US2004127523A1PendingUtilityA1
Methods of treating cancer with HDAC inhibitors
Priority: Mar 4, 2002Filed: Sep 16, 2003Published: Jul 1, 2004
Est. expiryMar 4, 2022(expired)· nominal 20-yr term from priority
A61P 37/02A61P 9/10A61P 9/04A61P 43/00A61P 7/00A61P 37/06A61P 3/10A61P 9/00A61P 35/04A61P 35/02A61P 31/18A61P 29/00A61P 25/28A61P 31/04A61P 35/00A61P 25/04A61P 25/00A61P 25/16A61P 21/00A61P 17/02A61P 19/02A61P 19/00A61K 31/19A61K 31/13A61K 31/44A61P 17/06A61K 9/1652A61K 31/165A61P 19/10A61K 9/4866A61P 11/00A61K 9/0019A61K 31/164A61P 1/16A61P 1/04A61P 21/02A61P 13/12A61P 17/04A61K 47/38A61K 47/12A61P 11/06A61P 17/00A61K 38/12C07C 259/04
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Claims
Abstract
The present invention relates to methods of treating cancers, e.g., lymphoma. More specifically, the present invention relates to methods of treating diffuse large B-cell lymphoma (DLBCL), by administration of pharmaceutical compositions comprising HDAC inhibitors, e.g., suberoylanilide hydroxamic acid (SAHA). The oral formulations of the pharmaceutical compositions have favorable pharmacokinetic profiles such as high bioavailability and surprisingly give rise to high blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating diffuse large B-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat diffuse large B-cell lymphoma in said subject.
2 . The method of claim 1 , wherein the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA), represented by the structure:
3 . The method of claim 1 , wherein the HDAC inhibitor is pyroxamide, represented by the structure:
4 . The method of claim 1 , wherein the HDAC inhibitor is represented by the structure:
wherein R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to 8.
5 . The method of claim 1 , wherein the HDAC inhibitor is represented by the structure:
wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.
6 . The method of claim 1 , wherein the HDAC inhibitor is represented by the structure:
wherein A is an amide moiety, R 1 and R 2 are each selected from substituted or unsubstituted aryl, arylalkyl, naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
7 . The method of claim 1 , wherein said HDAC inhibitor is a hydroxamic acid derivative, a Short Chain Fatty Acid (SCFA), a cyclic tetrapeptide, a benzamide derivative, or an electrophilic ketone derivative.
8 . The method of claim 1 , wherein said HDAC inhibitor is a hydroxamic acid derivative selected from the group consisting of SAHA, Pyroxamide, CBHA, Trichostatin A (TSA), Trichostatin C, Salicylhydroxamic Acid, Azelaic Bishydroxamic Acid (ABHA), Azelaic-1-Hydroxamate-9-Anilide (AAHA), 6-(3-Chlorophenylureido) carpoic Hydroxamic Acid (3Cl-UCHA), Oxamflatin, A-161906, Scriptaid, PXD-101, LAQ-824, CHAP, MW2796, and MW2996.
9 . The method of claim 1 , wherein said HDAC inhibitor is a cyclic tetrapeptide selected from the group consisting of Trapoxin A, FR901228 (FK 228 or Depsipeptide), FR225497, Apicidin, CHAP, HC-Toxin, WF27082, and Chlamydocin.
10 . The method of claim 1 , wherein said HDAC inhibitor is a Short Chain Fatty Acid (SCFA) selected from the group consisting of Sodium Butyrate, Isovalerate, Valerate, 4 Phenylbutyrate (4-PBA), Phenylbutyrate (PB), Propionate, Butyramide, Isobutyramide, Phenylacetate, 3-Bromopropionate, Tributyrin, Valproic Acid and Valproate.
11 . The method of claim 1 , wherein said HDAC inhibitor is a benzamide derivative selected from the group consisting of CI-994, MS-27-275 (MS-275) and a 3′-amino derivative of MS-27-275.
12 . The method according to claim 1 , wherein said HDAC inhibitor is an electrophilic ketone derivative selected from the group consisting of a trifluoromethyl ketone and an α-keto amide.
13 . The method according to claim 1 , wherein said HDAC inhibitor is a natural product, a psammaplin or Depudecin.
14 . The method of claim 1 , wherein the pharmaceutical composition is administered orally.
