JP2009538318A - Methods and compositions using immunomodulatory compounds in combination therapy - Google Patents

Abstract

Provided herein are compositions comprising one or more immunomodulatory compounds and valproic acid, hydroxyurea or trichostatin A, CD34 + hematopoietic stem cells in vitro and in vivo for bone marrow remodeling and bone marrow transplantation Methods for their use in proliferation, increasing fetal hemoglobin expression, and methods for the treatment, prevention, and / or management of cancer, tumors, and blood diseases and disorders.
[Selection] Figure 1

Description

  This application claims the benefit of US Provisional Application No. 60 / 808,602, filed May 26, 2006, the contents of which are incorporated herein by reference in their entirety.

(1. Field)
Provided herein are compositions comprising one or more immunomodulatory compounds and valproic acid, hydroxyurea or trichostatin A, CD34 + hematopoietic stem cells in vitro and in vivo for bone marrow remodeling and bone marrow transplantation Methods for their use in proliferation, increasing fetal hemoglobin expression, and methods for the treatment, prevention, and / or management of cancer, tumors, and blood diseases and disorders.

(2. Background)
(IMiDs (trademark))
Many studies have been conducted with the aim of providing compounds that can be used safely and efficiently to treat diseases associated with abnormal production of TNF-α. For example, Marriott, JB et al., Expert Opin. Biol. Ther. 1 (4): 1-8 (2001); GW Muller et al., Journal of Medicinal Chemistry, 39 (17): 3238-3240 (1996); And GW Muller et al., Bioorganic & Medicinal Chemistry Letters, 8: 2669-2674 (1998). Some studies have focused on a group of compounds selected for their ability to strongly inhibit TNF-α production by LPS-stimulated PBMC. LGCorral et al., Ann. Rheum. Dis. 58: (Suppl I) 1107-1 113 (1999). A compound or immunomodulator called IMiDs ™ (Celgene) shows not only strong inhibition of TNF-α, but also significant inhibition of LPS-induced monocyte ILlB production and IL12 production. LPS-induced IL6 is also partially inhibited by immunomodulatory compounds. These compounds are potent stimulators of LPS-induced IL10 (Id.).

G.W.Mullerらの米国特許第5,635,517号に記載され、その全体において本明細書中に取り込まれている。 (2.2 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione)
4- (Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione is an immunomodulatory compound having the following chemical structure:

GWMuller et al., US Pat. No. 5,635,517, which is incorporated herein in its entirety.

G.W.Mullerらの米国特許第5,635,517号に記載され、その全体において本明細書中に取り込まれている。 (2.3 3- (4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione)
3- (4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is an immunomodulatory compound having the following chemical structure:

GWMuller et al., US Pat. No. 5,635,517, which is incorporated herein in its entirety.

(2.4 Trichostatin A (TSA))
Trichostatin A (TSA) is a histone deacetylase inhibitor having the following structure:

(2.5 Hydroxyurea (HU))
Hydroxyurea (HU) is a ribonucleotide reductase having the following structure:

(2.6 Valproic acid)
Valproic acid is a histone deacetylase inhibitor having the following structure:

  Valproic acid was shown to have the activity of increasing hematopoietic stem cell proliferation and self-renewal, and potent antitumor activity was seen in vitro and in vivo (Kaiser et al. (2006 Haematologica 91 (2)): 248 -251; Li et al., MoL Cancer Then 4 (12): 1912-1922). However, improvements are needed to provide safe and effective therapies for treating diseases and disorders associated with hematopoietic stem cells (Bug et al., 2005, Cancer Res. 65 (7): 2537-2541). .

  Therefore, there is a need for techniques for safe and effective methods of CD34 + hematopoietic stem cell proliferation in vitro and in vivo.

(3. Summary)
In this embodiment, an immunomodulatory compound in combination with valproic acid, hydroxyurea or trichostatin A is additive and synergistic to CD34 + hematopoietic stem cell proliferation, fetal hemoglobin (Hb) expression, and malignant cell apoptosis and anti-cell proliferation. Based on the discovery that it has a positive effect.

  In one embodiment, 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione in combination with valproic acid, hydroxyurea or trichostatin A (herein) (Also referred to as “Compound 1”) or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione (herein (Also referred to as “compound 2”) have additive and synergistic effects on CD34 + hematopoietic stem cell proliferation, fetal hemoglobin expression, and apoptosis and anti-cell proliferation of malignant cells.

  Accordingly, provided herein is an effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid , Hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof (eg, pharmaceutical composition), CD34 + hematopoietic stem cells Methods of their use in proliferation, fetal hemoglobin expression and apoptosis and anti-cell proliferation of cancer cells, and methods for the treatment, prevention or management of diseases and disorders associated therewith.

  Further provided herein is an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4 -Amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer thereof And a composition comprising valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof (e.g., pharmaceutical Composition), methods for their use in CD34 + hematopoietic stem cell proliferation, fetal hemoglobin expression and cancer cell apoptosis and anti-cell proliferation, and methods for the treatment, prevention or management of diseases and disorders associated therewith.

FIG. 1 shows TSA (i.e., trichostatin A) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3 on Namalva cell proliferation. -Synergistic and additive effects of dione).

FIG. 2 shows TSA (i.e. trichostatin A) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3 for Namalva cell apoptosis. -Synergistic and additive effects of dione).

FIG. 3 shows VPA (i.e. valproic acid) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3- Show the synergistic and additive effects of

FIG. 4 shows VPA (i.e. valproic acid) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3- for Namalva cell apoptosis. 2 shows the synergistic and additive effects of dione).

FIG. 5 shows VPA (i.e. valproic acid) and compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2 on Namalva cell proliferation. , 6-dione) show synergistic and additive effects. The table shows the concentration of Compound 2 and VPA required to obtain an additive or synergistic effect.

FIG. 6 shows VPA (i.e. valproic acid) and compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2 against Namalva cell apoptosis. , 6-dione) show synergistic and additive effects. The table shows the concentration of Compound 2 and VPA required to obtain an additive or synergistic effect.

FIG. 7 shows TSA (i.e., trichostatin A) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1 against cord blood-derived CD34 + proliferation. , 3-dione) exhibits additive and synergistic effects. FIG. 7 shows the number of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 1 and VPA required to obtain an additive or synergistic effect.

FIG. 8 shows TSA (i.e., trichostatin A) and compound 1 (i.e., 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline--for cord blood-derived CD34 + proliferation. 1 shows the additive and synergistic effects of 1,3-dione). FIG. 8 represents the percentage of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 1 and TSA required to obtain an additive or synergistic effect.

FIG. 9 shows TSA (i.e. trichostatin A) and compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)- 2 shows the additive and synergistic effects of piperidine-2,6-dione). FIG. 9 shows the number of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 2 and TSA required to obtain an additive or synergistic effect.

FIG. 10 shows TSA (i.e., trichostatin A) and compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)- 2 shows the additive and synergistic effects of piperidine-2,6-dione). FIG. 10 represents the percentage of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 2 and TSA required to obtain an additive or synergistic effect.

FIG. 11 shows VPA (i.e. valproic acid) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1, for cord blood-derived CD34 + proliferation. It shows the additive and synergistic effects of 3-dione). FIG. 11 shows the number of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 1 and VPA required to obtain an additive or synergistic effect.

FIG. 12 shows VPA (i.e. valproic acid) and Compound 1 (i.e. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1, for cord blood-derived CD34 + proliferation. It shows the additive and synergistic effects of 3-dione). FIG. 12 represents the percentage of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 1 and VPA required to obtain an additive or synergistic effect.

FIG. 13 shows VPA (i.e. valproic acid) and compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine on cord blood-derived CD34 + proliferation. Additive and synergistic effects of -2,6-dione). FIG. 13 shows the number of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 2 and VPA required to obtain an additive or synergistic effect.

FIG. 14 shows VPA (i.e. valproic acid) and compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine on cord blood derived CD34 + proliferation. Additive and synergistic effects of -2,6-dione). FIG. 14 represents the percentage of CD34 + cells obtained after 6 days of culture. The table shows the concentration of Compound 2 and VPA required to obtain an additive or synergistic effect.

FIG. 15 shows HU (i.e., hydroxyurea) and compound 1 (i.e., 4- (amino) -2- (2,6-dioxo) for fetal hemoglobin expression in CD34 + cells from normal donors with differentiated erythrocytes for 6 days. (3-piperidyl))-isoindoline-1,3-dione) or compound 2 (i.e. 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2 , 6-dione).

FIG. 16 shows HU (i.e., hydroxyurea) and compound 1 (i.e. 4- (amino) -2- () for fetal hemoglobin expression in CD34 + cells from sickle cell anemia patients (SCA) with erythrocyte differentiation for 6 days. 2 shows the synergistic effect of 2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione).

(5. Detailed explanation)
This embodiment includes immunomodulatory compounds (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1- Oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione), and valproic acid, hydroxyurea or trichostatin A, CD34 + hematopoietic stem cell proliferation, fetal hemoglobin expression and malignant cell apoptosis And based on the discovery of having additive and synergistic effects on anti-cell proliferation.

  Accordingly, in one embodiment, provided herein is a composition (eg, a pharmaceutical composition) comprising an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or A composition comprising 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione and valproic acid, hydroxyurea or trichostatin A (e.g. Pharmaceutical composition).

