Claims for Patent: 10,028,962

Summary for Patent: 10,028,962

Title:	2-amino-6-methy1-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,- 3-thiazol-4-yl amides
Abstract:	The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, ##STR00001## and the variable R.sup.1 is as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
Inventor(s):	Brodney; Michael Aaron (Newton, MA), Beck; Elizabeth Mary (Oxford, GB), Butler; Christopher Ryan (Canton, MA), Zhang; Lei (Auburndale, MA), O\'Neill; Brian Thomas (Haddam, CT), Barreiro; Gabriela (Sao Paulo, BR), LaChapelle; Erik Alphie (Uncasville, CT), Rogers; Bruce Nelsen (Belmont, MA)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	15/629,215
Patent Claims:	1. A method of treating Alzheimer's disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical combination, the pharmaceutical combination comprising a compound selected from the group consisting of N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; and N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer; and one or more additional pharmaceutical agent. 2. The method of claim 1 wherein the additional pharmaceutical agent is selected from the group consisting of an anti-obesity agent, an anti-diabetic agent, a lipid lowering agent, an anti-hypertensive agent, an acetylcholinesterase inhibitor, an antibody to amyloid-.beta., an amyloid-lowering or amyloid-inhibiting agent, an alpha-adrenergic receptor agonist, a beta-adrenergic blocking agent, an anticholinergic, an anticonvulsant, an antipsychotic, a calcium channel blocker, an O-methyltransferase inhibitor, a central nervous system stimulant, a corticosteroid, a dopamine receptor agonist or antagonist, a dopamine reuptake inhibitor, a gamma-aminobutyric receptor agonist, an immunosuppressant, an interferon, a muscarinic receptor agonist, a nicotinic receptor agonist, a norepinephrine reuptake inhibitor, a histamine 3 antagonist, a N-methyl-D-aspartate receptor antagonist, a monoamine oxidase inhibitor, a phosphodiesterase inhibitor, a serotonin 5-HT.sub.1A receptor antagonist, a serotonin 5-HT.sub.2C receptor agonist, a serotonin 5-HT.sub.4 receptor agonist/antagonist, a serotonin 5-HT.sub.3C receptor antagonist, a serotonin 5-HT.sub.6 receptor antagonist, a serotonin 5-HT reuptake inhibitor, a glycine transporter-1 inhibitor, a P450 inhibitor and an anti-tau agent. 3. The method of claim 2 wherein the additional pharmaceutical agent is an amyloid-lowering or amyloid-inhibiting agent which is selected from the group consisting of a BACE inhibitor, a gamma secretase modulator and a RAGE inhibitor. 4. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 5. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 6. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 7. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 8. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 9. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 10. The method of claim 1 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 11. A method of inhibiting the production of an A.beta. peptide in a patient, the method comprising administering to the patient a pharmaceutical combination, the pharmaceutical combination comprising a compound selected from the group consisting of N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; and N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer; and one or more additional pharmaceutical agent. 12. The method of claim 11 wherein the additional pharmaceutical agent is selected from the group consisting of an anti-obesity agent, an anti-diabetic agent, a lipid lowering agent, an anti-hypertensive agent, an acetylcholinesterase inhibitor, an antibody to amyloid-.beta., an amyloid-lowering or amyloid-inhibiting agent, an alpha-adrenergic receptor agonist, a beta-adrenergic blocking agent, an anticholinergic, an anticonvulsant, an antipsychotic, a calcium channel blocker, an O-methyltransferase inhibitor, a central nervous system stimulant, a corticosteroid, a dopamine receptor agonist or antagonist, a dopamine reuptake inhibitor, a gamma-aminobutyric receptor agonist, an immunosuppressant, an interferon, a muscarinic receptor agonist, a nicotinic receptor agonist, a norepinephrine reuptake inhibitor, a histamine 3 antagonist, a N-methyl-D-aspartate receptor antagonist, a monoamine oxidase inhibitor, a phosphodiesterase inhibitor, a serotonin 5-HT.sub.1A receptor antagonist, a serotonin 5-HT.sub.2C receptor agonist, a serotonin 5-HT.sub.4 receptor agonist/antagonist, a serotonin 5-HT.sub.3C receptor antagonist, a serotonin 5-HT.sub.6 receptor antagonist, a serotonin 5-HT reuptake inhibitor, a glycine transporter-1 inhibitor, a P450 inhibitor and an anti-tau agent. 13. The method of claim 12 wherein the additional pharmaceutical agent is an amyloid-lowering or amyloid-inhibiting agent which is selected from the group consisting of a BACE inhibitor, a gamma secretase modulator and a RAGE inhibitor. 14. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 15. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 16. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 17. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 18. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 19. