1. A compound of the formula:
wherein:
J is a linking functional group and is independently:
\u2014C(\u2550O)- or \u2014O\u2014C(\u2550O)\u2014 or \u2014C(\u2550O)\u2014O\u2014;
Cy is a cyclyl group and is independently:
C3-20carbocyclyl, C3-20heterocyclyl, or C5-20aryl;
and is optionally substituted;
Q1 is a cyclyl leader group, and is independently a divalent bidentate group obtained by removing two hydrogen atoms from a ring carbon atom of a saturated monocyclic hydrocarbon having from 4 to 7 ring atoms, or by removing two hydrogen atoms from a ring carbon atom of saturated monocyclic heterocyclic compound having from 4 to 7 ring atoms including 1 nitrogen ring atom or 1 oxygen ring atom; and is optionally substituted;
If J is\u2014O\u2014C(\u2550O)\u2014 or C(\u2550O)\u2014O\u2014, then:
Q2 is an acid leader group, and is independently:
C1-8 alkylene;
and is optionally substituted; or:
Q2 is an acid leader group, and is independently:
C5-20arylene;
C5-20arylene-C1-7alkylene;
C1-7alkylene-C5-20arylene; or,
C1-7alkylene-C5-20arylene-C1-7alkylene;
and is optionally substituted;
if J is\u2014C(\u2550O)\u2014, then:
Q2 is an acid leader group, and is independently:
C5-20arylene;
C5-20arylene-C1-7alkylene;
C1-7alkylene-C5-20arylene; or,
C1-7alkylene-C5-20arylene-C1-7alkylene;
and is optionally substituted;
and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.
2. A compound according to claim 1, wherein J is \u2014O\u2014C(\u2550O)\u2014 or \u2014C(\u2550O)\u2014O\u2014.
3. A compound according to claim 1, wherein J is \u2014O\u2014C(\u2550O)\u2014.
4. A compound according to claim 1, wherein J is \u2014C(\u2550O)\u2014O\u2014.
5. A compound according to claim 1, wherein J is \u2014C(\u2550O)\u2014.
6. A compound according to claim 1, wherein Q1 is independently a group of the formula:
wherein:
the ring independently has from 4 to 7 ring atoms;
Z is independently\u2014CH2\u2014, \u2014N(RN) \u2014 or \u2014O\u2014;
RN, if present, is independently \u2014H, C1-7alkyl, C5-20aryl \u2014C1-7alkyl, C0320 heterocyclyl, or C5-20aryl; and
Q1 is optionally further substituted.
7. A compound according to claim 6, wherein Q1 is independently a group of the formula:
wherein y is independently 1, 2, 3, or 4.
8. A compound according to claim 7, wherein Q1 is independently selected from:
9. A compound according to claim 8, wherein Q1 is independently:
10. A compound according to claim 8, wherein Q1 is independently:
11. A compound according to claim 8, wherein Q1 is independently:
12. A compound according to claim 6, wherein RN if present, is independently selected from:\u2014H, -Me, -Et, -Ph, and\u2014CH2-Ph.
13. A compound according to claim 6, wherein RN if present, is independently \u2014H.
14. A compound according to claim 1, wherein substituents on Q1, if present, are independently selected from:
\u2014F, \u2014Cl, \u2014Br, \u2014I, \u2014OH, \u2014OMe, \u2014OEt, \u2014O(iPr), \u2014Ph, \u2014C(\u2550O)Me, \u2014NH2, \u2014NMe2, \u2014NEt2, morpholino, \u2014CONH2, -CONMe2, \u2014NHCOMe, and \u25500;
and wherein, if a substituent is on an arylene group, it may additionally be selected from: \u2014Me, \u2014Et, -iPr, -tBu, \u2014CF3.