  In another embodiment, provided herein is a method for increasing CD34 + hematopoietic stem cell proliferation in vitro or in vivo, wherein the CD34 + hematopoietic stem cell comprises an effective amount of an immunomodulatory compound, and valproic acid, A method comprising contacting with hydroxyurea or trichostatin A in vitro or in vivo.

  In another embodiment, provided herein is a method of increasing CD34 + hematopoietic stem cell proliferation in vitro or in vivo, wherein CD34 + hematopoietic stem cells are treated with an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2, There is a method comprising contacting in vitro or in vivo with 6-dione and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of treating, preventing, or managing a disease or disorder treatable, preventable, or manageable by proliferation of CD34 + hematopoietic stem cells in vitro or in vivo. A method comprising administering to a patient in need thereof an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of treating, preventing, or managing a disease or disorder treatable, preventable, or manageable by proliferation of CD34 + hematopoietic stem cells in vitro or in vivo. An effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino- A method comprising administering 1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of transplanting bone marrow, wherein the bone marrow is contacted in vitro with an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A; Subsequent transplantation to a patient in need thereof.

  In another embodiment, provided herein is a method of transplanting bone marrow, wherein the bone marrow is treated with an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl). ) -Isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione and valproic acid, hydroxyurea Or a method comprising contacting in vitro with trichostatin A followed by transplantation to a patient in need thereof.

  In another embodiment, provided herein is a method of reconstructing bone marrow, wherein an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A is provided to a patient in need thereof. Administration. In certain embodiments, provided herein is a method of remodeling bone marrow of a patient who has received or is undergoing chemotherapy and / or radiation therapy, wherein the patient has an effective amount of immunization Administering a modulatory compound and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of remodeling bone marrow, wherein an effective amount of 4- (amino) -2- (2,6-dioxo is added to a patient in need thereof. (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, and A method comprising administering valproic acid, hydroxyurea or trichostatin A. In certain embodiments, provided herein is a method of reconstructing bone marrow of a patient who has received or is undergoing chemotherapy and / or radiation therapy, wherein the patient has an effective amount of 4 -(Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole-2 -Yl) -piperidine-2,6-dione and a method comprising administering valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of remodeling bone marrow comprising contacting the bone marrow with an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A. It is the method of including. In certain embodiments, the bone marrow has undergone or is undergoing chemotherapy or radiation therapy.

  In another embodiment, provided herein is a method of remodeling bone marrow, wherein the bone marrow is treated with an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl). ) -Isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione and valproic acid, hydroxyurea Or a method comprising contacting with trichostatin A. In certain embodiments, the bone marrow has or has undergone chemotherapy or radiation therapy.

  In another embodiment, provided herein includes, but is not limited to, malignant melanoma, pancreatic cancer, carcinoid unknown primary, renal cancer, breast cancer, adrenocortical cancer, colorectal cancer, endocrine tumor, A method for treating, preventing or managing solid tumors such as melanoma, neuroblastoma, osteosarcoma, retinoblastoma, Wilms tumor or non-small cell lung cancer (NSCLC), in an effective amount for patients in need thereof Administering an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein includes, but is not limited to, malignant melanoma, pancreatic cancer, carcinoid unknown primary, renal cancer, breast cancer, adrenocortical cancer, colorectal cancer, endocrine tumor, A method for treating, preventing or managing solid tumors such as melanoma, neuroblastoma, osteosarcoma, retinoblastoma, Wilms tumor or non-small cell lung cancer (NSCLC), in an effective amount for patients in need thereof 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole- A method comprising administering 2-yl) -piperidine-2,6-dione and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of treating, preventing, or managing a blood disease or disorder (e.g., a blood cancer or tumor) that is effective for a patient in need thereof. Administering an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of treating, preventing, or managing a blood disease or disorder (e.g., a blood cancer or tumor) that is effective for a patient in need thereof. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole -2-yl) -piperidine-2,6-dione and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein are myelodysplastic syndromes, multiple myeloma, beta hemoglobinopathy, leukemia, myeloma, lymphoma, myeloproliferative disorder, non-Hodgkin lymphoma, chronic lymphocytes For the treatment, prevention or management of sexual leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia and acute myeloblastic leukemia in an effective amount of immunomodulation for patients in need thereof Compound (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro -Isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxy Urea or trichostatin A or a pharmaceutically acceptable salt thereof , Solvates, hydrates, prodrugs, stereoisomers or polymorphs.

  In another embodiment, provided herein is a method for increasing fetal hemoglobin expression in a cell, wherein the fetal hemoglobin-expressing cell is treated with an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin. A method comprising contacting with A.

  In another embodiment, provided herein is a method of increasing fetal hemoglobin expression in a cell, wherein the fetal hemoglobin-expressing cell is treated with an effective amount of 4- (amino) -2- (2, 6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6- A method comprising contacting dione and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method for increasing fetal hemoglobin expression in a patient in need of increasing fetal hemoglobin expression, wherein the patient is in need of an effective amount of immunomodulation. Administering a compound and valproic acid, hydroxyurea or trichostatin A. In certain embodiments, provided herein is a method for increasing fetal hemoglobin expression in a patient having sickle cell anemia (SCA), wherein the compound has an effective amount of an immunomodulatory compound. And valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of increasing fetal hemoglobin expression in a patient in need of increasing fetal hemoglobin expression, wherein the effective amount of 4- (Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole-2- Yl) -piperidine-2,6-dione and valproic acid, hydroxyurea or trichostatin A. In certain embodiments, provided herein is a method for increasing fetal hemoglobin expression in a patient with SCA, wherein the patient has an effective amount of 4- (amino) -2- ( 2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2, A method comprising administering 6-dione and valproic acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of inducing apoptosis of malignant cells, wherein the malignant cells are contacted with an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A. A method comprising:

  In another embodiment, provided herein is a method of inducing apoptosis of malignant cells, wherein the malignant cells are treated with an effective amount of 4- (amino) -2- (2,6-dioxo ( 3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, and valpro A method comprising contacting with an acid, hydroxyurea or trichostatin A.

  In another embodiment, provided herein is a method of inhibiting the growth of malignant cells, wherein the malignant cells are contacted with an effective amount of an immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A. A method comprising:

  In another embodiment, provided herein is a method of inhibiting the growth of malignant cells, wherein the malignant cells are treated with an effective amount of 4- (amino) -2- (2,6-dioxo ( 3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, and valpro A method comprising contacting with acid, hydroxyurea or trichostatin A.

(5.1 definition)
As used herein, the term “patient” refers to any animal (eg, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, mouse, rabbit or guinea pig), in one embodiment. , Mammals such as non-primates or primates (eg monkeys or humans), and in another embodiment, humans. In certain embodiments, the human is an infant, child, adolescent or adult. In certain embodiments, the patient previously had or is at risk of having a blood disease or disorder. At-risk patients include, but are not limited to, humans who have a genetic history of a blood disease or disorder, or who have a physical health condition at risk of a blood disease or disorder. In one embodiment, the human patient has been previously treated or is currently being treated for a blood disease or disorder.

  The phrase “immunomodulatory compound and valproic acid, hydroxyurea or trichostatin A” includes: (a) an immunomodulatory compound and valproic acid; (b) an immunomodulatory compound and hydroxyurea; and (c) an immunomodulatory compound and trichostatin A; Each of which includes a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  The phrase "4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-iso" Indol-2-yl) -piperidine-2,6-dione and valproic acid, hydroxy or urea trichostatin A '' are: (a) 4- (amino) -2- (2,6-dioxo (3-piperidyl) -Isoindoline-1,3-dione and valproic acid; (b) 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione and trichostatin A; (c) 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione and hydroxyurea; (d) 3- (4-amino-1-oxo- 1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione and valproic acid; (e) 3- (4-amino-1-oxo-1,3-dihydro-isoindole-2- Yl) -piperidine-2,6-dione and trichostatin A; and (f) 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -Piperidine-2,6-dione and hydroxyurea; each comprising a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  The term “pharmaceutically acceptable salt” as used herein refers to salts prepared from pharmaceutically acceptable acids, such as inorganic and organic acids, unless otherwise specified. Suitable acids include, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzene sulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethene sulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glutamic acid, glucorenic acid ), Galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamonic acid, pantothenic acid, phenylacetic acid, propionic acid, Inorganic acids and organic acids such as phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid are included. Particular suitable acids are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.

  The term “solvate” as used herein, unless otherwise specified, further includes stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Means a compound or salt thereof provided in the text. When the solvent is water, the solvate is a “hydrate”.

  As used herein, the term “polymorph” means a compound described herein in a specific crystalline arrangement. Polymorphs can be obtained by using different post-treatment conditions and / or solvents. In particular, polymorphs can be prepared by recrystallization of the compounds described herein in certain solvents.

As used herein, the term “prodrug”, unless otherwise stated, is a compound that can be hydrolyzed, oxidized, or reacted under biological conditions (in vitro or in vivo) to provide a compound. Is a derivative of Examples of prodrugs include biohydrolyzable moieties (e.g., biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolysables. Compounds including, but not limited to, a soluble phosphate analog). Other examples of prodrugs include compounds that contain a —NO, —NO ₂ , —ONO, or —ONO ₂ moiety. Prodrugs are generally obtained by well-known methods, for example, “Burger's Medicinal Chemistry and Drug Discovery”, 172-178, 949-982 (edited by Manfred E. Wolff, 5th edition 1995). ), And “Design of prodrugs” (edited by H. Bundgaard, Elselvier, New York 1985).

