`US007157456B2
`
`Illlllllll
`
`(12) United States Patent
`(12) United States Patent
`Straub et al.
`Straub et a1.
`
`(io) Patent No.:
`(10) Patent N0.:
`(45) Date of Patent:
`(45) Date of Patent:
`
`US 7,157,456 B2
`US 7,157,456 B2
`Jan. 2, 2007
`Jan. 2, 2007
`
`AND
`(54) SUBSTITUTED OXAZOLIDINONES
`(54) SUBSTITUTED OXAZOLIDINONES AND
`THEIR USE IN THE FIELD OF BLOOD
`THEIR USE IN THE FIELD OF BLOOD
`COAGULATION
`COAGULATION
`
`(75)
`Inventors: Alexander Straub, Wuppertal (DE);
`(75) Inventors: Alexander Straub, Wuppertal (DE);
`Thomas Lampe, Wuppertal (DE); Jens
`Thomas Lampe, Wuppertal (DE); Jens
`Pohlmann, Wuppertal (DE); Susanne
`Pohlmann, Wuppertal (DE); Susanne
`Rohrig, Essen (DE); Elisabeth
`Rohrig, Essen (DE); Elisabeth
`Perzborn, Wuppertal (DE); Karl-Heinz
`Perzborn, Wuppertal (DE); Karl-Heinz
`Schlemmer, Wuppertal (DE); Joseph
`Schlemmer, Wuppertal (DE); Joseph
`Pernerstorfer, Wuppertal (DE)
`Pernerstorfer, Wuppertal (DE)
`
`(73) Assignee: Bayer HealthCare AG, Leverkusen
`73
`Assi nee: Ba er HealthCare AG, Leverkusen
`g
`y
`(DE)
`(DE)
`the
`Subject to any disclaimer,
`Sub'ect to an disclaimer, the term of this
`J
`y
`patent is extended or adjusted under 35
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 59 days.
`U.S.C. 154(b) by 59 days.
`
`( * ) Notice:
`*
`Notice:
`
`(21) Appl. No.:
`(21) App1.No.:
`
`10/181,051
`10/1s1,051
`
`(22) PCT Filed:
`(22) PCT Filed:
`
`Dec. 11, 2000
`Dec. 11, 2000
`
`(86) PCT No.:
`(86) PCT N0.:
`
`PCT/EP00/12492
`PCT/EP00/12492
`
`§ 371 (c)(1),
`§ 371 (0X1)’
`(2), (4) Date:
`(2), (4) Date:
`
`Jun. 24, 2002
`Jun. 24, 2002
`
`(87) PCT Pub. No.: WOOl/47919
`(87) PCT Pub. No.: WO01/47919
`
`PCT Pub. Date: Jul. 5, 2001
`PCT Pub. Date: Jul. 5, 2001
`
`(65)
`(65)
`
`Prior Publication Data
`Prior Publication Data
`US 2003/0153610 Al Aug. 14, 2003
`US 2003/0153610 A1
`Aug. 14, 2003
`
`Foreign Application Priority Data
`(30)
`Foreign Application Priority Data
`(30)
`Dec. 24, 1999
`(DE)
`199 62 924
`Dec. 24, 1999 (DE) .............................. .. 199 62 924
`
`(51) Int. CI.
`(51) Int. Cl.
`(2006.01)
`A6IK 31/5377
`(2006.01)
`A61K 31/53 77
`(2006.01)
`C07D 409/14
`(2006.01)
`0070 409/14
`514/236.8; 544/139
`(52) U.S. CI
`(52) US. Cl. .................................. .. 514/236.8;544/139
`(58) Field of Classification Search
`544/139;
`(58) Field of Classi?cation Search .............. .. 544/139;
`514/236.8
`514/236.8
`See application
`file for complete search history.
`See application ?le for complete search history.
`References Cited
`References Cited
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`
`(56)
`(56)
`
`2,811,555 A
`10/1957 Larive et al.
`2,811,555 A 10/1957 Larive et al.
`10/1966 Straley et al.
`3,279,880 A
`3,279,880 A 10/1966 Straley et al.
`2/1985 Lormeau et al.
`4,500,519 A
`2/1985 Lormeau et al.
`4,500,519 A
`11/1987 Madi-Szabo et al.
`4,705,779 A
`4,705,779 A 11/1987 Madi-Szabo et al.
`10/1993 Carlson et al.
`5,254,577 A
`5,254,577 A 10/1993 Carlson et al.
`9/1994 Jiang
`5,349,045 A
`9/1994 Jiang
`5,349,045 A
`7/1996 Raddatz et al.
`5,532,255 A
`7/1996 Raddatz et al.
`5,532,255 A
`10/1996 Gante et al
`5,561,148 A
`.. 514/376
`5,561,148 A 10/1996 Gante et al. .............. .. 514/376
`5,565,571 A * 10/1996 Barbachyn et al.
`.. 546/144
`5,565,571 A * 10/1996 Barbachyn et al. ....... .. 546/144
`5,654,428 A * 8/1997 Barbachyn et al.
`.. 544/235
`5,654,428 A *
`8/1997 Barbachyn et al. ....... .. 544/235
`5,654,435 A * 8/1997 Barbachyn et al.
`546/271.4
`5,654,435 A *
`8/1997 Barbachyn et al. .... .. 546/271.4
`5,688,792 A
`11/1997 Barbachyn et al.
`5,688,792 A 11/1997 Barbachyn et al.
`5,756,732 A *
`5/1998 Barbachyn et al.
`544/112
`5,756,732 A *
`5/1998 Barbachyn et al. ....... .. 544/112
`5,792,765 A
`8/1998 Riedl et al.
`5,792,765 A
`8/1998 Riedl et al.