15. A compound according to claim 1, wherein Cy is independently C3-20carbocyclyl; and is optionally substituted.
16. A compound according to claim 1, wherein Cy is independently C3-20heterocyclyl; and is optionally substituted.
17. A compound according to claim 1, wherein Cy is independently C5-20aryl; and is optionally substituted.
18. A compound according to claim 1, wherein Cy is independently C5-20carboaryl or C5-20heteroaryl; and is optionally substituted.
19. A compound according to claim 1, wherein Cy is independently C5-20aryl derived from one of the following:
benzene, pyridine, furan, indole, pyrrole, imidazole, naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole; and is optionally substituted.
20. A compound according to claim 1, wherein Cy is independently C5-20aryl derived from benzene and is optionally substituted.
21. A compound according to claim 1, wherein Cy is independently an optionally substituted phenyl group of the formula:
wherein n is independently an integer from 0 to 5, and each RA is independently a substituent.
22. A compound according to claim 21, wherein n is 0.
23. A compound according to claim 21, wherein n is 1, and the RA group is in the 4\u2032-position.
24. A compound according to claim 21, wherein n is 2, and one RA group is in the 4 \u2032-position, and the other RA group is in the 2\u2032-position.
25. A compound according to claim 21, wherein n is 2, and one RA group is in the 4\u2032 position, and the other RA group is in the 3\u2032 position.
26. A compound according to claim 1, wherein each of the substituents on Cy, if present, is independently selected from:
(1) ester;
(2) amido;
(3) acyl;
(4) halo;
(5) hydroxy;
(6) ether;
(7) C17alkyl; substituted C17alkyl;
(8) C52oaryl; substituted C52oaryl;
(9) sulfonyl;
(10) sulfonamido.
27. A compound according to claim 1, wherein each of the substituents on Cy, if present, is independently selected from:
(1)\u2014C(\u2550O)OR1, wherein R1 is independently C1-7alkyl as defined in (7);
(2)\u2014C(\u2550O)NR2R3, wherein each of R2 and R3 is independently\u2014H or C1-7alkyl as defined in (7);
(3)\u2014C(\u2550O)R4, wherein R4 is independently C1-7alkyl as defined in (7) or C5-20aryl as defined in (8);
(4)\u2014F, \u2014Cl, \u2014Br, \u2014I;
(5)\u2014OH;
(6)\u2014OR5, wherein R5 is independently C1-7alkyl as defined in (7) or C5-20aryl as defined in (8);
(7) C1-7alkyl; substituted C1-7alkyl;
halo-C1-7alkyl;
amino-C1-7alkyl;
carboxy-C1-7alkyl;
hydroxy-C1-7alkyl;
C1-7alkoxy-C1-7alkyl;
C5-20aryl-C1-7alkyl;
(8) C5-20aryl; substituted C5-20aryl;
(9)\u2014SO02R7, wherein R7 is independently C1-7alkyl as defined in (7) or C5-20aryl as defined in (8);
(10)\u2014SO2NR8R9, wherein each of R8 and R9 is independently\u2014H or C1-7alkyl as defined in (7).