  As used herein, the terms “biohydrolyzable carbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureido” and “biohydrolyzable phosphate”, unless otherwise specified, respectively Means carbamate, carbonate, ureido and phosphate of any of the following compounds: 1) does not interfere with the biological activity of the compound and provides advantageous properties of the compound in vivo, such as uptake, duration of action, or onset of action Or 2) a compound that is biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkyl amines, substituted ethylene diamines, amino acids, hydroxyalkyl amines, heterocyclic and heteroaromatic amines, and polyether amines.

  As used herein, the term “stereoisomer” refers to all enantiomerically / stereoisomerically pure and enantiomeric / stereoisomers provided herein unless otherwise specified. Includes isomerically enriched compounds.

  The compounds provided herein can exist as racemic mixtures of enantiomers or mixtures of diastereomers. Embodiments provided herein include the use of stereoisomerically pure forms of this type of compound, as well as the use of mixtures of these forms. For example, mixtures containing equal or unequal enantiomers of a compound can be used in the methods and compositions provided herein. These isomers can be synthesized asymmetrically or resolved using standard methods such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., “Enantiomers, Racemates and Resolutions” (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33: 2725. (1977); Eliel, EL, `` Stereochemistry of Carbon Compounds '' (McGraw-Hill, NY, 1962); and Wilen SH, `` Tables of Resolving Agents and Optical Resolutions), p. 268 (EL Eliel, Univ. Of Notre Dame Press, Notre Dame, IN, 1972). As used herein, “stereoisomerically pure”, “enantiomerically pure”, or “optically pure”, unless stated otherwise, includes a stereoisomer and includes: Means substantially free of counter stereoisomers or enantiomers. For example, if a compound contains 80%, 90%, or 95% or more of one stereoisomer and no more than 20%, 10%, or 5% of the counter stereoisomer, the compound is either stereoisomeric or Enantiomerically pure. In certain cases, the compound is greater than about 80% ee (enantioexcess), in one embodiment, greater than 90% ee for a particular chiral center, and in another embodiment, 95% ee for a particular chiral center. In some cases, a compound is considered optically active or stereoisomerically / enantiomerically pure (ie, substantially R form or substantially S form) with respect to a chiral center.

  Also, as used herein, the terms “stereoisomerically enriched” or “enantiomerically enriched” refer to mixtures other than racemates, eg, mixtures of stereoisomers of a compound, unless otherwise specified. (Eg R / S = 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, and 70/30).

  As used herein, the terms “treat”, “treating” and “treatment” refer to a disease or condition that occurs while a patient is suffering from a particular disease or disorder, unless otherwise specified. It is intended to act to reduce the severity of the disorder or its symptoms, or to delay or delay the progression of the disease or disorder or its symptoms.

  As used herein, the terms “prevent”, “preventing” and “prevention”, unless otherwise specified, refer to a disease or condition that occurs before a patient has a particular disease or disorder or symptom thereof. Intended to inhibit or reduce the severity of the disorder or its symptoms. Patients at risk for blood diseases or disorders are candidates for this type of prophylactic therapy.

  As used herein, the terms “manage”, “managing” and “management” refer to a disease in a patient who has already suffered from a particular disease or disorder or symptom thereof, unless otherwise specified. Or preventing recurrence of the disorder or symptom thereof, and / or increasing the time that a patient suffering from the disease or disorder or symptom thereof remains in remission. These terms include adjusting the threshold, onset, and / or duration of the disease or disorder or symptom thereof, or changing the way the patient addresses the disease or disorder or symptom thereof.

  The term “effective amount” of a compound or composition as used herein is an amount sufficient to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease, unless otherwise specified. Or an amount sufficient to delay or minimize one or more symptoms associated with a disease or disorder. In one embodiment, the term `` effective amount '' used in the compositions, methods of use, and methods of treatment, prevention, and management provided herein is an immunomodulatory compound (e.g., 4- (amino)- 2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine -2,6-dione), or pharmaceutically acceptable salts, solvates, hydrates, prodrugs, stereoisomers or polymorphs thereof, and valproic acid, hydroxyurea or trichostatin A, or Amounts of pharmaceutically acceptable salts, solvates, hydrates, prodrugs, stereoisomers or polymorphs that are useful in the methods described herein when used in combination with each other. Or a therapeutic benefit to the patient, such as treatment, prevention, and / or management of a disease or disorder. Providing either or means an amount of delay or minimize one or more symptoms associated with a disease or disorder. For example, the phrase “effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1, 3-Dihydro-isoindol-2-yl) -piperidine-2,6-dione, and valproic acid, hydroxyurea or trichostatin A include: When used in the combinations described herein, disease Or an effective amount of each compound that provides a therapeutic benefit to the patient, such as treatment, prevention, and / or management of a disorder, or the effectiveness of each compound that delays or minimizes one or more symptoms associated with the disease or disorder amount.

  The term “effective amount” includes an amount that improves overall therapy, an amount that reduces or avoids the cause of a disease or disorder or its symptoms, or an amount that enhances the therapeutic effectiveness of another therapeutic agent. it can.

  The terms `` co-administration '' and `` combination '' refer to two therapeutic agents (i.e. immunomodulatory compounds (e.g. 4- (amino) -2- ( 2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6 -Dione, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A, or a pharmaceutically acceptable salt thereof, Solvates, hydrates, prodrugs, stereoisomers or polymorphs) In one embodiment, both agents are present in the cell or in the patient's body at the same time, or their biology In another embodiment, the two therapeutic agents are in the same set. In yet another embodiment, the two therapeutic agents are another composition or unit dosage form.

  The term “leukemia” refers to a malignant tumor of hematopoietic tissue. In certain embodiments, leukemia includes, but is not limited to, myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. Not. Leukemia can recur and is often refractory or resistant to conventional therapies. The term “recurrence” refers to a situation in which there is a return of leukemia cells and a decrease in normal blood cells in the bone marrow in patients who have had a leukemia remission after therapy. The term “refractory or resistant” refers to a situation in which patients have leukemia cells remaining in their bone marrow even after intensive treatment.

  The term “remodeling” with respect to the bone marrow includes growing normal hematopoietic progenitor cells to reconstruct a normal blood cell population.

  The terms "unit dosage form" and "single unit dosage form" include: tablets; chewable tablets; caplets; capsules such as soft elastic gelatin capsules; sachets; cachets; lozenges; lozenges; Liquids; gels; liquid dosage forms suitable for oral or mucosal administration to patients, such as suspensions (eg, aqueous or non-aqueous liquid suspensions), emulsions (eg, oil-in-water emulsions or oils) Aqueous liquid emulsions), solutions, and elixirs; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for oral or parenteral administration to a patient ). A unit dosage form does not necessarily have to be administered as a unit dose.

(5.2 Immunomodulatory compounds)
Specific examples of immunomodulatory compounds include, but are not limited to, the following: cyano and carboxy derivatives of substituted styrenes (such as those disclosed in US Pat. No. 5,929,117); 1-oxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindoline and 1,3-dioxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindoline (e.g., U.S. Pat. 5,874,448 and 5,955,476); tetrasubstituted 2- (2,6-dioxopiperzin-3-yl) -1-oxoisoindoline described in U.S. Pat.No. 5,798,368; 1-oxo And l, 3-dioxo-2- (2,6-dioxopiperidin-3-yl) -isoindoline (e.g., 4-methyl derivative of thalidomide) (disclosed in U.S. Pat.Nos. 5,635,517, 6,476,052, 6,555,554, and 6,403,613). Including, but not limited to, those described in U.S. Pat.No. 6,380,239. 1-oxo and 1,3-dioxoisoindoline substituted at the 4- or 5-position of the indoline ring (e.g. 4- (4-amino-1,3-dioxoisoindoline-2-yl)- 4-carbamoylbutanoic acid); isoindoline-1-one and isoindoline-1 substituted in the 2-position with 2,6-dioxo-3-hydroxypiperidin-5-yl as described in US Pat. No. 6,458,810 , 3-diones (e.g., 2- (2,6-dioxo-3-hydroxy-5-fluoropiperidin-5-yl) -4-aminoisoindoline-1-one); disclosed in U.S. Patent Nos. 5,698,579 and 5,877,200 Non-polypeptide cyclic amides; aminothalidomide, and analogs, hydrolysis products, metabolites, derivatives, and precursors of aminothalidomide, and substituted 2- (2,6-dioxopiperidin-3-yl) Phthalimide and substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindole ( For example, those described in U.S. Pat.Nos. 6,281,230 and 6,316,471); and isoindole-imide compounds (e.g., U.S. Patent Application Serial No. 09 / 972,487, filed December 21, 2001, filed October 5, 2001). U.S. Patent Application No. 10 / 032,286 filed on the day, and International Application No. PCT / US01 / 50401 (International Publication No. WO 02/059106). The entirety of each of the patents and patent applications identified in this specification is incorporated herein by reference. In one embodiment, the immunomodulatory compound does not comprise thalidomide.

