium salt. from the group consisting of lower alkyl, halo-gen, amino, and cyano; R 2 and R3 each is independently (1) 35 8. The compound of claim 6 in the form of a calcium salt. hydrogen, (2) lower alkyl which may have 1 to 3 substituents independently selected from the group * * * * *

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Andrew T. Berry Jonathan M.H. Short McCARTER & ENGLISH, LLP Four Gateway Center 100 Mulberry Street Newark, NJ 07102 Telephone: (973) 622-4444 Facsimile: (973) 624-7070 Attorneys for Plaintiffs AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, IPR Pharmaceuticals, Inc., and Shionogi Seiyaku Kabushiki Kaisha

Of Counsel: Ford F. Farabow, Jr. Charles E. Lipsey York M. Faulkner FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P. 901 New York Avenue, N.W. Washington, DC 20001 Telephone: (202) 408-4000 Facsimile: (202) 408-4400 Henry J. Renk FITZPATRlCK, CELLA, HARPER & SCINTO 30 Rockefeller Plaza New York, NY 10112 Telephone: (212) 218-2100 Facsimile: (212) 218-2200

UNITED STATES DISTRICT COURT FOR THE DISTRICT OF NEW JERSEY NEWARK DIVISION : : : : : : : : : : : : : : : :

ASTRAZENECA PHARMACEUTICALS LP, ASTRAZENECA UK LIMITED, IPR PHARMACEUTICALS, INC., and SHIONOGI SEIYAKU KABUSHIKI KAISHA, Plaintiffs, vs. AUROBINDO PHARMA LIMITED, and AUROBINDO PHARMA USA INC. Defendants.

Civil Action No. __________

RULE 7.1 DISCLOSURE STATEMENT

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Pursuant to Fed. R. Civ. P. 7.1(a), and to enable Judges and Magistrate Judges of the Court to evaluate possible disqualification or recusal, Plaintiffs state that AstraZeneca PLC, a publicly-held company, is the ultimate parent company of AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, and IPR Pharmaceuticals Inc. No other publicly-held corporation owns 10% or more of the stock of AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, or IPR Pharmaceuticals Inc. Shionogi Seiyaku Kabushiki Kaisha has no parent corporation. No publicly-held corporation owns 10% or more of the stock of Shionogi Seiyaku Kabushiki Kaisha.

Dated: December 18, 2007

S/Andrew T. Berry Andrew T. Berry Jonathan M.H. Short McCARTER & ENGLISH, LLP Four Gateway Center 100 Mulberry Street Newark, NJ 07102 Telephone: (973) 622-4444 Facsimile: (973) 624-7070 Of Counsel: Ford F. Farabow, Jr. Charles E. Lipsey York M. Faulkner FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, L.L.P. 901 New York Avenue, N.W. Washington, DC 20001 Telephone: (202) 408-4000 Facsimile: (202) 408-4400 Henry J. Renk FITZPATRlCK, CELLA, HARPER & SCINTO 30 Rockefeller Plaza New York, NY 10112 Telephone: (212) 218-2100 Facsimile: (212) 218-2200

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Attorneys for Plaintiffs AstraZeneca Pharmaceuticals LP, AstraZeneca UK Limited, IPR Pharmaceuticals, Inc., and Shionogi Seiyaku Kabushiki Kaisha

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