1. A memory structure comprising;
a) a substrate;
b) a plurality of bottom electrodes overlying the substrate;
c) a plurality of top electrodes overlying the bottom electrodes; and
d) a continuous active layer interposed between the plurality of top electrodes and the plurality of bottom electrodes, wherein the continuous active layer is a perovskite material.
2. The memory structure of claim 1, wherein the bottom electrodes comprise a bottom electrode material that allows for epitaxial formation of the continuous active layer overlying the bottom electrodes.
3. The memory structure of claim 2, wherein the bottom electrode material is YBCO.
4. The memory structure of claim 1, wherein the bottom electrode material is platinum.
5. The memory structure of claim 1, wherein the continuous active layer is a colossal magnetoresistance (CMR) material.
6. The memory structure of claim 1, wherein the continuous active layer is Pr0.7Ca0.3MnO8 (PCMO).
7. The memory structure of claim 1, wherein the continuous active layer is Gd0.7Ca0.3BaCo2O5+5.
8. The memory structure of claim 1, wherein the substrate comprises an amorphous material, a polycrystalline material or a crystalline material.
9. The memory structure of claim 8, wherein the substrate comprises Si, LaAlO3, or TiN.
10. The memory structure of claim 1, wherein the plurality of bottom electrodes comprise substantially parallel rows.
11. The memory structure of claim 1, wherein the plurality of top electrodes comprise substantially parallel lows.
12. The memory structure of claim 1, wherein the plurality of bottom electrodes and the plurality of top electrodes overlying the plurality of bottom electrodes form a cross point array.
13. The memory structure of claim 12, wherein the plurality of top electrodes overlie the plurality of bottom electrodes at a substantially ninety degree angle.
14. The memory structure of claim 1, wherein the plurality of bottom electrodes is between about 5 nm and 500 nm thick.
15. The memory structure of claim 1, wherein the continuous active layer is between about 5 nm and 600 nm thick.
16. The memory structure of claim 1, wherein the plurality of top electrodes comprise platinum, copper, silver, or gold.
17. A memory structure comprising;
a) a substrate;
b) a plurality of bottom electrodes overlying the substrate, wherein the plurality of bottom electrodes comprise substantially parallel rows;
c) a plurality of top electrodes, which comprise substantially parallel rows, overlying the bottom electrodes at a substantially ninety degree angle, whereby a cross point is formed at each point where one of the plurality of top electrodes crosses over one of the plurality of bottom electrodes; and
d) a continuous active layer interposed between the plurality of top electrodes and the plurality of bottom electrodes and extending through more than one cross point.
18. The memory structure of claim 17, wherein the continuous active layer is Pr0.7Ca0.3MnO3 (PCMO).
19. The memory structure of claim 17, wherein the continuous active layer is Gd0.7Ca0.3BaCo2O5+5.
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 oral dosage form of a compound selected from boronic acids which have a neutral thrombin PI domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and salts, prodrugs and prodrug salts of such acids, the dosage form comprising a solid phase formulation comprising the compound and being adapted for reconstitution of the formulation to form a liquid preparation.
2. The dosage form of claim 1 wherein the thrombin P1 domain comprises a neutral aminoboronic acid residue.
3. The dosage form of claim 1 wherein the boronic acid is of formula (I):
wherein
Y comprises a moiety which, together with the fragment \u2014CH(R9)\u2014B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R9 is \u2014(CH2)m\u2014W where m is from 2, 3, 4 or 5 and W is \u2014OH or halogen, wherein halogen is F, Cl, Br or I.
4. The dosage form of claim 3 wherein R9 is an alkoxyalkyl group.
5. The dosage form of claim 3 wherein Y comprises
an amino group bonded to structural fragment \u2014CH(R9)\u2014B(OH)2, and
a hydrophobic moiety which is linked to said amino group and which, together with said structural fragment, has affinity for the substrate binding site of thrombin.
6. The dosage form of claim 5 wherein Y comprises an amino acid which binds to the S2 subsite of thrombin, the amino acid being N-terminally linked to a moiety which binds the S3 subsite of thrombin.
7. The dosage form of claim 6 wherein Y is an optionally N-terminally protected dipeptide which binds to the S3 and S2 binding sites of thrombin and the peptide linkages in the acid are optionally and independently N-substituted by a C1-C13 hydrocarbyl optionally containing in-chain or in-ring nitrogen, oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl.
8. The dosage form of claim 7 wherein the S3-binding amino acid residue is of (R) configuration, the S2-binding residue is of (S) configuration, and the fragment \u2014NHCH(R9)\u2014B(OH)2 is of (R) configuration.