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 20. The method of claim 11 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 21. A method of inhibiting .beta.-site amyloid precursor protein (APP) Cleaving Enzyme 1 (BACE1) in a patient, the method comprising administering to the patient a pharmaceutical combination, the combination comprising a compound selected from the group consisting of N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; and N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer; and one or more additional pharmaceutical agent. 22. The method of claim 21 wherein the additional pharmaceutical agent is selected from the group consisting of an anti-obesity agent, an anti-diabetic agent, a lipid lowering agent, an anti-hypertensive agent, an acetylcholinesterase inhibitor, an antibody to amyloid-.beta., an amyloid-lowering or amyloid-inhibiting agent, an alpha-adrenergic receptor agonist, a beta-adrenergic blocking agent, an anticholinergic, an anticonvulsant, an antipsychotic, a calcium channel blocker, an O-methyltransferase inhibitor, a central nervous system stimulant, a corticosteroid, a dopamine receptor agonist or antagonist, a dopamine reuptake inhibitor, a gamma-aminobutyric receptor agonist, an immunosuppressant, an interferon, a muscarinic receptor agonist, a nicotinic receptor agonist, a norepinephrine reuptake inhibitor, a histamine 3 antagonist, a N-methyl-D-aspartate receptor antagonist, a monoamine oxidase inhibitor, a phosphodiesterase inhibitor, a serotonin 5-HT.sub.1A receptor antagonist, a serotonin 5-HT.sub.2C receptor agonist, a serotonin 5-HT.sub.4 receptor agonist/antagonist, a serotonin 5-HT.sub.3C receptor antagonist, a serotonin 5-HT.sub.6 receptor antagonist, a serotonin 5-HT reuptake inhibitor, a glycine transporter-1 inhibitor, a P450 inhibitor and an anti-tau agent. 23. The method of claim 22 wherein the additional pharmaceutical agent is an amyloid-lowering or amyloid-inhibiting agent which is selected from the group consisting of a BACE inhibitor, a gamma secretase modulator and a RAGE inhibitor. 24. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 25. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 26. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 27. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 28. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 29. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 30. The method of claim 21 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 31. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; and N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer; one or more additional pharmaceutical agent; and a pharmaceutically acceptable vehicle, diluent or carrier. 32. The pharmaceutical composition of claim 31 wherein the additional pharmaceutical agent is selected from the group consisting of an anti-obesity agent, an anti-diabetic agent, a lipid lowering agent, an anti-hypertensive agent, an acetylcholinesterase inhibitor, an antibody to amyloid-.beta., an amyloid-lowering or amyloid-inhibiting agent, an alpha-adrenergic receptor agonist, a beta-adrenergic blocking agent, an anticholinergic, an anticonvulsant, an antipsychotic, a calcium channel blocker, an O-methyltransferase inhibitor, a central nervous system stimulant, a corticosteroid, a dopamine receptor agonist or antagonist, a dopamine reuptake inhibitor, a gamma-aminobutyric receptor agonist, an immunosuppressant, an interferon, a muscarinic receptor agonist, a nicotinic receptor agonist, a norepinephrine reuptake inhibitor, a histamine 3 antagonist, a N-methyl-D-aspartate receptor antagonist, a monoamine oxidase inhibitor, a phosphodiesterase inhibitor, a serotonin 5-HT.sub.1A receptor antagonist, a serotonin 5-HT.sub.2C receptor agonist, a serotonin 5-HT.sub.4 receptor agonist/antagonist, a serotonin 5-HT.sub.3C receptor antagonist, a serotonin 5-HT.sub.6 receptor antagonist, a serotonin 5-HT reuptake inhibitor, a glycine transporter-1 inhibitor, a P450 inhibitor and an anti-tau agent. 33. The pharmaceutical composition of claim 32 wherein the additional pharmaceutical agent is an amyloid-lowering or amyloid-inhibiting agent which is selected from the group consisting of a BACE inhibitor, a gamma secretase modulator and a RAGE inhibitor. 34. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrid- ine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 35. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy) pyrazine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 36. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-chloropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 37. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-fluoropyridine-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 38. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 39. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer. 40. The pharmaceutical composition of claim 31 in which the compound is N-{2-[(4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]- thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}-3-chloro-5-(difluoromethoxy)pyridine-- 2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

Details for Patent 10,028,962

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2034-04-10