Other specific immunomodulatory compounds include 1-oxo- and 1,3 substituted with amino in the benzo ring, as described in US Pat. No. 5,635,517 (incorporated herein by reference). -Including but not limited to -dioxo-2- (2,6-dioxopiperidin-3-yl) isoindoline. These compounds have the structure I:

Wherein one of X and Y is C═O, the other of X and Y is C═O or CH ₂ , and R ² is hydrogen or lower alkyl, especially methyl. Certain immunomodulatory compounds include, but are not limited to:

  1-oxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline;

  1-oxo-2- (2,6-dioxopiperidin-3-yl) -5-aminoisoindoline;

  1-oxo-2- (2,6-dioxopiperidin-3-yl) -6-aminoisoindoline;

  1-oxo-2- (2,6-dioxopiperidin-3-yl) -7-aminoisoindoline;

  l, 3-dioxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline; and

  1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) -5-aminoisoindoline.

Other specific immunomodulatory compounds include substituted 2- (2,6-dioxopiperidin-3-yl) phthalimide and substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindole ( For example, it belongs to the types of U.S. Patent Nos. 6,281,230, 6,316,471, 6,335,349 and 6,476,052, and International Patent Application No.PCT / US97 / 13375 (International Publication No.WO 98/03502) . Each of these documents is incorporated herein by reference. Exemplary compounds are of the formula:

  Where

One of X and Y is C = O and the other of X and Y is C = O or CH ₂ ;

(i) each of R ¹ , R ² , R ³ and R ⁴ is independently of the others halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, or ( ii) ^one of R ¹ , R ² , R ³ and R ⁴ is -NHR ⁵ and the remainder of R ¹ , R ² , R ³ and R ⁴ is hydrogen;

R ⁵ is hydrogen or alkyl of 1 to 8 carbon atoms;

R ⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl or halo;

Provided that X and Y are C = O and (i) each of R ¹ , R ² , R ³ and R ⁴ is fluoro, or ^one of R ¹ , R ² , R ³ and R ⁴ is If amino, R ⁶ is other than hydrogen.

A representative compound of this type is of the formula:

In the formula, R ¹ is hydrogen or methyl. In separate embodiments, the methods and compositions provided herein are in an enantiomerically pure form (e.g., optically pure (R) or (S) enantiomer) of an immunomodulatory compound. Including use.

  Still other specific immunomodulatory compounds are isoindoles disclosed in US Patent Application Publication Nos. US 2003/0096841 and US 2003/0045552, and International Application No. PCT / US01 / 50401 (International Publication No.WO 02/059106). -Belongs to imides. Each of these documents is incorporated herein by reference.

式中、 Exemplary compounds are Formula II and pharmaceutically acceptable salts, hydrates, solvates, inclusion compounds, enantiomers, diastereomers, racemates, and mixtures of stereoisomers:

Where

One of X and Y is C = O and the other is CH ₂ or C = O;

R ¹ is H, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, benzyl, aryl, (C ₀ -C ₄₎ alkyl - (C ₁ -C ₆₎ heterocycloalkyl, (C ₀ -C ₄₎ alkyl - (C ₂ -C ₅₎ ^{heteroaryl, C (O) R 3,} C (S) R 3, C (O) OR ⁴ , (C ₁ -C ₈ ) alkyl-N (R ⁶ ) ₂ , (C ₁ -C ₈ ) alkyl-OR ⁵ , (C ₁ -C ₈ ) alkyl-C (O) OR ⁵ , C (O) NHR ³ , C (S) NHR ³ , C (O) NR ³ R ^{3 ′} , C (S) NR ³ R ^{3 ′} , or (C ₁ -C ₈ ) alkyl-O (CO) R ₅ ;

R ² is H, F, benzyl, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl or (C ₂ -C ₈ ) alkynyl;

R ³ and R ^{3 ′} are independently alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, benzyl, aryl, (C _0- C ₄₎ alkyl - (C ₁ -C ₆₎ heterocycloalkyl, (C ₀ -C ₄₎ alkyl - (C ₂ -C ₅₎ heteroaryl, (C ₀ -C ₈₎ alkyl -N (R ⁶⁾ ₂ , (C ₁ -C ₈ ) alkyl-OR ⁵ , (C ₁ -C ₈ ) alkyl-C (O) OR ⁵ , (C ₁ -C ₈ ) alkyl-O (C0) R ⁵ , or C (O) OR ⁵ ;

R ⁴ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₁ -C ₄ ) alkyl-OR ⁵ , benzyl, aryl, (C ₀ -C ₄₎ alkyl - (C ₁ -C ₆₎ heterocycloalkyl, or (C ₀ -C ₄₎ alkyl - (C ₂ -C ₅₎ heteroaryl;

R ⁵ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, benzyl, aryl or (C ₂ -C ₅ ) heteroaryl;

Each occurrence of R ⁶ is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, benzyl, aryl, (C ₂ -C ₅ ) Heteroaryl or (C ₀ -C ₈ ) alkyl-C (O) OR ⁵ , or the R ⁶ group can be attached to form a heterocycloalkyl group;

  n is O or l; and

  * Represents a chiral carbon center.

In certain compounds of formula II, when n is 0, R ¹ is (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, benzyl, aryl, (C ₀ -C ₄ ) alkyl- (C ₁ -C ₆ ) heterocycloalkyl, (C ₀ -C ₄ ) alkyl- (C ₂ -C ₅ ) heteroaryl, C (O) R ³ , C (O) OR ⁴ , (C ₁ -C ₈ ) alkyl-N (R ⁶ ) ₂ , (C ₁ -C ₈ ) alkyl-OR ⁵ , (C ₁ -C ₈ ) alkyl-C (O) OR ⁵ , C (S NHR ³ or (C ₁ -C ₈ ) alkyl-O (CO) R ⁵ ;

R ² is H or (C ₁ -C ₈ ) alkyl; and

R ³ is, (C1-C8) alkyl, (C ₃ -C ₇₎ cycloalkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, benzyl, aryl, (C ₀ -C ₄₎ Alkyl- (C ₁ -C ₆ ) heterocycloalkyl, (C ₀ -C ₄ ) alkyl- (C ₂ -C ₅ ) heteroaryl, (C ₅ -C ₈ ) alkyl-N (R ⁶ ) ₂ ; (C ₀ -C ₈ ) alkyl-NHC (O) OR ⁵ ; (C ₁ -C ₈ ) alkyl-OR ⁵ , (C ₁ -C ₈ ) alkyl-C (O) OR ⁵ , (C ₁ -C ₈ ) alkyl -O (CO) be R ⁵ or C (O) oR ^5; and other variables have the same definition.

In other specific compounds of formula II, R ² is H or (C ₁ -C ₄ ) alkyl.

In other specific compounds of formula II, R ¹ is (C ₁ -C ₈ ) alkyl or benzyl.

である。 In other specific compounds of formula II, R ¹ is H, (C ₁ -C ₈ ) alkyl, benzyl, CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₃ or

It is.

であり、 In another embodiment of the compounds of formula II, R ¹ is

And

Where Q is O or S and each occurrence of R7 is independently H, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₈ ) Alkenyl, (C ₂ -C ₈ ) alkynyl, benzyl, aryl, halogen, (C ₀ -C ₄ ) alkyl- (C ₁ -C ₆ ) heterocycloalkyl, (C ₀ -C ₄ ) alkyl- (C _2- C ₅ ) heteroaryl, (C ₀ -C ₈ ) alkyl-N (R ⁶ ) ₂ , (C ₁ -C ₈ ) alkyl-OR ⁵ , (C ₁ -C ₈ ) alkyl-C (O) OR ⁵ , (C ₁ -C ₈ ) alkyl-O (CO) R ⁵ , or C (O) OR ⁵ , or adjacent occurrences of R ⁷ are taken together to form a bicyclic alkyl or aryl ring. Can be.

In other specific compounds of formula II, R ¹ is C (O) R ³ .

In other specific compounds of formula II, R ³ is (C ₀ -C ₄ ) alkyl- (C ₂ -C ₅ ) heteroaryl, (C ₁ -C ₈ ) alkyl, aryl or (C ₀ -C ₄ ) alkyl -OR ^5.

  In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.

In other specific compounds of formula II, R ¹ is C (O) OR ⁴ .

In other specific compounds of formula II, the H of C (O) NHC (O) can be replaced with (C ₁ -C ₄ ) alkyl, aryl or benzyl.

  Additional examples of this type of compound include, but are not limited to: [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H— Isoindol-4-ylmethyl] -amide; (2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl) -carbamine Acid tert-butyl ester; 4- (aminomethyl) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione; N- (2- (2,6-dioxo-piperidine) -3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl) -acetamide; N-{(2- (2,6-dioxo (3-piperidyl) -1, 3-Dioxoisoindoline-4-yl) methyl} cyclopropyl-carboxamide; 2-chloro-N-{(2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline- 4-yl) methyl} acetamide; N- (2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoli N-4-yl) -3-pyridylcarboxamide; 3- {1-oxo-4- (benzylamino) isoindolin-2-yl} piperidine-2,6-dione; 2- (2,6-dioxo (3 -Piperidyl))-4- (benzylamino) isoindoline-1,3-dione; N-{(2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline-4- Yl) methyl} propanamide; N-{(2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline-4-yl) methyl} -3-pyridylcarboxamide; N- { (2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline-4-yl) methyl} heptanamide; N-{(2- (2,6-dioxo (3-piperidyl ))-1,3-Dioxoisoindoline-4-yl-methyl} -2-furylcarboxamide; {N- (2- (2,6-dioxo (3-piperidyl))-1,3-dioxoiso Indoline-4-yl) carbamoyl} methyl acetate; N- (2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline-4-yl) pe Tanamide; N- (2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline-4-yl) -2-thienylcarboxamide; N-{[2- (2,6- Dioxo (3-piperidyl))-1,3-dioxoisoindoline-4-yl] methyl} (butylamino) carboxamide; N-{[2- (2,6-dioxo (3-piperidyl))-1, 3-dioxoisoindoline-4-yl] methyl} (octylamino) carboxamide; and N-{[2- (2,6-dioxo (3-piperidyl))-1,3-dioxoisoindoline-4- Yl] methyl} (benzylamino) carboxamide.