`548/152
`5,801,246 A * 9/1998 Barbachyn et al.
`5,801,246 A *
`9/1998 Barbachyn et al. ....... .. 548/152
`5,827,857 A
`10/1998 Riedl et al.
`5,827,857 A 10/1998 Riedl et al.
`
`5,910,504 A
`6/1999 Hutchinson et al.
`5,910,504 A
`6/1999 Hutchinson et al.
`5,922,708 A
`7/1999 Riedl et al.
`5,922,708 A
`7/1999 Riedl et al.
`5,929,248 A *
`7/1999 Barbachyn et al.
`548/184
`5,929,248 A *
`7/1999 Barbachyn et al. ....... .. 548/184
`5,972,947 A
`10/1999 Tsaklakidis et al.
`5,972,947 A 10/1999 Tsaklakidis et al.
`5/2000 Stolle et al.
`6,069,160 A
`5/2000 Stolle et al.
`6,069,160 A
`6/2001 Bohanon
`6,251,869 B1
`6/2001 Bohanon
`6,251,869 B1
`
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`
`AU
`AU
`CA
`CA
`CA
`CA
`CA
`CA
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`term
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`WO wo
`WO
`WO
`WO wo
`WO
`WO
`WO
`WO
`wo
`WO
`WO
`WO
`WO
`WO
`
`of
`
`744002
`744002
`2 437 587
`2 437 587
`2 451 258
`2 451 258
`2 464 290
`2 464 290
`196 04 223
`196 04 223
`0 127 902
`0 127 902
`0 316 594
`0 316 594
`0 352 781
`0 352 781
`this
`0 623 615
`0 623 615
`0645376
`0645376
`0 738 726
`0 738 726
`0 785 200
`0 785 200
`WO-93/09103
`WO-93/09103
`WO-93/23384
`WO-93/23384
`WO-97/03072
`WO-97/03072
`WO-97/09328
`WO-97/09328
`WO-97/10223
`WO-97/10223
`WO-98/01446
`WO-98/01446
`WO-98/54161
`WO-98/54161
`WO-99/02525
`WO-99/02525
`
`7/1999
`7/1999
`8/2002
`8/2002
`1/2003
`1/2003
`5/2003
`5/2003
`8/1997
`8/1997
`12/1984
`12/1984
`5/1989
`5/1989
`1/1990
`1/1990
`11/1994
`11/1994
`3/1995
`3/1995
`10/1996
`10/1996
`7/1997
`7/1997
`5/1993
`5/1993
`11/1993
`11/1993
`1/1997
`1/1997
`3/1997
`3/1997
`3/1997
`3/1997
`1/1998
`1/1998
`12/1998
`12/1998
`1/1999
`1/1999
`
`(Continued)
`(Continued)
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
`""This reference is not being famished since it was cited in the
`*This reference is not being furnished since it Was cited in the
`International Search Report for PCT/EP 00/12492.*
`International Search Report for PCT/EP 00/ 12492.*
`
`(Continued)
`(Continued)
`Primary Examiner—Kamal A. Saeed
`Primary ExamineriKamal A. Saeed
`Assistant Examiner—Rebecca Anderson
`Assistant ExamineriRebecca Anderson
`(74) Attorney, Agent, or Firm—Connolly Bove Lodge &
`(74) Attorney, Agent, or FirmiConnolly Bove Lodge &
`Hutz LLP
`HutZ LLP
`
`(57)
`(57)
`
`ABSTRACT
`ABSTRACT
`
`Novel
`The invention relates to the field of blood coagulation.
`The invention relates to the ?eld of blood coagulation. Novel
`oxazolidinone derivatives of the general formula (I)
`oxaZolidinone derivatives of the general formula (I)
`
`(I)
`
`o
`
`X
`
`R2 JR
`Ri
`\N
`0
`R5
`R5
`R6
`R6
`
`R3'
`
`R4
`
`R8—
`
`R7
`R7
`
`R1, Y O
`
`0
`
`use as medicinally
`
`their
`their preparation and
`processes for
`processes for their preparation and their use as medicinally
`active compounds for the prophylaxis and/or treatment of
`active compounds for the prophylaxis and/or treatment of
`disorders are described.
`disorders are described.
`
`30 Claims, No Drawings
`30 Claims, No Drawings
`
`MYLAN - EXHIBIT 1008
`
`
`
`US 7,157,456 B2
`US 7,157,456 B2
`Page 2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`WO-99/03846
`WO-99/03846
`9906371
`9906371
`WO-99/24428
`WO-99/24428
`WO-99/29688
`WO-99/29688
`WO-99-31092
`WO-99-31092
`9937304
`9937304
`WO-99/37630
`WO-99/37630
`WO-99/37641
`WO-99/37641
`WO-99/40094
`WO-99/40094
`WO-99/59616
`WO-99/59616
`WO-01/42242
`WO-01/42242
`WO-01/44212
`WO-01/44212
`WO-01/46185
`WO-01/46185
`WO-02/064575
`WO-02/064575
`WO-03/000256
`WO-03/000256
`WO-03/035133
`WO-03/035133
`
`1/1999
`1/1999
`2/1999
`2/1999
`5/1999
`5/1999
`6/1999
`6/1999
`* 6/1999
`* 6/1999
`7/1999
`7/1999
`7/1999
`7/1999
`7/1999
`7/1999
`8/1999
`8/1999
`11/1999
`11/1999
`6/2001
`6/2001
`6/2001
`6/2001
`6/2001
`6/2001
`8/2002
`8/2002
`1/2003
`1/2003
`5/2003
`5/2003
`
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
`Cancer and Metastasis Review, vol. 17, pp. 91-106, (1998).*
`Cancer and Metastasis Review, vol. 17, pp. 91-106, (1998).*
`Science (1999), vol. 286, 531-537 *
`Science (1999), vol. 286, 531-537.*
`FDAmulls drug to slow late-stage Alzheimers's [online], [retrieved
`FDA mulls drug to slow late-stage AlZheimers’s [online], [retrieved
`on Sep. 9, 2003], Retrieved from the internet, URL;http://www.cnn.
