Title:
INHIBITORS OF FACTOR Xa
Document Type and Number:
WIPO Patent Application WO/2000/071515
Kind Code:
A2
Abstract:
Compounds, e.g. described in Table (1), their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.
Inventors:
ZHU BING-YAN
SCARBOROUGH ROBERT M
SCARBOROUGH ROBERT M
Application Number:
PCT/US2000/014193
Publication Date:
November 30, 2000
Filing Date:
May 24, 2000
Export Citation:
Assignee:
COR THERAPEUTICS INC (US)
International Classes:
A61K31/155; A61K31/18; A61K31/275; A61K31/401; A61K31/402; A61K31/451; A61P7/02; A61P9/00; A61P9/04; A61P9/10; C07C311/46; C07D207/16; C07D211/60; C07D241/04; C07D243/08; C07D401/04; C07D403/04; C07D413/04; (IPC1-7): C07D207/00
Domestic Patent References:
| WO1998006694A1 | 1998-02-19 | |||
| WO1998028269A1 | 1998-07-02 |
Other References:
WALLIS R B: "INHIBITORS OF COAGULATION FACTOR XA: FROM MACROMOLECULAR BEGINNINGS TO SMALL MOLECULES" CURRENT OPINION IN THERAPEUTIC PATENTS,, 1 August 1993 (1993-08-01), pages 1173-1179, XP000653726 ISSN: 0962-2594
Attorney, Agent or Firm:
MORGAN, LEWIS & BOCKIUS LLP (S. 1800 M. Street N.W. Washington, DC, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:
| 1. | A compound according to the formula I: AYDEGJZL wherein: A is selected from: (a) C,C6alkyl; (b) C3C8cycloalkyl; (c) phenyl, which is independently substituted with 02 R'subsituents; (d) naphthyl, which is independently substituted with 02 R'subsituents; and (e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 02 R'subsituents; R'is selected from: Halo, C26alkynyl,C38cycloalkyl,C04alkylC3C26alkenyl, 8cycloalkyl,CN, NO2, (CH2)mNR2R3, SO2NR2R3, SO2R2, CF3, OR2, and a 5 6 membered aromatic heterocyclic system containing from 14 heteroatoms selected from N, O and S, wherein from 14 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, ClC4alkyl,CN Cl 4alkyl, C26alkenyl, C2 6alkynyl, andNO2;C04alkylC38cycloalkyl R2 and R3 are independently selected from the group consisting of : H, C26alkynyl,C38cycloalkyl,C04alkylC38cycloalkyl,C26alkenyl, C04alkylphenyl and C04alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C14alkyl, C26alkenyl, C26alkynyl, C38cycloalkyl, C04alkyIC38cycloalkyl,CN, and NO2; m is an integer of 02; Y is a member selected from the group consisting of : a direct link,C (=O),N (R4),C (=O)N (R4), N (R4)C (=O),SO2,O, N(R4)SO2;SO2N(R4)and is selected from: H, C26alkynyl,C38cycloalkyl,C04alkylC38cycloalkyl,C26alkenyl, CO4alkylphenyl and CO4alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, Cl4alkyl, C38cycloalkyl,C04alkylC38cycloalkyl,Cn,andC26alkenyl,C26alkynyl, NO2 ;. |
| 2. | D is a direct link or is a member selected from the group consisting of : (a) phenyl, which is independently substituted with 0. |
| 3. | R'a subsituents; (b) naphthyl, which is independently substituted with 0. |
| 4. | R'e subsituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0. |
| 5. | R'a subsituents; R1a is selected from: Halo, C26alkynyl,C38cycloalkyl,C04alkylC3C26alkenyl, NO2,(CH2)mNR2aR3a,SO2NR2aR3a,SO2R2a,CF3,OR2a,and8cycloalkyl,CN, a 56 membered aromatic heterocyclic system containing from 14 heteroatoms selected from N, O and S, wherein from 14 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C, 4alkyll C26alkenyl, C2 6alkynyl, CNandNO2;C04alkylC38cycloalkyl, R2a and Ruz are independently selected from the group consisting of : H, C26alkynyl,C308cycloalkyl,C04alkylC38cycloalkyl,C26alkenyl, C04alkylphenyl and C04alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, Cl4alkyl, C38cycloalkyl,C04alkylC38cycloalkyl,CNandC26alkenyl,C26alkynyl, NO2;. E is a member selected from the group consisting of : N(R5)C(=O)N(R6),SO2N(R5),N(R5)C(=O),C(=O)N(R5), N (R')SO2N (R6)andN (R5)SO2N (R6)C (=O); Rs and R6 are independently selected from: H, C26alkynyl,C38cycloalkyl,C04alkylC38cycloalkyl,C26alkenyl, C04alkylheteroaryl,C14almkylCOOHandC04alkylphenyl,C04alkylnaphthyl, Cl4alkylCOOCl4alkyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C14alkyl, C38cycloalkyl,C04alkylC38cycloalkyl,CNandC26alkenyl,C26alkynyl, Nz G is a member selected from the group consisting of from: a direct link,CR7R8andCR'aR8aCR7aR8b wherein R7, R8, R7a, R8a, R7b and R8b are independently a member selected from from the group consisting of: hydrogen, C26alkynyl,C38cycloalkyl,C04alkylC3C26alkenyl, C04alkylnaphthyl,OR9,C04alkylCOOR9,8cycloalkyl,C04alkylphenyl, C04alkylC(=O)NR9R10,C04alkylC(=O)NR9CH2CH2OR10, N(R9)C(=O)\R10,C04alkylC(=O)NR9(CH2CH2OR10)2,N(R9)COR10, N (R9) SO2R'°, and a naturally occurring or synthetic amino acid side chain, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C14alkyl, C26alkenyl, C26alkynyl, C3 8cycloalkyl, CO4alkylC38cycloalkyl,CN andNO2; R9 and R'° are independently selected from: H, C14alkyl, C04alkylphenyl and CO4alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C26alkynyl,C38cycloalkyl,C04alkylC3C26alkenyl, 8cycloalkyl,CN andNO2, and wherein R9 and R'° taken together can form a 58 membered heterocylic ring; J is a member selected from the group consisting of : wherein the ring carbons or the second ring nitrogen of the amino ring structure and/or the ring carbons on the alkylene bridging groups attached to the amino ring structure may be independently substituted by a total of 0 to 4 R11, R11a, R11b and R11c groups; R11, R'la, R11b and R11c are independently a member selected from the group consisting of: hydrogen,OH,OCI4alkyl,Cl4alkyl, C26alkenyl, C26alkynyl, C3 8cycloalkyl, C04alkylC38cycloalkyl, C04alkylnaphthyl, C04alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC,alkyl, CH2COOC, 4alkylphenyl and CH2COOC14alkylnaphthyl ; Z is a member selected from the group consisting of : (a) phenyl, which is independently substituted with 02 R'b subsituents; (b) naphthyl, which is independently substituted with 02 Rlb subsituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 02 Rlb subsituents; Rlb is selected from: Halo, C26alkynyl,C38cycloalkyl,C04alkylC3C26alkenyl, 8cycloalkyl,CN,NO2, NR'"R"',SONRV,SO,R",CF,OR'",0CH, CH2OR2b, OCH2COOR2b, N (R2b)CH2CH2OR2b, N (CH2CH2OR2b) 2, N (R2b)C (=O) R3b, N (R)S02R,and a 56 membered aromatic heterocyclic system containing from 14 heteroatoms selected from N, O and S, wherein from 14 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C26alkynyl,C38cycloalkyl,C04alkylC3C26alkenyl, gcycloalkyl,CN andNO2; R2b and R3b are independently selected from the group consisting of : H, C26alkynyl,C38cycloalkyl,C04alkylC38cycloalkyl,C26alkenyl, CO4alkylphenyl and C04alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, Cl4alkyl, C38cycloalkyl,C04alkylC38cycloalkyl,CNandC26alkenyl,C26alkynyl, NO2; L is selected from: C(=O)NR12R13,(CH2)nNR12R13,C(=NR12)NR12R13,NR12R13,OR12,H,CN, NR12C(=NR12)R13;NR12C(=NR12)NR12R13,and R12 and independentlyselectedfrom:are NR14R15,C14alkyl,C04alkylphenyl,C04alkylnaphthyl,hydrogen,OR14, COOCl4alkyl, COOCO4alkylphenyl and COOC04alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C14alkyl, C26alkenyl, C26alkynyl, C38cycloalkyl, Co, alkylC3_8cycloalkyl,CN, andNO2; ; R'4 and Rus are independently selected from: H, C26alkynyl,C38cycloalkyl,C04alkylC38cycloalkyl,C26alkenyl, CO4alkylphenyl and C04alkylnaphthyl, wherein from 14 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C14alkyl, C26alkenyl, C26alkynyl, C38cycloalkyl, CO4alkylC38cycloalkyl,CN, and NO2; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. |