  Still other specific immunomodulatory compounds belong to the class of isoindole-imides disclosed in US Patent Application Publication US 2002/0045643, International Publication Number WO 98/54170, and US Patent No. 6,395,754. Each document is incorporated herein by reference.

式中、 Exemplary compounds are Formula III and pharmaceutically acceptable salts, hydrates, solvates, inclusion compounds, enantiomers, diastereomers, racemates, and mixtures of stereoisomers:

Where

One of X and Y is C = O and the other is CH ₂ or C = O;

R is H or CH ₂ OCOR ';

(i) whether each of R ¹ , R ² , R ³ or R ⁴ is independently of the others halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms Or (ii) ^one of R ¹ , R ² , R ³ or R ⁴ is nitro or —NHR ⁵ and the remainder of R ¹ , R ² , R ³ or R ⁴ is hydrogen;

R ⁵ is hydrogen or alkyl of 1 to 8 carbon atoms;

R ⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro;

R ′ is R ⁷ —CHR ¹⁰ —N (R ⁸ R ⁹ );

R ⁷ is m-phenylene or p-phenylene or — (C _n H _2n ) —, where n has a value of O to 4;

Each of R ⁸ and R ⁹ is, independently of the others, hydrogen or alkyl of 1 to 8 carbon atoms, or R ⁸ and R ^{9 taken} together are tetramethylene, pentamethylene, Hexamethylene, or —CH ₂ CH ₂ X ₁ CH ₂ CH ₂ —, wherein X ₁ is −0—, —S—, or —NH—;

R ¹⁰ is hydrogen, alkyl of 8 to 8 carbon atoms, or phenyl; and

  * Represents a chiral carbon center.

Other representative compounds are of the formula:

  Where

One of X and Y is C = O and the other of X and Y is C = O or CH ₂ ;
(i) each of R ¹ , R ² , R ³ or R ⁴ ₄ is independently of the others halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms Or one of R ¹ , R ² , R ³ and R ⁴ is -NHR ⁵ and the remainder of R ¹ , R ² , R ³ and R ⁴ is hydrogen;

R ⁵ is hydrogen or alkyl of 1 to 8 carbon atoms;

R ⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro;

R ⁷ is m-phenylene or p-phenylene or — (C _n H _2n ) — (where n has a value from 0 to 4);

Each of R ⁸ and R ⁹ is, independently of the others, hydrogen or alkyl of 1 to 8 carbon atoms, or R ⁸ and R ^{9 taken} together are tetramethylene, pentamethylene, Hexamethylene, or —CH ₂ CH ₂ X ¹ CH ₂ CH ₂ —, wherein X ¹ is —O—, —S—, or —NH—;

R ¹⁰ is hydrogen, alkyl of 8 to 8 carbon atoms, or phenyl.

Other representative compounds are of the formula:

  Where

One of X and Y is C = O and the other of X and Y is C = O or CH ₂ ;

Each of R ¹ , R ² , R ³ and R ⁴ is independently of the others halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, or ( ii) ^one of R ¹ , R ² , R ³ and R ⁴ is nitro or protected amino, and the remainder of R ¹ , R ² , R ³ and R ⁴ is hydrogen; and

R ⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro.

Other representative compounds are of the formula:

  Where

One of X and Y is C = O and the other of X and Y is C = O or CH ₂ ;

(i) whether each of R ¹ , R ² , R ³ and R ⁴ is independently of the others halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms Or (ii) ^one of R ¹ , R ² , R ³ and R ⁴ is -NHR ⁵ and the remainder of R ¹ , R ² , R ³ and R ⁴ is hydrogen;

R ⁵ is hydrogen, alkyl of 1 to 8 carbon atoms or CO—R ⁷ —CH (R ¹⁰ ) NR ⁸ R ⁹ (each of R ⁷ , R ⁸ , R ⁹ and R ^{10 is} as defined herein) Defined in); and

R ⁶ is alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro.

Specific examples of compounds are those of the formula:

  Where

One of X and Y is C = O and the other of X and Y is C = O or CH ₂ ;

R ⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, chloro or fluoro;

R ⁷ is m-phenylene, p-phenylene or — (C _n H _2n ) — (where n has a value from 0 to 4);

Each of R ⁸ and R ⁹ is, independently of the others, hydrogen or alkyl of 1 to 8 carbon atoms, or R ⁸ and R ^{9 taken} together are tetramethylene, pentamethylene, Hexamethylene, or —CH ₂ CH ₂ X ¹ CH ₂ CH ₂ —, wherein X ¹ is —O—, —S—, or —NH—; and

R ¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl.

  Specific immunomodulatory compounds include 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione and 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2,6-dione.

G.W. Mullerらの米国特許第5,635,517号に記載されており、その全体において本明細書中に引用により取り込まれている。4-(アミノ)-2-(2,6-ジオキソ(3-ピペリジル))-イソインドリン-1,3-ジオンは、従来の有機合成を用いて、及び市販の開始物質を用いて製造することができる。例えば、この例に限らないが、4-(アミノ)-2-(2,6-ジオキソ(3-ピペリジル))-イソインドリン-1,3-ジオンは、米国特許第5,635,517号に記載されているように調製することができる。 4- (Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione has the following chemical structure:

GW Muller et al., US Pat. No. 5,635,517, which is incorporated by reference herein in its entirety. 4- (Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione should be prepared using conventional organic synthesis and using commercially available starting materials. Can do. For example, but not limited to this example, 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione is described in US Pat. No. 5,635,517. Can be prepared as follows.

3- (4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is an immunomodulatory compound having the following chemical structure:

  U.S. Pat. No. 5,635,517 to G.W. Muller et al., Which is incorporated herein by reference in its entirety. 3- (4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is obtained using conventional organic synthesis and using commercially available starting materials. Can be manufactured. For example, but not limited to this example, 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is described in US Pat. No. 5,635,517. Can be prepared as described.

  In another embodiment, certain immunomodulatory compounds of the invention are polymorphs of 3- (4-amino-1-oxo-1,3dihydro-isoindol-2-yl) -piperidine-2,6-dione For example, Forms A, B, C, D, E, F, G, and H disclosed in U.S. Provisional Patent Application No. 60 / 499,723, filed September 4, 2003, and corresponding U.S. Non-Provisional Patent Applications. Is included. Both documents are incorporated herein by reference. For example, Form A of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is a non-solvent that can be obtained from a non-aqueous solvent system It is a Japanese crystalline substance. Form A has a powder X-ray diffraction pattern containing significant peaks at about 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2θ, with a maximum melting point of about 270 ° C. measured by differential scanning calorimetry. is there. Form A is weakly hygroscopic or non-hygroscopic and has been previously discovered 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2, It appears to be the most thermodynamically stable anhydrous polymorph of 6-dione.

  Form B of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione included hexane, toluene, water, etc. Although not, it is a hemihydrate crystalline material that can be obtained from various solvent systems. Form B has a powder X-ray diffraction pattern with significant peaks at about 16, 18, 22, and 27 degrees 2θ, and has an endotherm at about 146 and 268 ° C. according to the DSC curve. Confirmed as dehydrated and melted by stage microscopy. Interconversion studies have shown that Form B converts to Form E in aqueous solvent systems and to other forms in acetone and other anhydrous systems.

  Form C of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is obtained from a solvent such as but not limited to acetone. A semi-solvated crystalline material that can be used. Form C has a powder X-ray diffraction pattern with significant peaks at about 15.5 and 25 degrees 2θ, with a maximum melting point of about 269 ° C. measured by differential scanning calorimetry. Form C is not hygroscopic at humidity below about 85% RH, but may convert to Form B at high relative humidity.

  Form D of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is a solvated crystal prepared from a mixture of acetonitrile and water It is a sexual polymorph. Form D has a powder X-ray diffraction pattern with significant peaks at about 27 and 28 degrees 2θ, with a maximum melting point of about 270 ° C. measured by differential scanning calorimetry. Form D is weakly hygroscopic or non-hygroscopic, but usually may be converted to form B when subjected to stress in a state where the relative humidity is high.

  Form E of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is represented by 3- (4-amino-1-oxo-1, 3-Dihydro-isoindol-2-yl) -piperidine-2,6-dione was slurried in water and then 3- (4-amino-1-) in a solvent system with an acetone: water ratio of about 9: 1. Oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is a dihydrated, crystalline material that can be obtained by slow evaporation. Form E has a powder X-ray diffraction pattern with significant peaks at about 20, 24.5 and 29 degrees 2θ, with a maximum melting point of about 269 ° C. measured by differential scanning calorimetry. Form E may convert to Form C in an acetone solvent system and to Form G in a THF solvent system. In aqueous solvent systems, Form E appears to be the most stable form. Desolvation experiments performed on Form E show that Form E may convert to Form B when heated at about 125 ° C. for about 5 minutes. Form B may convert to Form F when heated at 175 ° C. for about 5 minutes.