`on Sep. 9, 2003]. Retrieved from the internet, URL;http://www.cnn.
`com/2003/HEALTH/conditions/09/24/alZheimers.drug.ap/index.
`com/2003/HEALTH/conditions/09/24/alzheimers.drug.ap/index.
`html>.*
`htm1>.*
`Ullmann's Encycolpedia of Industrial Chemistry, Fifth Revised Ed.,
`Ullmann’s Encycolpedia of Industrial Chemistry, Fifth Revised Ed.,
`Editors.: Elvers, B., Hawkins, S., VCH Verlagsgesellschaft mbH,
`Editors.: Elvers, B., Hawkins, S., VCH Verlagsgesellschaft mbH,
`Weinheim, 1985-1996, ch. 5, 488-506.
`Weinheim, 1985-1996, ch. 5, 488-506.
`Zhu, B., Scarborough, R., "Recent Advances in Inhibitors of Factor
`Zhu, B., Scarborough, R., “Recent Advances in Inhibitors of Factor
`Xa in the Prothrombinase Complex", Cur. Opinions Card. Pulm.
`Xa in the Prothrombinase Complex”, Cur. Opinions Card. Pulm.
`Ren. Inv. Drugs, 1: 63-87 (1999).
`Ren. Inv. Drugs, 1: 63-87 (1999).
`Uzan, A., "Antithrombotic Agents", Emerging Drugs: The Prospect
`UZan, A., “Antithrombotic Agents”, Emerging Drugs: The Prospect
`for Improved Medicines, 3: 189-208, (1998).
`for Improved Medicines, 3: 189-208, (1998).
`Kaiser, B., "Thrombin and Factor Xa Inhibitors", Drugs of the
`Kaiser, B., “Thrombin and Factor Xa Inhibitors”, Drugs of the
`Future, 23: 423-436 (1998).
`Future, 23: 423-436 (1998).
`Al-Obeidi, F., Ostrem, J., "Factor Xa Inhibitors", Expert Opin.
`Al-Obeidi, F., Ostrem, J., “Factor Xa Inhibitors”, Expert Opin.
`Therapeutic Patents, 9: 931-953 (1999).
`Therapeutic Patents, 9: 931-953 (1999).
`Al-Obeidi, F., Ostrem, J., "Factor Xa Inhibitors by Classical and
`Al-Obeidi, F., Ostrem, J., “Factor Xa Inhibitors by Classical and
`Combinatorial Chemistry", DDT, 3: 223-231 (May 1998).
`Combinatorial Chemistry”, DDT, 3: 223-231 (May 1998).
`Hauptmann, J., Sturzebecher, J., "Synthetic Inhibitors of Thrombin
`Hauptrnann, J ., SturZebecher, J ., “Synthetic Inhibitors of Thrombin
`and FActor Xa: From Bench to Bedside", Thrombosis Research, 93:
`and FActor Xa: From Bench to Bedside”, Thrombosis Research, 93:
`203-241 (1999).
`203-241 (1999).
`Pschyrembel, Klinisches Worterbuch, 257. Auflage, 1994, Walter de
`Pschyrembel, Klinisches Worterbuch, 257. Au?age, 1994, Walter de
`Gruyter Verlag, p. 199-200, Stichwort "Blutgerinnung".
`Gruyter Verlag, p. 199-200, Stichwort “Blutgerinnung”.
`Rompp Lexikon Chemie, Ver. 1.5, 1998, Georg Thieme Verlag
`Rompp Lexikon Chemie, Ver. 1.5, 1998, Georg Thieme Verlag
`Stuttgart, Stichwort "Blutgerinnung" Lubert Stryer, Biochemie,
`Stuttgart, Stichwort “Blutgerinnung” Lubert Stryer, Biochemie,
`Spektrum der Wissenschaft Verlagsgesellschaft mbH Heidelberg,
`Spektrum der Wissenschaft Verlagsgesellschaft mbH Heidelberg,
`1990, p. 259.
`1990, p. 259.
`Pschyrembel, Klinisches Worterbuch, 257. Auflage, 1994, Walter de
`Pschyrembel, Klinisches Worterbuch, 257. Au?age, 1994, Walter de
`Gruyter Verlag, p. 610, Stichwort "Heparin".
`Gruyter Verlag, p. 610, Stichwort “Heparin”.
`Rompp Lexikon Chemie, Ver. 1.5, 1998, Georg Thieme Verlag
`Rompp Lexikon Chemie, Ver. 1.5, 1998, Georg Thieme Verlag
`Stuttgart, Stichwort "Heparin".
`Stuttgart, Stichwort “Heparin”.
`Pschyrembel, Klinisches Worterbuch, 257. Auflage, 1994, Walter de
`Pschyrembel, Klinisches Worterbuch, 257. Au?age, 1994, Walter de
`Gruyter Verlag, p. 292, Stichwort "Cumarinderivate".
`Gruyter Verlag, p. 292, Stichwort “Cumarinderivate”.