9. The dosage form of claim 1 wherein said compound is a pharmaceutically acceptable base addition salt of a said acid.
10. An oral pharmaceutical dosage form adapted to be reconstituted either
prior to administration into a liquid for oral administration, or
in the mouth,
and comprising a compound selected from boronic acids of formula (III) and salts, prodrugs and prodrug salts thereof:
where:
X is H (to form NH2) or an amino-protecting group;
aa1 is an amino acid having a hydrocarbyl side chain containing no more than 20 carbon atoms and comprising at least one cyclic group having up to 13 carbon atoms;
aa2 is an imino acid having from 4 to 6 ring members; and
R1 is a group of the formula \u2014CH2)s-Z, where s is 2, 3 or 4 and Z is \u2014OH, \u2014OMe, \u2014OEt or halogen, wherein halogen is F, Cl, Br or I.
11. The dosage form of claim 10 wherein aa1 is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof.
12. The dosage form of claim 10 wherein aa2 is a residue of an imino acid of formula (IV)
where R11 is \u2014CH2\u2014, \u2014CH2\u2014CH2\u2014, \u2014CH2\u2550CH2\u2014, \u2014S\u2014CH2\u2014, \u2014S\u2014C(CH3)2\u2014 or \u2014CH2\u2014CH2\u2014CH2\u2014, which residue, when the ring contained therein is 5- or 6-membered, is optionally substituted at one or more \u2014CH2\u2014 groups by from 1 to 3 C1-C3 alkyl groups.
13. The dosage form of claim 10 wherein aa1 is of (R)-configuration, aa2 is of (S)-configuration and the fragment \u2014NH\u2014CH(R1)\u2014B(OH)2 is of (R)-configuration.
14. The dosage form of claim 10 wherein R1 is 2-bromoethyl, 2-chloroethyl, 2-methoxyethyl, 3-bromopropyl, 3-chloropropyl or 3-methoxypropyl.
15. The dosage form of claim 10 where X is R6\u2014(CH2)p\u2014C(O)\u2014, R6\u2014(CH2)p\u2014S(O)2\u2014, R6\u2014(CH2)p\u2014NH\u2014C(O)\u2014 or R6\u2014(CH2)p\u2014O\u2014C(O)\u2014 wherein p is 0, 1, 2, 3, 4, 5 or 6 and R6 is H or a 5 to 13-membered cyclic group optionally substituted by one or more halogens andor by 1, 2 or 3 substituents selected from amino, nitro, hydroxy, a C5-C6 cyclic group, C1-C4 alkyl and C1-C4 alkyl containing, andor linked to the cyclic group through, an in-chain O, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C5-C6 cyclic group.
16. The dosage form of claim 10 wherein the boronic acid is of formula (VIII):
X\u2014(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2\u2003\u2003(VIII).
17. The dosage form of claim 9 wherein the salt comprises a salt of the boronic acid with a metal.
18. The dosage form of claim 17 wherein the metal comprises an alkali metal.
19. The dosage form of claim 1 which comprises boronate ions derived from the boronic acid and has a stoichiometry consistent with the boronate ions carrying a single negative charge.
20. The dosage form of claim 1 which comprises:
a pharmaceutical formulation which contains said compound and is in the form of powder or granules; and
a sealed container in which the formulation is contained and from which the formulation is to be dispensed for reconstitution.
21-22. (canceled)
23. The dosage form of claim 20 wherein the container is a sachet.
24. The dosage form of claim 1 wherein the solid phase formulation is a pharmaceutical formulation in the form of an effervescent tablet which contains an effervescent system, or is a fast melt pharmaceutical formulation.
25. (canceled)
26. The dosage form of claim 20 which comprises from about 0.2 to about 1.5 mol of the compound, calculated on the basis of the boronic acid.
27. (canceled)
28. The dosage form of claim 1 which is adapted to be reconstituted to form a solution having a volume of from about 50 ml to about 150 ml.
29. A pharmaceutical formulation comprising a pharmaceutically acceptable base addition salt of the acid Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2, the formulation being in the form of a powder or granules in a sachet or of an effervescent tablet.
30. A method of making an oral dosage form for preventing thrombosis, comprising:
reacting a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites with a base selected from the group consisting of basic metal compounds and organic nitrogen-containing compounds having a pKb of at least 7, to form a reaction product; and
formulating the reaction product into a solid phase formulation which comprises the reaction product and is adapted for reconstitution of the formulation to form a liquid preparation.
31. A method for the manufacture of a medicament to be reconstituted to form a drinkable preparation, comprising making the medicament with a compound as defined in claim 1.
