Claims for Patent: 10,517,850

Summary for Patent: 10,517,850

Title:	Combination of TAFIa inhibitor with plasminogen activator
Abstract:	The present invention provides a pharmaceutical composition for treatment or prevention of thrombosis or embolism or a sequela thereof, comprising a particular TAFIa inhibitor and a plasminogen activator, the TAFIa inhibitor being administered in combination with the plasminogen activator, and a method for treating or preventing thrombosis or embolism or a sequela thereof, comprising administering a particular TAFIa inhibitor in combination with a plasminogen activator to a warm-blooded animal.
Inventor(s):	Noguchi; Kengo (Tokyo, JP), Ito; Yusuke (Tokyo, JP), Edo; Naoko (Tokyo, JP)
Assignee:	DAIICHI SANKYO COMPANY, LIMITED (Tokyo, JP)
Application Number:	15/736,933
Patent Claims:	1. A pharmaceutical composition for treatment or prevention of thrombosis or embolism or a sequela thereof, comprising a compound of formula (I): ##STR00004## or a pharmacologically acceptable salt thereof, and a plasminogen activator, wherein R is a hydrogen atom, a [(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]carbonyl group, a [1-(isobutyryloxy)ethoxy]carbonyl group, a [1-(2,2-dimethylpropanoyloxy)ethoxy]carbonyl group, a {1-[(cyclohexylcarbonyl)oxy]ethoxy}carbonyl group, or a (1-acetoxyethoxy)carbonyl group, and the pharmaceutical composition exhibits synergistic fibrinolytic activity. 2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are included in separate preparations. 3. The pharmaceutical composition of claim 1, wherein both the compound of formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are included in a single preparation. 4. The pharmaceutical composition of claim 1, wherein the plasminogen activator is a tissue plasminogen activator (t-PA). 5. The pharmaceutical composition of claim 4, wherein the t-PA is alteplase. 6. The pharmaceutical composition of claim 1, wherein the plasminogen activator is urokinase (u-PA). 7. The pharmaceutical composition of claim 1, wherein R is a hydrogen atom. 8. The pharmaceutical composition of claim 7, wherein the pharmacologically acceptable salt is a p-toluenesulfonate. 9. The pharmaceutical composition of claim 1, wherein R is a [1-(isobutyryloxy)ethoxy]carbonyl group. 10. The pharmaceutical composition of claim 9, wherein R is a [(1R)-1-(isobutyryloxy)ethoxy]carbonyl group. 11. The pharmaceutical composition of claim 1, wherein the thrombosis or embolism is acute coronary syndrome; venous thromboembolism; thrombosis or embolism occurring in the cardiovascular system after a surgical operation; thrombosis or embolism after an artificial joint replacement operation; inflammation-related intravascular disease; peripheral vascular disorder-derived or -related disease; tumor-related disease; or organ disorder attributed to thrombus or embolus. 12. The pharmaceutical composition of claim 11, wherein the thrombosis or embolism is myocardial infarction, stable angina, or unstable angina; deep vein thrombosis or pulmonary embolism; thrombosis or embolism occurring in the cardiovascular system after vessel revascularization, angioplasty, stent placement, or bypass surgery; thrombosis or embolism after a knee joint replacement operation or hip joint replacement operation; intravascular disease related to sepsis or disseminated intravascular coagulation syndrome (DIC); disease derived from or related to peripheral arterial occlusion (PAO), arteriosclerosis, or diabetes mellitus; disease related to solid cancer or blood cancer; or organ disorder attributed to pulmonary embolus, cerebral infarction, or renal infarction. 13. The pharmaceutical composition of claim 1, wherein the thrombosis or embolism is disease caused by contact with foreign matter in the body; or disease caused by contact between blood and a medical device outside the body. 14. The pharmaceutical composition of claim 13, wherein the thrombosis or embolism is disease caused by contact with a medical device. 15. The pharmaceutical composition of claim 14, wherein the thrombosis or embolism is disease caused by contact with a joint prosthesis used in joint replacement, a vascular catheter, a vascular prosthesis, an intravascular stent, or a prosthetic valve. 