Claims
- 1. A method for inhibiting proteolysis in a mammal, comprising administering to the mammal an effective amount of a compound having the Formula VII:
- 2. The method of claim 1, wherein a trypsin-like protease is inhibited.
- 3. The method of claim 1, wherein R1 is C6-10 ar(C1-4) alkyl, C6-10 aryl, C4-7 cycloalkyl(C1-4)alkyl, heterocycle or heterocyclo(C1-4)alkyl, any of which is optionally substituted; and wherein the heterocycle of said heterocycle or heterocyclo(C1-4)alkyl is a 5- to 7-member mono-cyclic, or 9-to 10-member bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from N, O and S.
- 4. The method of claim 1, wherein RI is C6-10 ar(C1-4) alkyl C6-10 aryl, C4-7 cycloalkyl(C1-4)alkyl, any of which is optionally substituted by 1-5 of hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C1-6 alkoxy, C6-10 ar(C1-6)alkoxy, C1-6 aminoalkyl, C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-6 hydroxyalkoxy, (C1-6)alkoxy(C2-6)alkoxy, mono- and di-C1-4 alkylamino (C2-6)alkoxy, C2-10 mono(carboxyalkyl)amino, bis(C2-10 carboxyalkyl) amino, C6-14 ar(C1-6) alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, C2-6 carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, or perfluoroethoxy.
- 5. The method of claim 1, wherein Z is —SO2— or a covalent bond.
- 6. The method of claim 1, wherein X is O.
- 7. A method of claim 1, wherein R12, R13, R14 and R15 are independently one of hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl.
- 8. A method of claim 1, wherein:
R1 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, any of which may be optionally substituted; Z is —SO2—, —OCO—, or —CO—; Het is selected from the group consisting of 138where R3 and R5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, carboxymethyl, alkoxycarbonylmethyl, —CO2Rx, —CH2ORx or —ORx,
where Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations; R12, R13, R14 and R15 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R12 and R13 are taken together to form —(CH2)y—, where y is 2 to 5 , while R14 and R15 are defined as above; or R14 and R15 are taken together to form —(CH2)q—, where q is 2 to 5, while R12 and R13 are defined as above; or R12 and R14 are taken together to form —(CH2)r—, where r is 0 or 1 to 4, while R13 and R15 are defined as above; and R6-R9, Ra, Rb, Rc, X, n and m are as defined in claim 1.
- 9. A method of inhibiting thrombin-induced platelet aggregation and clotting of fibrinogen in plasma, comprising administering to the mammal a compound of claim 1.
- 10. A method for inhibiting thrombin in blood comprising adding to the blood a compound of claim 1.
- 11. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to the blood a compound of claim 1.
- 12. A method for inhibiting thrombus formation in blood comprising adding to the blood a compound of claim 1.
- 13. A process for preparing an alkoxyguanidine compound of claim 1, comprising:
reacting a compound of Formula IX: 139or a salt thereof, with a compound of Formula X: 140where R3, R5, R12 R13, R14 R15, Ra, Rb Rc, n and m are as defined in claim 1, and R51 is hydrogen or Ar—Z—, where Ar is aryl, Z is as defined in claim 1, and provided that Ra, Rb and Rc are not hydrogen.
- 14. A method of treating pancreatitis, thrombosis, ischemia, stroke, restenosis, emphysema or inflammation in a mammal, comprising administering to the mammal an effective amount of a compound having the Formula VII:
- 15. The method of claim 14, wherein R1 is C6-10 ar(C1-4) alkyl, C6-10 aryl, C4-7 cycloalkyl(C1-4)alkyl, heterocycle or heterocyclo(C1-4)alkyl, any of which is optionally substituted; and wherein the heterocycle of said heterocycle or heterocyclo(C1-4)alkyl is a 5- to 7-member mono-cyclic, or 9- to 10-member bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from N, O and S.
- 16. The method of claim 14, wherein R1 is C6-10 ar(C1-4) alkyl, C6-10 aryl, C4-7 cycloalkyl(C1-4)alkyl, any of which is optionally substituted by 1-5 of hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C1-6 alkoxy, C6-10 ar(C1-6)alkoxy, C1-6 aminoalkyl, C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-6 hydroxyalkoxy, (C1-6)alkoxy(C2-6)alkoxy, mono- and di-C1-4 alkylamino (C2-6)alkoxy, C2-10 mono(carboxyalkyl)amino, bis(C2-10 carboxyalkyl) amino, C6-14 ar(C1-6) alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, C2-6 carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, or perfluoroethoxy.