28. A compound according to claim 1, wherein each of the substituents on Cy, if present, is independently selected from:
(1)\u2014C(\u2550O)OMe, \u2014C(\u2550O)OEt, \u2014C(\u2550O)O(Pr), \u2014C(\u2550O)O(iPr), \u2014C(\u2550O)O(nBu), \u2014C(\u2550O)O(sBu), \u2014C(\u2550O)O(iBu), \u2014C(\u2550O)O(tBu), \u2014C(\u2550O)O(nPe);
\u2014C(\u2550O)OCH2CH2OH, \u2014C(\u2550O)OCH2CH2OMe, \u2014C(\u2550O)OCH2CH2OEt;
(2)\u2014(C\u2550O)NH2, \u2014(C\u2550O)NMe2, \u2014(C\u2550O)NEt2, \u2014(C\u2550O)N(iPr)2, \u2014(C\u25500)N (CH2CH2OH)2;
(3) \u2014(C\u2550O)Me, \u2014(C\u2550O)Et, \u2014(0\u25500)-cHex, \u2014(C\u2550O)Ph;
(4) \u2014F, \u2014Cl, \u2014Br, \u2014I;
(5) \u2014OH;
(6\u2014OMe, \u2014GEt, \u2014O(iPr), \u2014O(tBu), \u2014OPh;
\u2014OCF3, \u2014OCH2CF3;
\u2014OCH2CH2OH, \u2014OCH2CH2OMe, \u2014OCH2CH2OEt;
\u2014OCH2CH2NH2, \u2014OCH2CH2NMe2, \u2014OCH2CH2N(iPr)2;
\u2014OPh, \u2014OPh-Me, \u2014Oph-OH, \u2014Oph-OMe, O-Ph-F, \u2014Oph-CI, \u2014Oph-Br, \u2014Oph-I;
(7) -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe;
\u2014CF3, \u2014CH2CF3;
\u2014CH2CH2OH, \u2014CH2CH2OMe, \u2014CH2CH2OEt;
\u2014CH2CH2NH2, \u2014CH2CH2NMe2, \u2014CH2CH2N(iPr)2;
\u2014CH2-Ph;
(8)-Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I;
(9)\u2014SO2Me, \u2014SO2Et, \u2014SO2Ph;
(10)\u2014SO2NH2, \u2014SO2NMe2, \u2014SO2NEt2.
29. A compound according to claim 1, wherein each of the substituents on Cy, if present, is independently selected from: \u2014C(\u2550O)OMe, \u2014OMe, \u2014C(\u2550O)Me, \u2014SO2Me, \u2014SO2NMe2, \u2014C(\u2550O)NH2, \u2014OCF3, and\u2014CH2CH2OH.
30. A compound according to claim 1, wherein the acid leader group, Q2, is independently:
C5-20arylene; and is optionally substituted.
31. A compound according to claim 1, wherein Q2 is independently C5-6arylene; and is optionally substituted.
32. A compound according to claim 1, wherein Q2 is independently phenylene; and is optionally substituted.
33. A compound according to claim 32, wherein the phenylene linkage is meta or para.
34. A compound according to claim 32, wherein the phenylene linkage is meta.
35. A compound according to claim 32, wherein the phenylene linkage is para.
36. A compound according to claim 30, wherein Q2 is independently unsubstituted.
37. A compound according to claim 1, wherein J is \u2014O\u2014C(\u2550O)\u2014 or \u2014C(\u2550O)\u2014O\u2014 and the acid leader group, Q2, is independently:
C1-8alkylene;
and is optionally substituted.
38. A compound according to claim 1, wherein J is \u2014P\u2014C(\u2550O)\u2014 or \u2014C(\u2550O)\u2014O\u2014 and Q2 is independently:
(a) a saturated C1-7alkylene group; or:
(b) a partially unsaturated C2-7alkylene group; or:
(c) an aliphatic C1-7alkylene group; or:
(d) a linear C1-7alkylene group; or:
(e) a branched C2-7alkylene group; or:
(f) a saturated aliphatic C1-7alkylene group; or:
(g) a saturated linear C1-7alkylene group; or:
(h) a saturated branched C2-7alkylene group; or:
(i) a partially unsaturated aliphatic C2-7alkylene group; or:
(j) a partially unsaturated linear C2-7alkylene group; or:
(k) a partially unsaturated branched C2-7alkylene group;
and is optionally substituted.
39. A compound according to claim 1, wherein J is\u2014O\u2014C(\u2550O)\u2014 or \u2014C(\u2550O)\u2014O\u2014 and Q2 is independently selected from:
\u2014(CH2)5\u2014; \u2014(CH2)6\u2014; \u2014(CH2)7\u2014; and \u2014(CH2)8\u2014.
40. A compound according to claim 1, wherein Q2 is independently:
C5-20arylene-C1-7alkylene;
C1-7alkylene-C5-20arylene; or,
C1-7alkylene-C5-20arylene-C1-7alkylene;
and is optionally substituted.