`Becker, M. R., Ewing, W. R., Davis, R. S., Pauls, H. W., Ly, C., Li,
`Becker, M. R., Ewing, W. R., Davis, R. S., Pauls, H. W., Ly, C., Li,
`A., Mason, H. J., Choi-Sledeski, Y. M., Spada, A. P., Chu, V,
`A., Mason, H. J., Choi-Sledeski, Y. M., Spada, A. P., Chu, V.,
`Brown, K. D., Colussi, D. J., Leadley, R. J., Bentley, R., Bostwick,
`Brown, K. D., Colussi, D. J., Leadley, R. J., Bentley, R., Bostwick,
`J., Kasiewski, C., and Morgan, S., "Synthesis, Sar and in Vivo
`J., Kasiewski, C., and Morgan, S., “Synthesis, Sar and in Vivo
`Activity of Novel Thienopyridine Sulfonamide Pyrrolidinones as
`Activity of Novel Thienopyridine Sulfonamide Pyrrolidinones as
`Factor Xa Inhibitors", Bioorganic & Medicinal Chemistry Letters,
`Factor Xa Inhibitors”, Bioorganic & Medicinal Chemistry Letters,
`9: 2753-2758 (1999).
`9: 2753-2758 (1999).
`Adams et al., Sulfanilamide Derivatives, J. Am. Chem. Soc. 1939,
`Adams et al., Sulfanilamide Derivatives, J. Am. Chem. Soc. 1939,
`vol. 61, pp. 2342-2349.
`vol. 61, pp. 2342-2349.
`Aebischer et al., Synthesis of N-Arylrolipram Derivatives—Potent
`Aebischer et al., Synthesis of N-Arylrolipram DerivativesiPotent
`and Selective Phosphodiesterase-IV Inhibitors— By Copper Cata-
`and Selective Phosphodiesterase-IV Inhibitorsi By Copper Cata
`lyzed Lactam-Aryl Halide Coupling, Hetercycles. 1998, vol. 48, pp.
`lyZed Lactam-Aryl Halide Coupling, Hetercycles. 1998, vol. 48, pp.
`2225-2229.
`2225-2229.
`Artico et al., Research on Compounds with Antiblastic Activity,
`Artico et al., Research on Compounds with Antiblastic Activity,
`Farmaco Ed. Sci. 1969, vol. 24, pp. 179-190.
`Farmaco Ed. Sci. 1969, vol. 24, pp. 179-190.
`
`Barbachyn et al., Identification of a Novel Oxazolidinone (
`Barbachyn et al., Identi?cation of a Novel OxaZolidinone (
`U-100480) with Potent Antimycobacterial Activity, J. Med. Chem.
`U-100480) with Potent Antimycobacterial Activity, J. Med. Chem.
`1996, vol. 39, pp. 680-685.
`1996, vol. 39, pp. 680-685.
`Bartoli et al., Electronic and Steric Effects in Nucleophilic Aromatic
`Bartoli et al., Electronic and Steric Effects in Nucleophilic Aromatic
`Substitution. Reaction by Phenoxides as Nucleophiles in Dimethyl
`Substitution. Reaction by Phenoxides as Nucleophiles in Dimethyl
`Sulfoxide, J. Org. Chem. 1975, vol. 40, pp. 872-874.
`Sulfoxide, J. Org. Chem. 1975, vol. 40, pp. 872-874.
`Berry et al., Antithrombotic Actions of Argatroban in Rat Models of
`Berry et al., Antithrombotic Actions of Argatroban in Rat Models of
`Venous, 'Mixed'and Arterial Thrombosis, and its Effects on the Tail
`Venous, ‘Mixed’and Arterial Thrombosis, and its Effects on the Tail
`Transection Bleeding Time, Br. J. Pharmacol. 1994, vol. 113, pp.
`Transection Bleeding Time, Br. J. Pharmacol. 1994, vol. 113, pp.
`1209-1214.
`1209-1214.
`Bouchet et al., '(Values of N-Substituted Azoles, J. Chem. Soc.
`Bouchet et al., 6Values of N-Substituted AZoles, J. Chem. Soc.
`Perkin Trans. 1974, vol. 2, pp. 449-451.
`Perkin Trans. 1974, vol. 2, pp. 449-451.
`Brickner et al., Synthesis and Antibacterial Activity of U-100592
`Brickner et al., Synthesis and Antibacterial Activity of U-100592
`and U-100766, Two Oxazolidinone ANtibacterial Agents for the
`and U-100766, Two OxaZolidinone ANtibacterial Agents for the
`Potential Treatment of Multidrug-Resistant Gram-Positive Bacterial
`Potential Treatment of Multidrug-Resistant Gram-Po sitive Bacterial
`Infections, J. Med. Chem. 1996, vol. 39, pp. 673.
`Infections, J. Med. Chem. 1996, vol. 39, pp. 673.
`Chern et al., Studies on Quinazolines IX: Fluorination versus
`Chern et al., Studies on QuinaZolines IX: Fluorination versus
`1,2-Migration in the Reaction of 1,3-Bifunctionalized amino-2-
`1,2-Migration in the Reaction of 1,3-BifunctionaliZed amino-2
`propanol with DAST, Tetrahedron Lett. 1998, vol. 39, pp. 8483
`propanol with DAST, Tetrahedron Lett. 1998, vol. 39, pp. 8483
`8486.
`8486.
`Dankwardt et al., Nonpeptide Bradykinin Antagonist Analogs
`Dankwardt et al., Nonpeptide Bradykinin Antagonist Analogs
`Based on a Model of a Sterling-Winthrop Nonpeptide brandykinin
`Based on a Model of a Sterling-Winthrop Nonpeptide brandykinin
`Antagonist Overlapped with Cyclic Hexapeptide Bradykinin
`Antagonist Overlapped with Cyclic Hexapeptide Bradykinin
`Antagonist Peptides, Bioorg. Med. Chem. Lett. 1997, vol. 7, No. 14,
`Antagonist Peptides, Bioorg. Med. Chem. Lett. 1997, vol. 7, No. 14,
`pp. 1921-1926.