15 . The method of claim 14 , wherein said composition is contained within a gelatin capsule.
16 . The method of claim 15 , wherein said carrier or diluent is microcrystalline cellulose.
17 . The method of claim 16 , further comprising sodium croscarmellose as a disintegrating agent.
18 . The method of claim 17 , further comprising magnesium stearate as a lubricant.
19 . The method of claim 14 , wherein said composition is administered to the subject at a total daily dosage of between about 254000 mg/m 2 .
20 . The method of claim 14 , wherein said composition is administered once-daily, twice-daily or three times-daily.
21 . The method of claim 20 , wherein said composition is administered once daily at a dose of about 200-600 mg.
22 . The method of claim 20 , wherein said composition is administered twice daily at a dose of about 200-400 mg.
23 . The method of claim 20 , wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.
24 . The method of claim 23 , wherein said composition is administered three to five days per week.
25 . The method of claim 23 , wherein said composition is administered three days a week.
26 . The method of claim 25 , wherein said composition is administered at a dose of about 200 mg.
27 . The method of claim 25 , wherein said composition is administered at a dose of about 300 mg.
28 . The method of claim 25 , wherein said composition is administered at a dose of about 400 mg.
29 . The method of claim 20 , wherein said composition is administered three times daily at a dose of about 100-250 mg.
30 . A method of treating diffuse large B-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure:
and a pharmaceutically acceptable carrier or diluent, wherein the amount of SAHA is effective to treat diffuse large B-cell lymphoma in said subject.
31 . The method of claim 30 , wherein the pharmaceutical composition is administered orally.
32 . The method of claim 31 , wherein said composition is contained within a gelatin capsule.
33 . The method of claim 32 , wherein said carrier or diluent is microcrystalline cellulose.
34 . The method of claim 33 , further comprising sodium croscarmellose as a disintegrating agent.
35 . The method of claim 34 , further comprising magnesium stearate as a lubricant.
36 . The method of claim 31 , wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
37 . The method of claim 31 , wherein said composition is administered once-daily, twice-daily or three times-daily.
38 . The method of claim 37 , wherein said composition is administered once daily at a dose of about 200-600 mg.
39 . The method of claim 37 , wherein said composition is administered twice daily at a dose of about 200-400 mg.
40 . The method of claim 37 , wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.
41 . The method of claim 40 , wherein said composition is administered three to five days per week.
42 . The method of claim 40 , wherein said composition is administered three days a week.
43 . The method of claim 42 , wherein said composition is administered at a dose of about 200 mg.
44 . The method of claim 42 , wherein said composition is administered at a dose of about 300 mg.
45 . The method of claim 42 , wherein said composition is administered at a dose of about 400 mg.
46 . The method of claim 37 , wherein said composition is administered three times daily at a dose of about 100-250 mg.
47 . A method of treating diffuse large B-cell lymphoma in a subject, said method comprising the step of administering to the subject a total daily dose of up to about 800 mg of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure:
and a pharmaceutically acceptable carrier or diluent, wherein the amount of SAHA is effective to treat diffuse large B-cell lymphoma in said subject.
48 . The method of claim 47 , wherein the pharmaceutical composition is administered orally.
49 . The method of claim 48 , wherein said composition is contained within a gelatin capsule.
50 . The method of claim 49 , wherein said carrier or diluent is microcrystalline cellulose.
51 . The method of claim 50 , further comprising sodium croscarmellose as a disintegrating agent.
52 . The method of claim 51 , further comprising magnesium stearate as a lubricant.
53 . The method of claim 48 , wherein said composition is administered once-daily, twice-daily or three times-daily.
54 . The method of claim 53 , wherein said composition is administered once daily at a dose of about 200-600 mg.
55 . The method of claim 53 , wherein said composition is administered twice daily at a dose of about 200-400 mg.
56 . The method of claim 53 , wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.
57 . The method of claim 56 , wherein said composition is administered three to five days per week.
58 . The method of claim 56 , wherein said composition is administered three days a week.
59 . The method of claim 58 , wherein said composition is administered at a dose of about 200 mg.
60 . The method of claim 58 , wherein said composition is administered at a dose of about 300 mg.
61 . The method of claim 58 , wherein said composition is administered at a dose of about 400 mg.
62 . The method of claim 53 , wherein said composition is administered three times daily at a dose of about 100-250 mg.Cited by (0)
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