41. A compound according to claim 1, wherein Q2 is independently:
C5-6arylene-C1-7alkylene;
C1-7alkylene-C5-6arylene; or,
C1-7alkylene-C5-6arylene-C1-7alkylene; and is optionally substituted.
42. A compound according to any claim 1, wherein Q2 is independently:
phenylene-C1-7alkylene;
C1-7alkylene-phenylene; or,
C1-7alkylene-phenylene-C1-7alkylene;
and is optionally substituted.
43. A compound according to claim 1, wherein Q2 independently has a backbone of from 5 to 6 atoms.
44. A compound according to claim 1, wherein each of the substituents on Q2, if present, is independently selected from:
halo, hydroxy, ether, C1-7alkoxy, C5-20aryl, acyl, amino, amido, acylamido, nitro, and oxo; and wherein, if a substituent is on an arylene group, it may additionally be selected from: C1-7alkyl and substituted C1-7alkyl.
45. A compound according to claim 1, wherein each of the substituents on Q2, if present, is independently selected from:
\u2014F, \u2014Cl, \u2014Br, \u2014I, \u2014OH, \u2014OMe, \u2014OFt, \u2014O(iPr), -Ph, \u2014C(\u2550O)Me, \u2014NH2, \u2014NMe2, \u2014NEt2, morpholino, \u2014CONH2, \u2014CONMe2, \u2014NHCOMe, \u2014NO2, and \u2550O; and wherein, if a substituent is on an arylene group, it may additionally be selected from:-Me, -Et, -iPr, -tBu, \u2014CF3.
46. A compound of the formula:
wherein:
J is independently:\u2014C(\u2550O)\u2014O \u2014;
Q1 is independently:
Q2 is phenylene, and is optionally substituted; Cy is phenyl, and is optionally substituted;
and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.
47. A compound selected from the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof:
1
PX118478
2
PX118479
3
PX118480
4
PX119101
5
PX118925
6
PX118926
7
PX118959
8
PX118966
9
PX119058
10
PX119059
11
PX119061
12
PX119062
13
PX119064
14
PX119065
15
PX119084
16
PX119100
17
PX119063
18
PX119085
19
PX119086
20
PX119102
21
PX119103
22
23
24
48. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
49. A method of inhibiting HDAC in a cell comprising contacting said cell with an effective amount of a compound according to claim 1.
50. A method of inhibiting HDAC in a subject comprising administering to a subject an effective amount of a compound according to claim 1.
51. A method of inhibiting HDAC in a subject comprising administering to a subject suffering from a proliferative condition an effective amount of a compound according to claim 1, wherein the proliferative condition is selected from:
cancer;
psoriasis;
a fibroproliferative disorder; liver fibrosis;
smooth muscle proliferative disorder; atherosclerosis; restenosis;
a neurodegenative disease; Alzheimer’s; Parkinson’s; Huntington’s chorea;
amyotropic lateral sclerosis; spino-cerebellar degeneration;
an inflammatory disease; osteoarthritis; rheumatoid arthritis;
a diseases involving angiogenesis; rheumatoid arthritis; diabetic retinopathy;
a haematopoietic disorder; anaemia; sickle cell anaemia; thalassaeimia;
a fungal infection;
a parasitic infection; malaria; trypanosomiasis; helminthiasis; a protozoal infection;
a bacterial infection;
a viral infection;
a condition treatable by immune modulation; multiple sclerosis; autoimmune diabetes; lupus; atopic dermatitis; an allergy; asthma; allergic rhinitis; and inflammatory bowel disease.
52. A method of inhibiting HDAC in a subject comprising administering to a subject suffering from cancer an effective amount of a compound according to claim 1.