`pp. 1921-1926.
`Dostert et al., 5-Hydroxymethyl-2-oxazolidinones, Chem. Abstr.
`Dostert et al., 5-Hydroxymethyl-2-oxaZolidinones, Chem. Abstr.
`1979, vol. 90, pp. 186926.
`1979, vol. 90, pp. 186926.
`Gregory et al., Antibacterials. Synthesis and Structure-Activity
`Gregory et al., Antibacterials. Synthesis and Structure-Activity
`Studies of 3-Aryl-2-oxooxazolidines. 1. The "B" Group, J. Med.
`Studies of 3-Aryl-2-oxooxaZolidines. 1. The “B” Group, J. Med.
`Chem. 1989, vol. 32, pp. 1673-1681.
`Chem. 1989, vol. 32, pp. 1673-1681.
`Grell et al., Repaglinide and Related Hypoglycemic Benzoic Acid
`Grell et al., Repaglinide and Related Hypoglycemic BenZoic Acid
`Derivatives, J. Med. Chem. 1998, vol. 41, pp. 5219-5246.
`Derivatives, J. Med. Chem. 1998, vol. 41, pp. 5219-5246.
`Gutcait et al., Studies on Quinazolines. 6. Asymmetric Synthesis of
`Gutcait et al., Studies on QuinaZolines. 6. Asymmetric Synthesis of
`(S)-(30)-and
`(R)-(-)-3-[[4-(2-Methoxyphenyl)piperaZin
`(S)-(30)-and
`(R)-(-)-3-[[4-(2-Methoxyphenyl)piperazin-
`1yl]methyl]-5 -methylthio -2,3 -dihydroimidaZo[1,2-c]quinaZolines,
`lyl]methyl]-5-methylthio-2,3-dihydroimidazo[l,2-c]quinazolines,
`Tetrahedron Asym. 1996, vol. 7, pp. 1641-1648.
`Tetrahedron Asym. 1996, vol. 7, pp. 1641-1648.
`Khanna et al., 1,2-Diarylpyrroles as Potent and Selective Inhibitors
`Khanna et al., 1,2-Diarylpyrroles as Potent and Selective Inhibitors
`of Cyclooxygenase-2, J. Med. Chem. 1997, vol. 40, pp. 1619-1633.
`of Cyclooxygenase-2, J. Med. Chem. 1997, vol. 40, pp. 1619-1633.
`Luvalle et al., Oxidation Processes. XXI. The Autoxidation of the
`Luvalle et al., Oxidation Processes. XXI. The Autoxidation of the
`p-Phenylenediamines, J. Am. Chem. Soc. 1948, vol. 70, pp. 2223
`p-Phenylenediamines, J. Am. Chem. Soc. 1948, vol. 70, pp. 2223
`2233.
`2233.
`Meng et al., Effect of Acetylsalicylic Acid on Experimentally
`Meng et al., Effect of Acetylsalicylic Acid on Experimentally
`Induced Arterial Thrombosis in Rats, Naunyn-Schmiedeberg' Arch.
`Induced Arterial Thrombosis in Rats, Naunyn-Schmiedeberg’ Arch.
`Pharmacol. 1977, vol. 301, pp. 115-119.
`Pharmacol. 1977, vol. 301, pp. 115-119.
`Pfeil et al., Synthese von Oxalactamen aus Aziridinium-
`Pfeil et al., Synthese von Oxalactamen aus AZiridinium
`tetrafluoroborat und Hydroxysaureestern, Agnew. Chem. 1967, vol.
`tetra?uoroborat und Hydroxysaureestern, Agnew. Chem. 1967, vol.
`79, p. 188.
`79, p. 188.
`Renger, Direct N-Arylation of Amides : An Improvement of the
`Renger, Direct N-Arylation of Amides : An Improvement of the
`Goldberg-Reaction, Synthesis, Sep. 1985, pp. 856-860.
`Goldberg-Reaction, Synthesis, Sep. 1985, pp. 856-860.
`Reppe et al., Justus Liebigs Ann. Chem. 1955, vol. 596, pp. 204.
`Reppe et al., Justus Liebigs Ann. Chem. 1955, vol. 596, pp. 204.
`Reppe et al., Justus Liebigs Ann. Chem. 1955, vol. 596, pp. 209.
`Reppe et al., Justus Liebigs Ann. Chem. 1955, vol. 596, pp. 209.
`Riedl et al., Recent Developments with Oxazolidinone Antiboiotics,
`Riedl et al., Recent Developments with OxaZolidinone Antiboiotics,
`Exp. Opin. Ther. Patents 1999, vol. 9 (5), pp. 625-633.
`Exp. Opin. Ther. Patents 1999, vol. 9 (5), pp. 625-633.
`Shakespeare, Palladium-Catalyzed Coupling of Lactams with
`Shakespeare, Palladium-Catalyzed Coupling of Lactams with
`Bromobenzenes, Tetrahedron Lett. 1999, vol. 40, pp. 2035-2038.
`BromobenZenes, Tetrahedron Lett. 1999, vol. 40, pp. 2035-2038.
`Snyder et al., Imidazo[4,5-f|quinolines III: Antibacterial 7-Methyl-
`Snyder et al., ImidaZo[4,5-f]quinolines III: Antibacterial 7-Methyl
`9-(substituted Arylamino)imidazo[4,5-f|quinolines, J. Pharm. Sci.
`9-(substituted Arylamino)imidaZo[4,5-f]quinolines, J. Pharm. Sci.
`1977, vol. 66, pp. 1204-1206.
`1977, vol. 66, pp. 1204-1206.