  Form F of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is an unsolvated that can be obtained by dehydration of Form E It is a crystalline substance. Form F has a powder X-ray diffraction pattern with significant peaks at about 19, 19.5 and 25 degrees 2θ, with a maximum melting point of about 269 ° C. measured by differential scanning calorimetry.

  Form G of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione can be obtained by converting Form B and Form E to tetrahydrofuran (THF) and the like ( Non-solvated, crystalline materials that can be obtained by slurrying in (but not limited to) solvents. Form G has a powder X-ray diffraction pattern with significant peaks at about 21, 23, and 24.5 degrees 2θ, with a maximum melting point of about 267 ° C. measured by differential scanning calorimetry.

  Form H of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is obtained by exposing Form E to 0% relative humidity It is a partially hydrated (about 0.25 mole), crystalline material. Form H has a powder X-ray diffraction pattern with significant peaks at about 15, 26 and 31 degrees 2θ, with a maximum melting point of about 269 ° C. measured by differential scanning calorimetry.

Other specific immunomodulatory compounds, each incorporated herein by reference, are described in, for example, US Pat. Nos. 5,874,448 and 5,955,476, 1-oxo-2- (2,6 -Dioxo-3-fluoropiperidin-3-yl) isoindoline and 1,3-dioxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindoline, but are not limited to these . Representative compounds are of the formula:

Where Y is oxygen or H ² and

Each R ^1, R ^2, R ³ and R ^4, the others independently hydrogen, halo, 1 to 4 carbon atoms alkyl, of 1 to 4 carbon atoms alkoxy, or amino.

Other specific immunomodulatory compounds are tetrasubstituted 2- (2,6-dioxopiperidin-3-yl) -1 as described in US Pat. No. 5,798,368, which is incorporated herein by reference. -Oxoisoindoline, but is not limited to. Exemplary compounds are of the formula:

Wherein each of R ¹ , R ² , R ³ and R ⁴ is independently of the others halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms.

Other specific immunomodulatory compounds are 1-oxo and 1,3-dioxo-2- (2,6-dioxo, disclosed in US Pat. No. 6,403,613, which is incorporated herein by reference. Examples include, but are not limited to, piperidin-3-yl) isoindoline. Exemplary compounds are of the formula:

  Where

Y is oxygen or H ₂

The ^first of R ¹ and R ² is halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano, or carbamoyl, and the ^second of R ¹ and R ² is hydrogen independently of the first. Halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, and

R ³ is hydrogen, alkyl or benzyl.

Specific examples of compounds are those of the formula:

Wherein the ^first of R ¹ and R ² is halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino, cyano or carbamoyl wherein each alkyl is 1 to 4 carbon atoms And

The ^second of R ¹ and R ² is independently of the first, hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms Alkylamino which is dialkylamino, cyano or carbamoyl, each alkyl having 1 to 4 carbon atoms, and

R ³ is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl. Specific examples include, but are not limited to, 1-oxo-2- (2,6-dioxopiperidin-3-yl) -4-methylisoindoline.

Other representative compounds are of the formula:

Wherein the ^first of R ¹ and R ² is halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino, cyano or carbamoyl wherein each alkyl is 1 to 4 carbon atoms And

The ^second of R ¹ and R ² is independently of the first, hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms Alkylamino which is dialkylamino, cyano or carbamoyl, each alkyl having 1 to 4 carbon atoms, and

R ³ is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl.

Other specific immunomodulatory compounds are described in U.S. Patent No. 6,380,239 and U.S. Patent Application No. 10 / 900,270 filed July 28, 2004, which are incorporated herein by reference. Examples include, but are not limited to, 1-oxo and 1,3-dioxoisoindolines substituted at the 4- or 5-position of the indoline ring. Representative compounds are those of the formulas and their salts:

The carbon atom represented by C ^* constitutes a chiral center (when n is not zero and R ¹ is not the same as R ² ); ^one of X ¹ and X ² is amino, nitro, carbon atoms 1-6 An alkyl or NH-Z, the other of X ¹ and X ² is hydrogen; each of R ¹ and R ² is independently hydroxy or NH-Z, R ³ is hydrogen, alkyl of 1 to 6 carbon atoms, halo or haloalkyl; Z is hydrogen, aryl, alkyl of 1 to 6 carbon atoms, formyl or acyl of 1 to 6 carbon atoms; and n Is a value of 0, 1 or 2; provided that when X ¹ is amino and n is 1 or 2, R ¹ and R ² are not simultaneously hydroxy.

Further representative compounds are of the formula:

In which the carbon atom denoted by C ^* constitutes a chiral center (when n is not zero and R ¹ is not the same as R ² ); ^one of X ¹ and X ² is an amino, nitro, carbon atom 1-6 alkyl or NH-Z, the other of X ¹ and X ² is hydrogen; each of R ¹ and R ² is independently hydroxy or NH-Z, R ³ is alkyl of 1 to 6 carbon atoms, halo or hydrogen; Z is hydrogen, aryl, or alkyl or acyl of 1 to 6 carbon atoms;
N is a value of 0, 1 or 2.

Specific examples include 2- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -4-carbamoylbutyric acid and 4- (4-amino-1-) each having the following structure: Oxo-1,3-dihydro-isoindol-2-yl) -4-carbamoylbutyric acid and pharmaceutically acceptable salts, solvates, prodrugs and stereoisomers thereof, including but not limited to :

Other representative compounds are those of the following formula and their salts:

The carbon atom represented by C ^* constitutes a chiral center (when n is not zero and R ¹ is not the same as R ² ); ^one of X ¹ and X ² is amino, nitro, carbon atoms 1-6 Each alkyl or NH-Z, the other of X ¹ and X ² is hydrogen; each of R ¹ and R ² is independently hydroxy or NH-Z, independently of the others R ³ is alkyl of 1 to 6 carbon atoms, halo or hydrogen; Z is hydrogen, aryl, or alkyl or acyl of 1 to 6 carbon atoms; and n is a value of 0, 1 or 2; It is.

Specific examples include 4-carbamoyl-4- {4-{(furan-2-yl-methyl) -amino] -1,3-dioxo-1,3-dihydro-isoindole-2 each having the following structure: -Yl} -butyric acid, 4-carbamoyl-2- {4-[(furan-2-yl-methyl) -amino] -1,3-dioxo-1,3-dihydro-isoindol-2-yl} -butyric acid 2- {4-[(furan-2-yl-methyl) -amino] -1,3-dioxo-1,3-dihydro-isoindol-2-yl} -4-phenylcarbamoyl-butyric acid, and 2- {4-[(Furan-2-yl-methyl) -amino] -1,3-dioxo-1,3-dihydro-isoindol-2-yl} -pentanedioic acid and pharmaceutically acceptable salts thereof , Solvates, prodrugs and stereoisomers, including but not limited to:

Other specific examples of compounds are those of the formula:

Wherein ^one of X ¹ and X ² is nitro or NH-Z and the other of X ¹ and X ² is hydrogen;

Each of R ¹ and R ² is, independently of the others, hydroxy or NH-Z;

R ³ is alkyl of 1 to 6 carbon atoms, halo or hydrogen;

  Z is hydrogen, phenyl, acyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; and

  n has a value of 0, 1 or 2;

Provided that when ^one of X ¹ and X ² is nitro and n is 1 or 2, R ¹ and R ² are groups other than hydroxy; and

When -COR ² and-(CH ₂ ) _n COR ¹ are different, the carbon atom represented by C ^* constitutes a chiral center. Other representative compounds are of the formula:

Wherein one of X ¹ and X ² is alkyl of 1 to 6 carbon atoms;

Each of R ¹ and R ² is, independently of the others, hydroxy or NH-Z;

R ³ is alkyl of 1 to 6 carbon atoms, halo or hydrogen;

  Z is hydrogen, phenyl, acyl having 1 to 6 carbon atoms, or alkyl having 1 to 6 carbon atoms; and

  n is a value of 0, 1 or 2; and

When -COR ² and-(CH ₂ ) _n COR ¹ are different, the carbon atom represented by C ^* constitutes a chiral center.

Still other specific immunomodulatory compounds include those described in US Pat. No. 6,458,810, which is incorporated herein by reference, in position 2,6-dioxo-3-hydroxypiperidine-5- Examples include, but are not limited to, isoindoline-1-one and isoindoline-1,3-dione substituted with yl. Exemplary compounds are of the formula:

  Where

  The carbon atom indicated by * constitutes a chiral center;

X is —C (O) — or —CH ₂ —;

R ¹ is alkyl of 1 to 8 carbon atoms or —NHR ³ ;

R ² is hydrogen, alkyl of 1 to 8 carbon atoms, or halogen;

  And,

R ³ is hydrogen;

  An alkyl of 1 to 8 carbon atoms substituted with an unsubstituted alkyl of 1 to 8 carbon atoms, or alkoxy, halo, amino, or an alkylamino of 1 to 4 carbon atoms;

  Cycloalkyl having 3 to 18 carbon atoms;

  Unsubstituted phenyl or phenyl substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms;

Unsubstituted benzyl, or alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halo, amino, alkylamino having 1 to 4 carbon atoms, or benzyl substituted with -COR ⁴ ;

R ⁴ is hydrogen;

  An alkyl of 1 to 8 carbon atoms substituted with an unsubstituted alkyl of 1 to 8 carbon atoms, or alkoxy, halo, amino, or an alkylamino of 1 to 4 carbon atoms;

  Cycloalkyl having 3 to 18 carbon atoms;

  Unsubstituted phenyl or phenyl substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms; or

  Unsubstituted benzyl or benzyl substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms.