53. A method of inhibiting HDAC in a subject comprising administering to a subject suffering from psoriasis an effective amount of a compound according to claim 1.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
The following is claimed:
1. A buffer storage system for storing groupings of data of varying size, comprising:
a buffer storage section having a first buffer subsection and a second buffer subsection, the first buffer subsection having a plurality of buffer units of a first buffer unit size, the second buffer subsection having a plurality of buffer units of a second buffer unit size wherein the second buffer unit size is larger than the first buffer unit size; and
a buffer management section that is operable to determine the size of an incoming data grouping and to direct the incoming data grouping to one of the buffer subsections based on the size of the data grouping.
2. The system according to claim 1 wherein the data grouping is a data packet.
3. The system according to claim 2 wherein the data packet is an IP packet.
4. The system according to claim 2 wherein the first buffer unit size is substantially equal to the size of the largest control packet of the TCPIP protocol.
5. The system according to claim 3 wherein the second buffer unit size is substantially equal to the largest data packet of the TCPIP protocol.
6. The system according to claim 2 wherein the data packet is an SONETSDH optical data packet.
7. The system according to claim 2 wherein the data packet is an WDM data packet.
8. The system according to claim 2 wherein the data packet is an Ethernet packet.
9. The system according to claim 1 wherein the buffer management section is also operable to determine the number of first buffer units and second buffer units that are allocated in the buffer storage section.
10. The system according to claim 8 wherein the buffer management section is operable to remember information relating to the frequency at which data groupings of a particular size are stored in the buffer storage section.
11. The system according to claim 9 wherein the buffer management section determines the number of first buffer units and second buffer units to be allocated based on the remembered frequency information.
12. The system according to claim 1 wherein the buffer management section comprises a data monitor that monitors and remembers information relating to the frequency at which data groupings of a particular size are stored in the buffer storage section.
13. The system according to claim 11 wherein the data monitor records the size of the data groupings in a frequency table.
14. The system according to claim 12 wherein the frequency table comprises bins for counting data groupings having a size within a determined range.
15. The system according to claim 1 wherein the buffer management section comprises a buffer memory allocator that is operable to determine the number of first buffer units and second buffer units that are allocated in the buffer storage section.
16. The system according to claim 1 further comprising an input queue for receiving an input data grouping and an output queue for outputting a data grouping.
17. The system according to claim 1 wherein the buffer storage section has a third buffer subsection, the third buffer subsection having a plurality of buffer units of a third buffer unit size, wherein the third buffer unit size is larger than the first buffer unit size and is smaller than the second buffer unit size.
18. A system for allocating buffer memory in a packet network that transmits a plurality of differently sized packets, comprising:
means for generating a first buffer unit size;
means for allocating a plurality of first buffer units in the buffer memory wherein the first buffer units each have the length of the first buffer unit size;
means for generating a second buffer unit size; and
means for allocating a plurality of second buffer units in the buffer memory wherein the second buffer units each have the length of the second buffer unit size, wherein the second buffer unit size is at least as large as the largest packet sent to the buffer memory and wherein the first buffer unit size is smaller than the second buffer unit size.
19. A method for allocating buffer memory in a packet network that transmits a plurality of differently sized packets, comprising the steps of:
allocating, in the buffer memory, a plurality of first buffer units having a first buffer unit size; and
allocating, in the buffer memory, a plurality of second buffer units having a second buffer unit size, wherein the second buffer unit size is larger than the first buffer unit size, and wherein the number of second buffer units allocated is based on the predicted frequency of receiving packets larger than the first buffer unit size.
20. The method of claim 19 wherein the packets are IP packets.
21. The method of claim 20 wherein the first buffer unit size is substantially equal to the size of the largest control packet of the TCPIP protocol.
22. The method of claim 20 wherein the second buffer unit size is substantially equal to the largest data packet of the TCPIP protocol.
23. The method of claim 19 further comprising the step of allocating, in the buffer memory, a plurality of third buffer units having a third buffer unit size, wherein the third buffer unit size is larger than the first buffer unit size and smaller than the second buffer unit size.