We claim:
1. A method of treating thrombosis in a mammal comprising administering to the mammal a pharmaceutical composition that inhibits thrombosis in the mammal, wherein the pharmaceutical composition contains a therapeutically-effective amount of a small organic compound that is potent and selective for inhibiting Factor XIa so that the differential rate of percent inhibition of thrombosis in the mammal is greater than the differential rate of percent increase in bleeding time.
2. The method of claim 1, in which the differential rate of percent inhibition of thrombosis weight in the mammal is at least 50% while the differential rate of percent increase in bleeding time is not increased or just measurably increased by less than 30%.
3. The method of claim 1, in which the small organic compound has an IC50 for inhibiting Factor XIa of less than 10 nM.
4. The method of claim 1, in which the small organic compound has an IC50 for inhibiting Factor XIa of less than 6 nM.
5. The method of claim 1, in which the small organic compound has an IC50 for inhibiting Factor XIa of less than 3 nM.
6. The method of claim 1, in which the small organic compound is highly selective for inhibiting Factor XIa.
7. A method of treating thrombosis in a mammal comprising administration of a small organic compound to the mammal having sufficient selectivity and potency for inhibition of Factor XIa, wherein the administration of the small molecule inhibits thrombosis in the mammal with no substantial effect on bleeding times in the mammal.
8. The method of claim 7, in which the small organic compound has an IC50 for inhibiting Factor XIa of less than 6 nM.
9. The method of claim 7, in which the small organic compound has an IC50 for inhibiting Factor XIa of less than 3 nM.
10. The method of claim 7, in which the small organic compound is highly selective for inhibiting Factor XIa.
11. A method of inhibiting Factor XIa in a mammal by administration of a small organic compound with an IC50 for inhibiting Factor XIa of less than 120 nM.
12. The method of claim 11, wherein the small organic compound has an IC50 for inhibiting Factor XIa of less than 10 nM.
13. The method of claim 11, wherein the small organic compound has an IC50 for inhibiting Factor XIa of less than 6 nM.
14. The method of claim 11, wherein the small organic compound has an IC50 for inhibiting Factor XIa of less than 1 nM.
15. A method of inhibiting Factor XIa in a mammal by administration of a small organic compound having the formula (I):
27
wherein:
R1 and R2 are hydrogen;
R3 is hydrogen or CH3;
R4 is selected from hydrogen, CH3, CO2R7, C(O)NR8R9, phenyl, benzyl, and phenylethyl, wherein R7 is hydrogen, C1-6alkyl, benzyl, or CH(OCOCH3)CH3; and each R4 group is optionally substituted with one to two R12;
Y is C(O) or SO2; wherein when Y is C(O), then R6 is C1-6alkyl, aryl, heteroaryl, or NR10R11, and when Y is SO2, then R6 is aryl or heteroaryl; and each R6 group is optionally substituted with one to two R12;
R8 and R9 are individually selected from hydrogen and C1-6alkyl, or R8 and R9 taken together form a five or six membered heterocyclo ring optionally substituted with one to two R12 and up to one R13;
R10 and R11 are individually selected from hydrogen, phenyl, or C1-6alkyl optionally substituted with phenyl, or R10 and R11 taken together form a five or six membered heterocyclo ring optionally substituted with one to two R12 and up to one R13;
R12 is selected from hydrogen, halogen, trifluoromethyl, trifluoromethoxy, lower alkyl, amino, lower alkylamino, CO2H, CO2(lower alkyl), or a five or six membered saturated or unsaturated heterocyclo having up to two nitrogen heteroatoms;
R13 is selected from C(O)(C1-6alkyl), CO2(C1-6alkyl), C(O)NH(C1-6alkyl), and five or six membered heterocyclo optionally substituted with one to two R14; and
R14 is selected from hydrogen, phenyl, or C1-6alkyl optionally substituted with phenyl;
or a progdrug carbamate thereof wherein at least one of R1 and R2 is COOR, wherein R is hydrogen, C1-6alkyl, benzyl, or CH(OCOCH3)CH3, or a pharmaceutically-acceptable salt or hydrate of said compound or prodrug carbamate.
16. The method of claim 15, wherein the small organic compound has the formula (Ia):
28
wherein:
R3 is hydrogen or CH3;
R4 is CH3, CO2H, CO2(C1-4alkyl),
29
Y is C(O) or SO2; wherein:
when Y is C(O), then R6 is methyl, ethyl propyl,
when Y is SO2, then R6 is selected from
30
and
R12 is selected from hydrogen, lower alkyl, amino, lower alkylamino, CO2H, and CO2(lower alkyl); or a progdrug carbamate thereof wherein at least one of R1 and R2 is COOR, wherein R is hydrogen, C1-6alkyl, benzyl, or CH(OCOCH3)CH3, or a pharmaceutically-acceptable salt or hydrate of said compound or prodrug carbamate; wherein the compound has an IC50 for inhibiting Factor XIa of less than 20 nM.
17. The method of claim 15, wherein the small organic compound has the formula (Ib),
31
wherein:
R6 is selected from:
32
or a progdrug carbamate thereof wherein at least one of R1 and R2 is COOR, wherein R12 is defined as above; R is hydrogen, C1-6alkyl, benzyl, or CH(OCOCH3)CH3, or a pharmaceutically-acceptable salt or hydrate of said compound or prodrug carbamate; wherein the compound has an IC50 for inhibiting Factor XIa of less than 3 nM.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An air pump, comprising a cylinder with a non-circular configuration in a cross section, a bar having a handle and an adapter at opposite ends respectively, a piston having a configuration fitted with the cylinder and connected to the adapter, a nozzle communicated with the cylinder and a pivot provided between the handle and the bar or between the bar and the piston, such that the handle is free for rotation relative to the cylinder.
2. The air pump as defined in claim 1, wherein the pivot is between the bar and the adapter having a C-shaped lock ring and a post on the bar and the adapter respectively, which the post has an annular slot to be engaged with the lock ring, such that the bar is connected to the adapter and free for rotation.
3. The air pump as defined in claim 2, wherein the post has a threaded bore at an end thereof to be mated with the bar and the lock ring is bonded to a top of the adapter.
4. The air pump as defined in claim 1, wherein the pivot is between the bar and the adapter having a C-shaped lock ring and a post on the bar and the adapter respectively, which a space is left under the lock ring and the post has an annular slot to be engaged with the lock ring and a rim under the slot to be received in the space, such that the bar is connected to the adapter and free for rotation.
5. The air pump as defined in claim 4, wherein the post is bonded to the bar and the lock ring is bonded to a top of the adapter with the space between the adapter and the lock ring.
6. The air pump as defined in claim 1, wherein the adapter has a ring to be connected to the piston.
7. The air pump as defined in claim 1, wherein the adapter has a configuration fitted with the configuration of the cylinder.