  Immunomodulatory compounds can be purchased, or can be prepared according to the methods described in the patents or patent publications disclosed herein or by methods known to those skilled in the art. Optically pure compounds can also be asymmetrically synthesized, or alternatively resolved using known resolving agents or chiral columns and other standard organic synthetic chemistry techniques.

  Various immunomodulatory compounds contain one or more chiral centers and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. The methods and compositions provided herein include the use of stereoisomerically pure forms of the compounds, as well as the use of mixtures of these forms. For example, equivalent or non-equivalent enantiomers of a particular immunomodulatory compound can be used in the methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. For example, Jacques, J. et al., “Enantiomers, Racemates and Resolutions” (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33: 2725 ( 1977); Eliel, EL, “Stereochemistry of Carbon Compounds” (McGraw-Hill, NY, 1962); and Wilen, SH, “Tables of Resolving Agents. and Optical Resolutions) "p.268 (EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972).

  Note that if there is a conflict between the indicated structure and the name given to that structure, the indicated structure should be given more weight. Further, where the stereochemistry of a structure or part of a structure is not indicated by, for example, bold or dotted lines, the structure or part of a structure should be construed as encompassing all of its stereoisomers.

(5.3 Trichostatin A, hydroxyurea, and valproic acid)
Trichostatin A (TSA) is a histone deacetylase inhibitor having the following structure:

  Trichostatin A can be prepared using conventional organic synthesis and using commercially available starting materials. Trichostatin A is commercially available (for example, Sigma-Aldrich, CAS RN: 58880-19-6).

Hydroxyurea (HU) is a ribonucleotide reductase having the following structure:

  Hydroxyurea can be produced using conventional organic synthesis and using commercially available starting materials. In addition, hydroxyurea is commercially available (for example, Sigma-Aldrich, CAS RN: 127-07-1).

Valproic acid is a histone deacetylase inhibitor having the following structure:

  Valproic acid can be prepared using conventional organic synthesis and using commercially available starting materials. Valproic acid is commercially available (for example, Sigma-Aldrich, CAS RN: 99-66-1, or its sodium salt CAS RN: 1069-66-5).

(5.4 Usage and treatment)
In one embodiment, provided herein is a method of increasing CD34 + hematopoietic stem cell proliferation in vivo or in vitro, wherein CD34 + hematopoietic stem cells are treated with an effective amount of an immunomodulatory compound (eg, 4- ( Amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -Piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutical thereof In certain embodiments, CD34 + hematopoietic stem cell proliferation comprises contacting with an acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph in vivo or in vitro. Contact the combination described in this specification Compared with off cells, in vitro or in vivo, about 25%, about 50%, about 100%, about 200%, about 300%, about 400%, an increase of about 500%, or about 1000%.

  In another embodiment, provided herein treats, prevents, or treats a disease or disorder or symptom thereof that is treatable, preventable, or manageable by proliferation of CD34 + hematopoietic stem cells in vitro or in vivo, or A method of managing an effective amount of an immunomodulatory compound (eg, 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3- Dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydration thereof Product, prodrug, stereoisomer or polymorph and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof Administration.

  In certain embodiments, the disease or disorder treatable, preventable, or manageable by CD34 + hematopoietic stem cell proliferation is a blood disease or disorder such as myelodysplastic syndrome, multiple myeloma, beta hemoglobinopathy, leukemia, myeloma Lymphoma, myeloproliferative disorder, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia.

  In another embodiment, provided herein is a method of treating, preventing, or managing a blood disease or disorder (e.g., blood cancer), wherein the patient in need thereof has an effective amount of immunity Regulatory compounds (eg 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3- Dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, A method comprising administering hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  In another embodiment, provided herein is a method of treating, preventing, or managing leukemia, wherein an effective amount of an immunomodulatory compound (eg, 4- (amino) is administered to a patient in need thereof. ) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -Piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutical thereof As an acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph.

  In another embodiment, provided herein is a method of treating, preventing, or managing mantle cell lymphoma, wherein an effective amount of an immunomodulatory compound (eg, 4- (Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole-2- Yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or Administering a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  In another embodiment, provided herein is a method of transplanting bone marrow, wherein the bone marrow is treated with an effective amount of an immunomodulatory compound (eg, 4- (amino) -2- (2,6- Dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) Or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate thereof , Hydrates, prodrugs, stereoisomers or polymorphs in vitro, followed by implantation into a patient in need thereof.

  In another embodiment, provided herein is a method of remodeling bone marrow, wherein a patient in need thereof has an effective amount of an immunomodulatory compound (eg, 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2 , 6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt thereof. A method comprising administering a salt, solvate, hydrate, prodrug, stereoisomer or polymorph.

  In certain embodiments, provided herein is a method of remodeling bone marrow of a patient who has received or is undergoing chemotherapy and / or radiation therapy, wherein the patient has an effective amount of immunization Regulatory compounds (eg 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3- Dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, A method comprising administering hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  In another embodiment, provided herein is a method of remodeling bone marrow, wherein the bone marrow is treated with an effective amount of an immunomodulatory compound (eg, 4- (amino) -2- (2,6 -Dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione Or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate thereof A method comprising contacting a product, hydrate, prodrug, stereoisomer or polymorph.

  In certain embodiments, provided herein is a method of remodeling bone marrow that has undergone or is undergoing chemotherapy and / or radiation therapy, wherein the bone marrow is treated with an effective amount of an immunomodulatory compound ( For example, 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-iso Indol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or A method comprising contacting with trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  Specific diseases associated with CD34 + hematopoietic stem cells include, but are not limited to, hematological cancer. In one embodiment, the hematological cancer is multiple myeloma, beta hemoglobinopathy, leukemia, myeloma, lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid Leukemia or acute myeloblastic leukemia.

  Specific uses of CD34 + hematopoietic stem cells include, but are not limited to, bone marrow remodeling and bone marrow transplantation. Accordingly, in another embodiment, provided herein is a method of treating, preventing, or managing a blood disease or disorder (e.g., blood cancer) that is effective for patients in need thereof. Amount of immunomodulatory compound (eg, 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1 , 3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and Effective amount of CD34 + hematopoiesis contacted or in contact with valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof A method comprising administering stem cells.

  Immunomodulatory compounds disclosed herein (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino 1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) and a combination of valproic acid, hydroxyurea or trichostatin A, preventable Specific diseases and disorders that can be and / or managed include, but are not limited to: myelodysplastic syndrome, multiple myeloma, beta hemoglobinopathy, leukemia, myeloma, lymphoma, myeloproliferative disorder, Non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia.

  In another embodiment, provided herein are myelodysplastic syndromes, multiple myeloma, beta hemoglobinopathy, leukemia, myeloma, lymphoma, myeloproliferative disorder, non-Hodgkin lymphoma, chronic lymphocytes For the treatment, prevention or management of sexual leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia and acute myeloblastic leukemia in an effective amount of immunomodulation for patients in need thereof Compound (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro -Isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxy Urea or trichostatin A or a pharmaceutically acceptable salt thereof , Solvates, hydrates, prodrugs, stereoisomers or polymorphs.

  In another embodiment, provided herein is a method of increasing cellular fetal hemoglobin expression, wherein fetal hemoglobin-expressing cells are treated with an effective amount of an immunomodulatory compound (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)- Piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutical thereof A method comprising contacting with an acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph.

  In another embodiment, provided herein is a method for increasing fetal hemoglobin expression in a patient in need of increasing fetal hemoglobin expression, wherein the patient is in need of an effective amount of immunomodulation. Compound (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro -Isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxy A method comprising administering urea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof.

  In another embodiment, provided herein is a method for inducing apoptosis of malignant cells, wherein the malignant cells are treated with an effective amount of an immunomodulatory compound (e.g., 4- (amino) -2- ( 2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt thereof , Solvates, hydrates, prodrugs, stereoisomers or polymorphs.

  In another embodiment, provided herein is a method of inhibiting the growth of malignant cells, wherein the malignant cells are treated with an effective amount of an immunomodulatory compound (e.g., 4- (amino) -2- ( 2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt thereof , Solvates, hydrates, prodrugs, stereoisomers or polymorphs.

  In one embodiment, the methods described herein may comprise a substantially pure (S) enantiomer or a substantially pure (R) enantiomer of an immunomodulatory compound (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)- Use of piperidine-2,6-dione).

  Immunomodulatory compounds (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3 -Dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof, and valproic acid , Hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer or polymorph thereof can be administered simultaneously, in parallel or sequentially. .

(5.4.1 Cycle therapy)
Certain embodiments, immunomodulatory compounds (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo -1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) and valproic acid, hydroxyurea or trichostatin A are administered to the patient in a circulating manner. Is associated with administration of active agents, followed by a period of withdrawal (ie no treatment), and repetition of this sequential administration, cycle therapy reduces the development of resistance to one or more therapies, The side effects of therapy can be avoided or reduced and / or the effectiveness of treatment can be improved.