- 17. The method of claim 14, wherein Z is —SO2— or a covalent bond.
- 18. The method of claim 14, wherein X is O.
- 19. A method of claim 14, wherein R12 R13, R14 and R15 are independently one of hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl.
- 20. A method of claim 14, wherein:
R1 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, any of which may be optionally substituted; Z is —SO2—, —OCO—, or —CO—; Het is selected from the group consisting of 144where R3 and R5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, carboxymethyl, alkoxycarbonylmethyl, —CO2Rx, —CH2ORx or —ORx,
where Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations; R12, R13, R14 and R15 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R12 and R13 are taken together to form —(CH2)y—, where y is 2 to 5 , while R14 and R15 are defined as above; or R14 and R15 are taken together to form —(CH2)q—, where q is 2 to 5, while R12 and R13 are defined as above; or R12 and R14 are taken together to form —(CH2)r—, where r is 0 or 1 to 4, while R13 and R15 are defined as above; and R6-R9, Ra, Rb, Rc, X, n and m are as defined in claim 14.
- 21. A method of treating thrombosis, comprising administering to the mammal an effective amount of a compound having the Formula VII:
- 22. The method of claim 21, wherein R1 is C6-10 ar(C1-4) alkyl, C6-10 aryl, C4-7 cycloalkyl(C1-4)alkyl, heterocycle or heterocyclo(C1-4)alkyl, any of which is optionally substituted; and wherein the heterocycle of said heterocycle or
heterocyclo(C1-4)alkyl is a 5- to 7-member mono-cyclic, or 9- to 10-member bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from N, O and S.
- 23. The method of claim 21, wherein Z is —SO2— or a covalent bond.
- 24. The method of claim 21, wherein X is O.
- 25. A method of claim 21, wherein R12, R13, R14 and R15 are independently one of hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl.
- 26. A method of claim 21, wherein:
R1 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, any of which may be optionally substituted; Z is —SO2—, —OCO—, or —CO—; Het is selected from the group consisting of 148where R3 and R5 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, carboxymethyl, alkoxycarbonylmethyl, —CO2Rx, —CH2ORx or —ORx,
where Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations; R12, R13, R14 and R15 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R12 and R13 are taken together to form —(CH2)y—, where y is 2 to 5, while R14 and R15 are defined as above; or R14 and R15 are taken together to form —(CH2)q—, where q is 2 to 5, while R12 and R13 are defined as above; or R12 and R14 are taken together to form —(CH2)r—, where r is 0 or 1 to 4, while R13 and R15 are defined as above; and R6-R9, Ra, Rb, Rc, X, n and m are as defined in claim 21.
- 27. In a device used in blood collection, blood circulation, and blood storage wherein said device includes an effective amount of a thrombin inhibiting compound or macromolecule as an anticoagulant, either embedded in, or physically linked to, one or more materials that form the structure of said device, the improvement comprising employing as said thrombin inhibitor one or more compounds having the Formula VII:
- 28. The device of claim 27, wherein said device is a catheter, blood dialysis machine, blood collection syringe, blood collection tube, blood line or extracorporeal blood circuit.
- 29. The device of claim 27, wherein said device is a stent that can be surgically inserted into a mammal.
Parent Case Info
[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60/079,107, filed Mar. 23, 1998, Appl. No. 60/067,324, filed Dec. 5, 1997, and Appl. No. 60/066,475, filed Nov. 26, 1997, the contents of all of which are fully incorporated by reference herein.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60079107 |
Mar 1998 |
US |
|
60067324 |
Dec 1997 |
US |
|
60066475 |
Nov 1997 |
US |
Divisions (3)
|
Number |
Date |
Country |
Parent |
09827292 |
Apr 2001 |
US |
Child |
10012445 |
Dec 2001 |
US |
Parent |
09482540 |
Jan 2000 |
US |
Child |
09827292 |
Apr 2001 |
US |
Parent |
09199167 |
Nov 1998 |
US |
Child |
09482540 |
Jan 2000 |
US |