`Surrey et al., The Preparation of N-Benzyl-3-morpholones and
`Surrey et al., The Preparation of N-BenZyl-3-morpholones and
`N-BenZyl-3-homomorpholones
`from
`N-(Hydroxyalkyl)
`N-Benzyl-3-homomorpholones
`from
`N-(Hydroxyalkyl)-
`chloroacetamides, J. Amer. Chem. Soc. 1955, vol. 77, pp. 633-636.
`chloroacetamides, J. Amer. Chem. Soc. 1955, vol. 77, pp. 633-636.
`Tong et al., The Mechanism of Dye Formation in Color Photogra
`Tong et al., The Mechanism of Dye Formation in Color Photogra
`phy. VII.
`Intermediate Bases
`in
`the Deamination of
`phy.
`VII.
`Intermediate Bases in
`the Deamination of
`Quinonediimines, J. Amer. Chem. Soc. 1960, vol. 82, pp. 1988
`Quinonediirnines, J. Amer. Chem. Soc. 1960, vol. 82, pp. 1988
`2001.
`2001.
`Tucker et al., Piperazinyl Oxazolidinone Antibacterial Agents Con
`Tucker et al., PiperaZinyl OxaZolidinone Antibacterial Agents Con
`taining a Pyridine, Diazene, or Triazene Heteroaromatic Ring, J.
`taining a Pyridine, DiaZene, or TriaZene Heteroaromatic Ring, J.
`Med. Chem. 1998, vol. 41, pp. 3727-3735.
`Med. Chem. 1998, vol. 41, pp. 3727-3735.
`Ziegler et al., Synthesis of Some Novel 7-Substituted
`Ziegler et
`al.,
`Synthesis of Some Novel 7-Substituted
`Quinolonecarboxylic Acids via Nitroso and Nitrone Cycloadditions,
`Quinolonecarboxylic Acids via Nitroso and Nitrone Cycloadditions,
`J. Hetercycl. Chem., May-Jun. 1988, vol. 25 (2), pp. 719-723.
`J. Hetercycl. Chem., May-Jun. 1988, vol. 25 (2), pp. 719-723.
`
`
`
`US 7,157,456 B2
`US 7,157,456 B2
`Page 3
`Page 3
`
`Bono, F., et al., "Human Umbilical Vein Endothelial Cells Express
`Bono, F., et al., “Human Umbilical Vein Endothelial Cells Express
`High Affinity Receptors for Factor Xa," Journal of Cellular Physi-
`High A?inity Receptors for Factor Xa,” Journal of Cellular Physi
`ology; vol. 172; pp. 36-43; (Jul. 1997).
`ology; vol. 172; pp. 36-43; (Jul. 1997).
`Cocks, T., et al., "Protease-activated receptors: sentries for inflam-
`Cocks, T., et al., “Protease-activated receptors: sentries for in?am
`mation?"TiPS; vol. 21; pp. 103-108; (Mar. 2000).
`mation?”TiPS; vol. 21; pp. 103-108; (Mar. 2000).
`Ross, R., Ph.D, "Atherosclerosis—An Inflammatory Disease," The
`Ross, R., Ph.D, “Atherosclerosis-An In?ammatory Disease,” The
`New England Journal of Medicine; vol. 340, No. 2; pp. 115-126;
`New England Journal of Medicine; vol. 340, No. 2; pp. 115-126;
`(Jan. 14, 1999).
`(Jan. 14, 1999).
`Nakata, M., et al.; "DX9065a, an Xa inhibitor, inhibits prothrombin-
`Nakata, M., et al.; “DX9065a, an Xa inhibitor, inhibits prothrombin
`induced A549 lung adenocarcinoma cell proliferation," Cancer
`induced A549 lung adenocarcinoma cell proliferation,” Cancer
`Letters; vol. 122; pp. 127-133; (Jan. 9, 1998).
`Letters; vol. 122; pp. 127-133; (Jan. 9, 1998).
`Cirino, G., et al., "Inflammation-coagulation network: are serine
`Cirino, G., et al., “In?ammation-coagulation network: are serine
`protease receptors the knot?" TiPS; vol. 21; pp. 170-172; (May
`protease receptors the knot?” TiPS; vol. 21; pp. 170-172; (May
`2000).
`2000).
`Kaiser, B., et al., "A Synthetic Inhibitor of Factor Xa, DX-9065a,
`Kaiser, B., et al., “A Synthetic Inhibitor of Factor Xa, DX-9065a,
`Reduces Proliferation of Vascular Smooth muscle Cells in Vivo in
`Reduces Proliferation of Vascular Smooth muscle Cells in Vivo in
`Rats," Thrombosis Research; vol. 98; pp. 175-185; (Apr. 15, 2000).
`Rats,” Thrombosis Research; vol. 98; pp. 175-185; (Apr. 15, 2000).
`Altieri, D., et al., "Identification of Effector Cell Protease Receptor-
`Altieri, D., et al., “Identi?cation of Effector Cell Protease Receptor
`1: A Leukocyte-Distributed Receptor for the Serine Protease Factor
`1: A Leukocyte-Distributed Receptor for the Serine Protease Factor
`Xa,"The Journal of Immunology; vol. 145, No. 1; pp. 246-253; (Jul.
`Xa,” The Journal ofImmunology; vol. 145, No. 1; pp. 246-253; (Jul.
`1, 1990).
`1, 1990).
`Coughlin, Shaun R., "Thrombin signaling and protease-activated
`Coughlin, Shaun R., “Thrombin signaling and protease-activated
`receptors," Nature; vol. 407; pp. 258-264; (Sep. 14, 2000).
`receptors,” Nature; vol. 407; pp. 258-264; (Sep. 14, 2000).
`Ornstein, D., MD, et al., "Cancer, thrombosis, and anticoagulants,"
`Ornstein, D., MD, et al., “Cancer, thrombosis, and anticoagulants,”
`Current Opinion in Pulmonary Medicine; vol. 6; pp. 301-308; (Jul.