16. The pharmaceutical composition of claim 13, wherein the thrombosis or embolism is disease caused by contact between blood and a pump oxygenator used in a cardiac operation or a medical device used in hemodialysis. 17. The pharmaceutical composition of claim 1, wherein the thrombosis or embolism is myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, or peripheral arterial occlusion. 18. A method of treating or preventing thrombosis or embolism or a sequela thereof, comprising administering a compound of formula (I): ##STR00005## or a pharmacologically acceptable salt thereof, in combination with a plasminogen activator to a warm-blooded animal, wherein R is a hydrogen atom, a [(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]carbonyl group, a [1-(isobutyryloxy)ethoxy]carbonyl group, a [1-(2,2-dimethylpropanoyloxy)ethoxy]carbonyl group, a {1-[(cyclohexylcarbonyl)oxy]ethoxy}carbonyl group, or a (1-acetoxyethoxy)carbonyl group, and the method exhibits synergistic fibrinolytic activity. 19. The method of claim 18, wherein the compound of formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are included in separate preparations and are administered at the same time or different times. 20. The method of claim 18, wherein both the compound of formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are included and administered in a single preparation. 21. The method of claim 18, wherein the plasminogen activator is a tissue plasminogen activator (t-PA). 22. The method of claim 21, wherein the t-PA is alteplase. 23. The method of claim 18, wherein the plasminogen activator is urokinase (u-PA). 24. The method of claim 18, wherein R is a hydrogen atom. 25. The method of claim 24, wherein the pharmacologically acceptable salt is a p-toluenesulfonate. 26. The method of claim 18, wherein R is a [1-(isobutyryloxy)ethoxy]carbonyl group. 27. The method of claim 26, wherein R is a [(1R)-1-(isobutyryloxy)ethoxy]carbonyl group. 28. The method of claim 18, wherein the thrombosis or embolism is acute coronary syndrome; venous thromboembolism; thrombosis or embolism occurring in the cardiovascular system after a surgical operation; thrombosis or embolism after an artificial joint replacement operation; inflammation-related intravascular disease; peripheral vascular disorder-derived or -related disease; tumor-related disease; or organ disorder attributed to thrombus or embolus. 29. The method of claim 28, wherein the thrombosis or embolism is myocardial infarction, stable angina, or unstable angina; deep vein thrombosis or pulmonary embolism; thrombosis or embolism occurring in the cardiovascular system after vessel revascularization, angioplasty, stent placement, or bypass surgery; thrombosis or embolism after a knee joint replacement operation or hip joint replacement operation; intravascular disease related to sepsis or disseminated intravascular coagulation syndrome (DIC); disease derived from or related to peripheral arterial occlusion (PAO), arteriosclerosis, or diabetes mellitus; disease related to solid cancer or blood cancer; or organ disorder attributed to pulmonary embolus, cerebral infarction, or renal infarction. 30. The method of claim 18, wherein the thrombosis or embolism is disease caused by contact with foreign matter in the body; or disease caused by contact between blood and a medical device outside the body. 31. The method of claim 30, wherein the thrombosis or embolism is disease caused by contact with a medical device. 32. The method of claim 31, wherein the thrombosis or embolism is disease caused by contact with a joint prosthesis used in joint replacement, a vascular catheter, a vascular prosthesis, an intravascular stent, or a prosthetic valve. 33. The method of claim 30, wherein the thrombosis or embolism is disease caused by contact between blood and a pump oxygenator used in a cardiac operation or a medical device used in hemodialysis. 34. The method of claim 18, wherein the thrombosis or embolism is myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, or peripheral arterial occlusion. 35. The method of claim 18, wherein the warm-blooded animal is a human.

Details for Patent 10,517,850

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2035-06-17
Genentech, Inc.	ACTIVASE	alteplase	For Injection	103172	11/13/1987		2035-06-17
Genentech, Inc.	CATHFLO ACTIVASE	alteplase	For Injection	103172	09/04/2001		2035-06-17