| 6. | 2 A compound of claim 1, wherein: A is selected from: (a) C,C6alkyl; (b) C3Cgcycloalkyl; (c) phenyl, which is independently substituted with 02 R'subsituents; (d) naphthyl, which is independently substituted with 02 R'subsituents; and (e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 02 R'subsituents; R'is selected from: halo, C14alkyl, CN, (CH2)mNR2R3, SO2NR2R3, SO2R2, CF3, OR2, and a 56 membered aromatic heterocyclic system containing from 14 heteroatoms selected from N, O and S; R2 and R3 are independently selected from the group consisting of : H, Cl4alkyl and Chalky laryl, m is an integer of 02; Y is a member selected from the group consisting of: a direct link,C (=O),N (R4),C (=O)N (R4),N (R4)C (=O),SO2,O, S02N (R4)andN (R4)SO2; R4 is selected from: H, Cl4alkyl and C04alkylaryl ;. D is absent or is a member selected from the group consisting of : (a) aryl, which is independently substituted with 02 R'a subsituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0 2 R'a subsituents; R1a is selected from: Halo, NO2,(CH2)mNR2aR3a,SO2NR2aR3a,SO2R2a,CF3,OR2a,CN, and a 56 membered aromatic heterocyclic ring containing from 14 heteroatoms selected from N, O and S; Wa and Wa are independently selected from the group consisting of : H, Cl4alkyl and C04alkylaryl ; E is a member selected from the group consisting of : N(R5)C(=O),SO2N(R5),N(R5)C(=O)N(R6), N (R')SO2N (R6)andN (R5)SO2N (R6)C (=O); W and R6 are independently selected from: H, C04alkylheteroaryl,C14alkylCOOHandC04alkylaryl, C14alkylCOOC14alkyl; G is a member selected from the group consisting of: a direct andCR7aR8aCR7aR8b CR7R8 wherein R7, R8, R7a, Rua, R7b and R8b are independently a member selected from from the group consisting of: hydrogen, C04alkylaryl,OR9,C04alkylC38cycloalkyl, C04alkylCOOR9, C04alkylC(=O)NR9R10, N(R9)COR10, N(R9) C (=O) R'°, N (R9) S02R'°, and common amino acid side chains; R9 and R'° are independently selected from: H, Cl4alkyl and CO4alkylaryl; J is a member selected from the group consisting of : wherein the ring carbons or the second ring nitrogen of the amino ring structure and/or the ring carbons on the alkylene bridging groups attached to the amino ring structure may be independently substituted by a total of 0 to 4 R", R"a, R"b and RllC groups; R11, Ralla, R'lb and R"'are independently a member selected from the group consisting of : OC14alkyl,C14alkyl,C26alkenyl,C26alkynyl,C3hydrogen,OH, 8cycloalkyl, C04alkylnaphthyl,C04alkylphenyl, CO4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC,alkyl, CH2COOC, 4alkylphenyl and CH2COOC, 4alkylnaphthyl; Z is a member selected from the group consisting of: (a) aryl, which is independently substituted with 02 R'b subsituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0 2 Rlb subsituents; Rlb is selected from: halo, NO2,NR2bR3b,SO2NR2bR3b,So2R2b,CF3,OR2b,OCH2 CN, N(R2b)CH2CH2OR2b,N(CH2CH2OR2b)2,CH2OR2b,OCH2COOR2b, N (R2b)C(=O)R3b, N (R2b)S02R3b, and a 56 membered aromatic heterocyclic ring containing from 14 heteroatoms selected from N, O and S; Wb and R3b are independently selected from the group consisting of : H, C04alkylaryl;and L is selected from: C(=O)NR12R13,(CH2)nNR12R13,C(=NR12)NR12R13,NR12R13,OR12,H,CN, NR12C(=NR12)R13;NR12C(=NR12)NR12R13and R13R12and are independently selected from: NR14R15,C14alkyl,C04alkylarylCOOC14alkyl,andhydrogen,OR14, COOCO4alkylaryl; and R'4 and R'S are independently selected from: H andC, 4alkyl. |