`Current Opinion in Pulmonary Medicine; vol. 6; pp. 301-308; (Jul.
`2000).
`2000).
`Dahhagh, K., et al., "Thrombin Stimulates Smooth Muscle Cell
`Dahhagh, K., et al., “Thrombin Stimulates Smooth Muscle Cell
`Procollagen Synthesis and mRNA Levels via a PAR-1 Mediated
`Procollagen Synthesis and mRNA Levels via a PAR-1 Mediated
`Mechanism," Thrombosis and Haemostatis; vol. 79, No. 2; pp.
`Mechanism,” Thrombosis and Haemostatis; vol. 79, No. 2; pp.
`405-409; (Feb. 1997).
`405-409; (Feb. 1997).
`Herault, J., et al., "Activation of Human Vascular Endothelial Cells
`Herault, J ., et al., “Activation of Human Vascular Endothelial Cells
`by Factor Xa: Effect of Specific Inhibitors," Biochemical Pharma-
`by Factor Xa: Effect of Speci?c Inhibitors,” Biochemical Pharma
`cology; vol. 57; pp. 603-610; (Mar. 1999).
`cology; vol. 57; pp. 603-610; (Mar. 1999).
`Leveugle, B., et al., "Heparin Oligosaccharides that Pass the
`Leveugle, B., et al., “Heparin Oligosaccharides that Pass the
`Blood—Brain Barrier Inhibit |3-Amyloid Precursor Protein Secre
`Blood-Brain Barrier Inhibit [5-Amyloid Precursor Protein Secre
`tion and Heparin Binding to |3-Amyloid Peptide," Journal of
`tion and Heparin Binding to [5-Amyloid Peptide,” Journal of
`Neurochemistry; vol. 70, No. 2; pp. 736-744; (Feb. 1998).
`Neurochemistry; vol. 70, No. 2; pp. 736-744; (Feb. 1998).
`Molino, M., et al., "Differential Expression of Functional Protease-
`Molino, M., et al., “Differential Expression of Functional Protease
`Activated Receptor-2 (PAR-2) in Human Vascular Smooth Muscle
`Activated Receptor-2 (PAR-2) in Human Vascular Smooth Muscle
`Cells," Arteriosclerosis, Thrombosis, and Vascular Biology; vol. 18,
`Cells,”Arteriosclerosis, Thrombosis, and Vascular Biology; vol. 18,
`No. 5; pp. 825-832; (May 1997).
`No. 5; pp. 825-832; (May 1997).
`Plescia, J., et al., "Activation of Mac-1 (CD 1 lb/CD 18)-bound factor
`Plescia, J ., et al., “Activation of Mac-1 (CD11b/CD18)-bound factor
`X by released cathepsin G defines an alternative pathway of
`X by released cathepsin G de?nes an alternative pathway of
`leucocyte initiation of coagulation," Biochemical Journal; vol. 319;
`leucocyte initiation of coagulation,” Biochemical Journal; vol. 319;
`pp. 873-879; (Nov. 1, 1996).
`pp. 873-879; (Nov. 1, 1996).
`Howells, G., et al., "Proteinase-activated receptor-2: expression by
`Howells, G., et al., “Proteinase-activated receptor-2: expression by
`human neutrophils," Journal of Cell Science; vol. 110; pp. 881-887;
`human neutrophils,” Journal of Cell Science; vol. 110; pp. 881-887;
`(Apr. 1, 1997).
`(Apr. 1, 1997).
`Herbert, J.-M., et al., "Effector Protease Receptor 1 Mediates the
`Herbert, J .-M., et al., “Effector Protease Receptor 1 Mediates the
`Mitogenic Activity of Factor Xa for Vascular Smooth Muscle Cells
`Mitogenic Activity of Factor Xa for Vascular Smooth Muscle Cells
`In Vitro and In Vivo." Journal of Clinical Investigation; vol. 101,
`In Vitro and In Vivo.” Journal of Clinical Investigation; vol. 101,
`No. 5; pp. 993-1000; (Mar. 1998).
`No. 5; pp. 993-1000; (Mar. 1998).
`Donnelly, K., et al., "Ancylostoma caninum Anticoagulant Peptide
`Donnelly, K., et al., “Ancylostoma caninum Anticoagulant Peptide
`Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to
`Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to
`Melanoma Cells In Vitro," Thrombosis and Haemostasis; vol. 79;
`Melanoma Cells In Vitro,” Thrombosis and Haemostasis; vol. 79;
`pp. 1041-1047 (May 1998).
`pp. 1041-1047 (May 1998).
`Ragosta, M., MD, et al., "Specific Factor Xa Inhibition Reduces
`Ragosta, M., MD, et al., “Speci?c Factor Xa Inhibition Reduces
`Restenosis After Balloon Angioplasty of Atherosclerotic Femoral
`Restenosis After Balloon Angioplasty of Atherosclerotic Femoral
`Arteries in Rabbits," Circulation; vol. 89, No. 3; pp. 1262-1271;
`Arteries in Rabbits,” Circulation; vol. 89, No. 3; pp. 1262-1271;
`(Mar. 1994).
`(Mar. 1994).
`Lindner, J., et al., "Delayed Onset of Inflammation in Protease-
`Lindner, J., et al., “Delayed Onset of In?ammation in Protease
`Activated Receptor-2-Deficient Mice," The Journal of Immunol-
`Activated Receptor-2-De?cient Mice,” The Journal of Immunol
`ogy; vol. 165; pp. 6504-6510 (Dec. 1, 2000).
`ogy; vol. 165; pp. 6504-6510 (Dec. 1, 2000).