32-33. (canceled)
34. A method of preparing an anticoagulant preparation, comprising reconstituting, into a liquid preparation for oral administration a solid phase formulation comprising:
a) a first species selected from the group consisting of a boronic acid of formula (I) below, said acid when in the form of a boronate anion thereof, an equilibrium form of said boronic acid and of said boronate ion, and combinations thereof:
wherein
Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue \u2014NHCH(R9)\u2014B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R9 is \u2014(CH2)m\u2014W where m is 2, 3, 4 or 5 and W is \u2014OH or halogen, wherein halogen is F, Cl, Br or I; and
(b) a second species selected from the group consisting of pharmaceutically acceptable metal ions and strongly basic organic nitrogen-containing compounds.
35. A method of inhibiting thrombin in the treatment of disease, comprising administering perorally to a subject in need thereof a therapeutically effective amount of a compound as defined in claim 1, said compound being put into solution or suspension from a solid phase formulation prior to the compound entering the stomach.
36. The method of claim 35, wherein the compound is put into solution or suspension by reconstituting with a liquid prior to administration or in saliva in the mouth.
37. A method of preventing thrombosis in the haemodialysis circuit of a patient, comprising reconstituting into a drinkable preparation a solid formulation comprising a salt as defined in claim 9, and orally administering the drinkable preparation.
38-39. (canceled)
40. A method of preventing deep vein thrombosis during an airplane flight in a subject comprising administering to the subject a therapeutically effective amount of a compound as defined in claim 1.
41-42. (canceled)
43. A method of preventing thrombosis in intermittent apheresis comprising administering a therapeutically effective amount of a compound as defined in claim 1, wherein said intermittent apheresis is not hemodialysis.
44. The method of claim 43, wherein the intermittent apheresis is extracorporeal liver detoxification.
45. The method of claim 43, wherein the compound is an oral medicament or is a parenteral medicament.
46. A method for the prevention of thrombosis in the haemodialysis circuit of a patient undergoing haemodialysis, comprising administering a therapeutically effective amount of a compound selected from boronic acids which have a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and salts, prodrugs and prodrug salts of such acids, the compound not being a base addition salt of such a boronic acid.
47. The method of claim 46 wherein the boronic acid is of formula (I):
wherein
Y comprises a moiety which, together with the fragment \u2014CH(R9)\u2014B(OH)2, has affinity for the substrate binding site of thrombin and R9 is an alkoxyalkyl group, and wherein Y comprises an amino acid which binds to the S2 subsite of thrombin, the amino acid being N-terminally linked to a moiety which binds the S3 subsite of thrombin, the S3-binding amino acid residue is of (R) configuration, the S2-binding residue is of (S) configuration, and the fragment \u2014CH(R9)\u2014B(OH)2 is of (R) configuration.
48. The method of claim 46 wherein the boronic acid is of formula (III):
where:
X is H (to form NH2) or an amino-protecting group;
aa1 is an amino acid having a hydrocarbyl side chain containing no more than 20 carbon atoms and comprising at least one cyclic group having up to 13 carbon atoms;
aa2 is an imino acid having from 4 to 6 ring members;
R1 is a group of the formula \u2014(CH2)s-Z, where s is 2, 3 or 4 and Z is \u2014OH, \u2014OMe, \u2014OEt or halogen, wherein halogen is F, Cl, Br or I.
49. The method of claim 46 wherein the boronic acid is a compound designated TRI 50c of the following formula
Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2.
50. The dosage form of claim 10 wherein the prodrugs are boronic acid derivatives capable of hydrolysing to release the free boronic acid.
51. A method for preventing flight deep vein thrombosis or thrombosis in intermittent apheresis, wherein said intermittent apheresis is not hemodialysis, comprising administering a therapeutically effective amount of a composition of matter comprising
a) a first species selected from the group consisting of a boronic acid of formula (I) below, said acid when in the form of a boronate anion thereof, an equilibrium form of said boronic acid and of said boronate ion, and combinations thereof:
wherein
Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue \u2014NHCH(R9)\u2014B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R9 is \u2014(CH2)m\u2014W where m is 2, 3, 4 or 5 and W is \u2014OH or halogen, wherein halogen is F, Cl, Br or I; and
(b) a second species selected from the group consisting of pharmaceutically acceptable metal ions and strongly basic organic nitrogen-containing compounds.
52. An aqueous solution comprising a pharmaceutically acceptable base addition salt of a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, the solution having a pH of about 9 or more.
53. The solution of claim 52 wherein the pH is about 9 to about 9.5.
54. An aqueous solution comprising a pharmaceutically acceptable base addition salt of a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites and a pharmaceutically acceptable organic acid, the solution having a pH of from about 4 to about 8.