| 7. | 3 A compound of claim 1, wherein: A is selected from: (a) phenyl, which is independently substituted with 02 R'subsituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0 2 R'subsituents; R'is selected from: halo, (CH2) mNR2R3, S02NR2R3 and SO2R2; W and R3 are independently selected from the group consisting of : H andC, 4alkyl; Y is a member selected from the group consisting of : a direct link,C (=O),SO2and0; D is a member selected from the group consisting of : (a) phenyl, which is independently substituted with 02 R'a subsituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0 2 R'a subsituents; Rla is selected from: Halo and Cl4alkyl; R2a and R3a are independently selected from the group consisting of : H, C04alkylaryl; E is a member selected from the group consisting of : N (R')C (=O) andC (=O)N (R) ; R5 and R6 are independently selected from: H, andC04alkylheteroaryl;C04alkylaryl G is a member selected from the group consisting of: a direct andCR7aR8aCR7aR8b CR7R8 wherein R7, R8, R7a,R8a,R7b and R8b are independently a member selected from from the group consisting of: hydrogen, C04alkylaryl,OR9,C04alkylC38cycloalkyl, NR9R10,C04alkylC(=O)NR9CH2CH2O C04alkylCOOR9,C04alkylC(=O) R10, C04alkylC (=O) NR9 (CH2CH2OR'°) 2,N (R9) COR'°,N (R9) C (=O) R'°, N(R9)SO2R10, and common amino acid side chains; R9 and R'° are independently selected from: H and Cl4alkyl, wherein the NR9R'° group of R7, R8, R7a, R8a, R7b and R8b is optionally cyclized to form a 58 membered heterocyclic group; J is a member selected from the group consisting of : wherein the ring carbons or the second ring nitrogen of the amino ring structure may be substituted by a total of 0 to 2 R"and R" groups; R", Ralla, R'"* and R11c are independently a member selected from the group consisting of : OC14alkyl,C14alkyl,C26alkenyl,C04alkylaryl,andahydrogen,OH, CO4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; Z is a member selected from the group consisting of : (a) phenyl, which is independently substituted with 02 Rlb subsituents; (b) an aromatic heterocyclic ring having from 5 to 10 ring atoms, wherein 1 4 ring atoms are selected from N, O and S, and wherein the ring may be subsituted independently by from 02 Rlb subsituents; and (c) a fused aromatic bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 14 ring atoms of the ring system are selected from N, O and S, wherein the bicyclic ring system may be substituted with 02 Rlb subsituents; Rlb is selected from: halo, C, 4alkyl, OH, OBn, OCH2CH2OH, OCH2CH2OCH3, OCH2COOH, OCH2C (=O)OCH3, NH2, NHCH2CH2OCH3, NHC (=O)OCH3, and NHS02CH3; L is selected from: H, andC(=NR12)NR12R13;and(CH2)nNR12R13 R12 and R13 are independently selected from: hydrogen and Cl4alkyl. |
| 8. | A compound of claim 1, wherein: A is a member selected from the group consisting of : D is a member selected from the group consisting of : E is a member selected from the group consisting of: : C (=O)NH,C (=O)N (CH3), C (=O)N (Bn),NHC (=O),N (CH3) C (=O) andN (Bn) C (=O) ; G is a member selected from the group consisting of: a direct link,CH (NH2)CH2,CH(NH (C (=O)CH3))CH2, CH (NH (C (=O)Ph))CH2,CH (C (=O)OR8),CH (R'), CH2CH(C(=O)N(R8,R8));CH2CH(C(=O)OR8),and R7 is a member selected from the group consisting of : H, phenyl, Bn,Oloweralkyl and cycohexyl; R8 is a member selected from the group consisting of : H, Cl 6alkyl,Oloweralkyl and C36cycloalkyl; J is a member selected from the group consisting of : wherein the second ring nitrogen of the amino ring structure may be substituted by a R'"group ; R11c is a member selected from the group consisting of : H, methyl, phenyl and benzyl; and Z and L taken together are a member selected from the group consisting of :. |
| 9. | A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 1. |