`Zhang, Y., et al., "Tissue Factor Controls the Balance of Angiogenic
`Zhang, Y., et al., “Tissue Factor Controls the Balance of Angiogenic
`and Antiangiogenic Properties of Tumor Cells in Mice," Journal of
`and Antiangiogenic Properties of Tumor Cells in Mice,” Journal of
`Clinical Investigation; vol. 94; pp. 1320-1327; (Sep. 1994).
`Clinical Investigation; vol. 94; pp. 1320-1327; (Sep. 1994).
`Green, D., et al., "Lower mortality In cancer patients treated with
`Green, D., et al., “Lower mortality In cancer patients treated with
`low-molecular-weight versus standard heparin," Letters to the Edi-
`low-molecular-weight versus standard heparin,” Letters to the Edi
`tor, The Lancet; vol. 339; p. 1476; (Jun. 13, 1992).
`tor, The Lancet; vol. 339; p. 1476; (Jun. 13, 1992).
`Ko, E, et al., "Coagulation Factor Xa Stimulates Platelet-derived
`K0, F., et al., “Coagulation Factor Xa Stimulates Platelet-derived
`Growth Factor Release and Mitogenesis in Cultured Vascular
`Growth Factor Release and Mitogenesis in Cultured Vascular
`Smooth Muscle Cells of Rat," Journal of Clinical Investigation; vol.
`Smooth Muscle Cells of Rat,” Journal of Clinical Investigation; vol.
`98, No. 6; pp. 1493-1501; (Sep. 1996).
`98, No. 6; pp. 1493-1501; (Sep. 1996).
`
`Kakkar, A., et al., "Antithrombotic therapy in cancer," British
`Kakkar, A., et al., “Antithrombotic therapy in cancer,” British
`Medical Journal; vol. 318; pp. 1571-1572; (Jun. 12, 1999).
`Medical Journal; vol. 318; pp. 1571-1572; (Jun. 12, 1999).
`Gasic, G., et al., "Coagulation factors X, Xa, and protein S as potent
`Gasic, G., et al., “Coagulation factors X, Xa, and protein S as potent
`mitogens of cultured aortic smooth muscle cells," Proceedings of
`mitogens of cultured aortic smooth muscle cells,” Proceedings of
`the National Academy of Sciences; vol. 89; pp. 2317-2320; (Mar.
`the National Academy of Sciences; vol. 89; pp. 2317-2320; (Mar.
`1992).
`1992).
`Cirino, G., et al., "Factor Xa as an Interface Between Coagulation
`Cirino, G., et al., “Factor Xa as an Interface Between Coagulation
`and Inflammation," Journal of Clinical Investigation; vol. 99, No.
`and In?ammation,” Journal of Clinical Investigation; vol. 99, No.
`10; pp. 2446-2451; (May 1997).
`10; pp. 2446-2451; (May 1997).
`Senden, N., et al., "Factor Xa Induces Cytokine Production and
`Senden, N., et al., “Factor Xa Induces Cytokine Production and
`Expression of Adhesion Molecules by Human Umbilical Vein
`Expression of Adhesion Molecules by Human Umbilical Vein
`Endothelial Cells," The Journal of Immunology; vol. 161; pp.
`Endothelial Cells,” The Journal of Immunology; vol. 161; pp.
`4318-4324; (Oct. 15, 1998).
`4318-4324; (Oct. 15, 1998).
`Papapetropoulos, A., et al., "Hypotension and inflammatory
`Papapetropoulos, A., et al., “Hypotension and in?ammatory
`cytokine gene expression triggered by factor Xa-nitric oxide sig
`cytokine gene expression triggered by factor Xa-nitric oxide sig
`naling," Proceedings of the National Academy of Sciences; vol. 95;
`naling,” Proceedings of the National Academy of Sciences; vol. 95;
`pp. 4738-4742; (Apr. 1998).
`pp. 4738-4742; (Apr. 1998).
`Camerer, E., et al., "Tissue factor-and factor X-dependent activation
`Camerer, E., et al., “Tissue factor-and factor X-dependent activation
`of protease-activated receptor 2 by factor Vila," Proceedings of the
`of protease-activated receptor 2 by factor VIIa,” Proceedings of the
`National Academy of Sciences; vol. 97, No. 10; pp. 5255-5260;
`National Academy of Sciences; vol. 97, No. 10; pp. 5255-5260;
`(May 9, 2000).
`(May 9, 2000).
`Donovan, F., et al., "Thrombin Induces Apoptosis in Cultured
`Donovan, F., et al., “Thrombin Induces Apoptosis in Cultured
`Neurons and Astrocytes via a Pathway Requiring Tyrosine Kinase
`Neurons and Astrocytes via a Pathway Requiring Tyrosine Kinase
`and RhoAActivities," The Journal of Neuroscience; vol. 17, No. 14;
`and RhoAActivities,” The Journal of Neuroscience; vol. 17, No. 14;
`pp. 5316-5326; (Jul. 15, 1997).
`pp. 5316-5326; (Jul. 15, 1997).
`Bouchard, B., et al., "Effector Cell Protease Receptor-1, a Platelet
`Bouchard, B., et al., “Effector Cell Protease Receptor-1, a Platelet
`Activation-dependent
`Membrane
`Protein,
`Regulates
`Membrane
`Protein,
`Regulates
`Activation-dependent
`Prothrombinase-catalyzed Thrombin Generation," The Journal of
`Prothrombinase-catalyZed Thrombin Generation,” The Journal of
`Biological Chemistry; vol. 272, No. 14; pp. 9244-9251; (Apr. 4,
`Biological Chemistry; vol. 272, No. 14; pp. 9244-9251; (Apr. 4,
`1997).
`1997).
`Molino, M., et