| 10. | A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 2. |
| 11. | A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 3. |
| 12. | A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 4. |
| 13. | A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 1. |
| 14. | The method of claim 9, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring postthrombolytic therapy or postcoronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparininduced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intraaortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. |
| 15. | A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 2. |
| 16. | The method of claim 11, wherein the condition is selected from the group consisting of : acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring postthrombolytic therapy or postcoronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparininduced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intraaortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. |
| 17. | A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 3. |
| 18. | The method of claim 13, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring postthrombolytic therapy or postcoronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparininduced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intraaortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. |
| 19. | A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 4. |
| 20. | The method of claim 15, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring postthrombolytic therapy or postcoronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparininduced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intraaortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. |
| 21. | A method for inhibiting the coagulation of biological samples, comprising the administration of a compound of claim 1. |
| 22. | A method for inhibiting the coagulation of biological samples, comprising the administration of a compound of claim 2. |
| 23. | A method for inhibiting the coagulation of biological samples, comprising the administration of a compound of claim 3. |
| 24. | A method for inhibiting the coagulation of biological samples, comprising the administration of a compound of claim 4. |
Description:
FURTHER INFORMATION CONTINUE FROM PCTnSA/210 Continuation of Box 1. 2 Present claims 1-3 relate to an extremely large number of possible compounds. Support within the meaning of Article 6 PCT and/or disclosure within the meaning of Article 5 PCT is to be found, however, for only a very small proportion of the compounds claimed. In the present case, the claims so lack support, and the application so lacks disclosure, that a meaningful search over the whole of the claimed scope is impossible.
Consequently, the search has been carried out for those parts of the claims which appear to be supported and disclosed, namely those parts relating to the compounds as indicated in the tables 1-29c and to claim 4.
The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure. INTERNATIONAL SEARCH REPORT Irn ional Application No IiNormatlon on peteM family members PCT/US 00/14193 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9806694 A 19-02-1998 AU 4064597 A 06-03-1998 EP 0934265 A 11-08-1999 WO 9828269 A 02-07-1998 AU 5602098 A 17-07-1998 CN 1246847 A 08-03-2000 EP 0946508 A 06-10-1999 HR 970698 A 31-10-1998 LT 99076 A, B 25-02-2000 Lit 12430 A 20-02-2000 LU 12430 B 20-07-2000 NO 992633 A 20-08-1999 PL 334250 A 14-02-2000 SI 20017 A 29-02-2000 US 6020357 A 01-02-2000 BR 9714073 A 09-05-2000
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