  Thus, in one particular embodiment, an immunomodulatory compound (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4- Amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) in combination with valproic acid, hydroxyurea or trichostatin A at an initial dose of 0.1-5 mg As long as the therapy is tolerated, doses increased 1-10 mg / day (weekly), administered daily, with a maximum dose of 50 mg / day In another embodiment, an immunomodulatory compound (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole-2 -Yl) -piperidine-2,6-dione) in combination with valproic acid, hydroxyurea or trichostatin A in a cycle of 4 or 6 weeks for about 1, 5, 10, or 25 mg / Amount of day Or it is administered in an amount of 10 mg / day, followed by one or two weeks of rest.

In one embodiment, during a 4-6 week cycle, an immunomodulatory compound (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) and valproic acid, hydroxyurea or trichostatin A are administered orally, Immunomodulatory compounds (e.g. 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3- Administration of dihydro-isoindol-2-yl) -piperidine-2,6-dione) is performed 30-60 minutes prior to valproic acid, hydroxyurea or trichostatin A. In another embodiment, the combination is In one particular embodiment, one cycle is from about 1 to about 25 mg / day of an immunomodulatory compound ( For example, 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindole -2-yl) -piperidine-2,6-dione), and about 1 to about 2000 mg / m ² / day, about 10 to about 1000 mg / m ² / day, about 10 to about 500 mg / m ² / day Daily administration of about 50 to about 200 mg / m ² / day of valproic acid, hydroxyurea or trichostatin A for 3 to 4 weeks followed by a 1 or 2 week withdrawal. The number of cycles when is administered to a patient will be from about 1 to about 24 cycles, more typically from about 2 to about 16 cycles, and even more typically from about 3 to about 4 cycles.

(5.5 Pharmaceutical compositions and dosage forms)
The pharmaceutical composition can be used to prepare individual single unit dosage forms. The pharmaceutical compositions and dosage forms provided herein include: an effective amount of an immunomodulatory compound (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl))- Isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt thereof Solvates, hydrates, prodrugs, stereoisomers or polymorphs, and effective amounts of valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate thereof, Prodrug, stereoisomer or polymorph. The pharmaceutical compositions and dosage forms provided herein can further comprise one or more excipients, carriers, or diluents. In addition, the pharmaceutical compositions and dosage forms provided herein can further comprise CD34 + hematopoietic stem cells or bone marrow.

  Single unit dosage forms provided herein can be oral, transmucosal (e.g., nasal, sublingual, vaginal, buccal or anal), parenteral (e.g., subcutaneous, intravenous, holus) for patients. Suitable for injection, intramuscular or intraarterial), topical (eg eye drops or other ophthalmic preparations), transdermal, or dermal administration. Examples of dosage forms include, but are not limited to: tablets (eg, chewable tablets); caplets; capsules such as soft elastic gelatin capsules; cachets; troches; lozenges; Suppositories; powders; aerosols (eg, nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to patients, such as suspensions (eg, aqueous or non-aqueous liquid suspensions) Liquids, oil-in-water emulsions or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to patients; eye drops, or other ophthalmic formulations suitable for topical administration; and patients A sterile solid (eg, crystalline or amorphous solid) that can be reconstituted to provide a liquid dosage form suitable for oral or parenteral administration.

  The composition, shape, and type of a dosage form will generally vary depending on its use. For example, the amount of one or more active ingredients contained in a dosage form used in the acute treatment of a disease can be increased compared to a dosage form used in the chronic treatment of the same disease. Similarly, the amount of one or more active ingredients contained in a parenteral dosage form can be reduced compared to an oral dosage form used to treat the same disease. One skilled in the art will readily understand how the specific dosage forms provided herein differ from one another. See, for example, “Remington's Pharmaceutical Sciences”, 20th edition Mack Publishing, Easton PA (2000).

  Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is administered to the patient. I will. For example, oral dosage forms such as tablets can contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient can also be determined by the specific active ingredients in the dosage form. For example, the degradation of certain active ingredients can be accelerated by excipients such as lactose or when exposed to water. In particular, an active ingredient containing a primary or secondary amine is easily accelerated and decomposed as described above. Thus, certain embodiments include pharmaceutical compositions and dosage forms that contain only a small amount, if any, of lactose and other mono- or disaccharides. As used herein, the term “lactose-free” means that the amount of lactose, if present, is insufficient to substantially increase the rate of degradation of the active ingredient. Means that.

  The lactose-free compositions provided herein can include excipients well known in the art, such excipients are, for example, United States Pharmacopeia (USP) 25-NF20 (2002) It is described in. In general, lactose-free compositions comprise active ingredients, binders / fillers and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts. Certain lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

  Further provided herein includes anhydrous pharmaceutical compositions and dosage forms comprising active ingredients. This is because water may accelerate the decomposition of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical art as a means of simulating long-term storage to determine properties such as shelf life or stability of the formulation over time. See Jens T. Carstensen (Drug Stability: Principles & Practice, 2nd edition, Marcel Dekker, NY, NY, 1995, pp. 379-80). Water and heat accelerate the degradation of some compounds, so moisture and / or moisture are generally encountered during the manufacture, handling, packaging, storage, shipping and use of the formulation, so The impact of can be very serious.

  The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are expected to come into substantial contact with moisture and / or moisture during manufacture, packaging and / or storage If done, it can be anhydrous.

  An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

  Further provided herein are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the degradation rate of the active ingredients. Such compounds are referred to herein as “stabilizers” and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. Similar to the amount and type of excipient, the amount and specific type of active ingredient in the dosage form may vary depending on various factors. Examples of such factors include, but are not limited to, the route by which the dosage form is administered to the patient. However, typical dosage forms provided herein are immunomodulatory compounds (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl)) in an amount of about 0.10 to about 150 mg. ) -Isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable product thereof. Including resulting salts, solvates, hydrates, prodrugs, stereoisomers or polymorphs. Typical dosage forms are immunomodulatory compounds (e.g., 4- (e.g., 4- ( Amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl ) -Piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug or polymorph thereof. In certain embodiments, the dosage form comprises an immunomodulatory compound (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl)) in an amount of about 1, 2, 5, 10, 25, or 50 mg. ) -Isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable product thereof. Including resulting salts, solvates, hydrates, stereoisomers, prodrugs or polymorphs. Typical dosage forms include valproic acid or a pharmaceutically acceptable salt, solvate, water thereof in an amount of 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. Including solvates, stereoisomers, prodrugs or polymorphs. Exemplary dosage forms include trichostatin A or a pharmaceutically acceptable salt, solvate thereof in an amount of 1 to about 5,000 mg, about 5 to about 1000 mg, about 10 to about 500 mg, or about 50 to about 200 mg, Includes hydrates, stereoisomers, prodrugs or polymorphs. Typical dosage forms include hydroxyurea or pharmaceuticals thereof in an amount of 1 to about 5000 mg, about 5 to about 2500 mg, about 10 to about 2000 mg, about 50 to about 1000 mg, about 50 to about 500 mg, or about 50 to about 250 mg. As acceptable salts, solvates, hydrates, stereoisomers, prodrugs or polymorphs. Of course, the specific amount of the drug will depend on the specific drug used and the type of disease or disorder being treated, prevented or managed.

(5.5.1 Oral dosage form)
Pharmaceutical compositions provided herein suitable for oral administration include, but are not limited to, tablets (eg, chewable tablets), caplets, capsules and solutions (eg, flavor syrups). Etc.) and can be provided as individual dosage forms. Such dosage forms contain a predetermined amount of active ingredient and can be prepared by pharmacological methods well known to those skilled in the art. See, for example, generally “Remington's Pharmaceutical Sciences”, 20th edition Mack Publishing, Easton PA (2000).

  A typical oral formulation provided herein is prepared by combining the active ingredient with at least one excipient in an intimate mixture according to conventional pharmaceutical mixing techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, examples of excipients suitable for use in oral solutions or aerosols include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral formulations (e.g., powders, tablets, capsules and caplets) include, but are not limited to, starch, sugar, microcrystalline cellulose, diluents, granulating agents , Lubricants, binders and disintegrants.

  If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared using any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, finely divided solid carriers or both, and then, if necessary, shaping the mixture into the desired formulation. Prepared by

  For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in free-flowing form, such as a powder or granules, optionally mixed with an excipient. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Examples of suitable binders for pharmaceutical compositions and dosage forms include, but are not limited to: natural or synthetic such as corn starch, potato starch, or other starches, gelatin, gum arabic, etc. Gum, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g. ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (For example, No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

  Examples of suitable forms of microcrystalline cellulose include AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pennsylvania) Commercially available materials and mixtures thereof include, but are not limited to: A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Examples of suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM.

  Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include talc, calcium carbonate (granule or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, Examples include but are not limited to silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions provided herein is typically present from about 50 to about 99 weight percent of the pharmaceutical composition or formulation.

  Disintegrants can be used in the compositions provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing excessive amounts of disintegrant may disintegrate during storage, while tablets containing excessive amounts of disintegrant may not disintegrate at a desired rate or under desired conditions. Accordingly, the solid oral dosage forms provided herein are used with a sufficient amount of disintegrant that does not alter the release of the active ingredient into an unfavorable form due to being overdose or underdose. Should be formed. The amount of disintegrant used varies depending on the type of formulation, but the amount can be easily identified by one skilled in the art. A typical pharmaceutical composition comprises about 0.5 to about 15 weight percent disintegrant, and in one embodiment about 1 to about 5 weight percent disintegrant.

  Disintegrants that can be used in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, Crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

  Lubricants that can be used in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin. Sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, Ethyl oleate, ethyl laurate, agar, and mixtures thereof. Examples of additional lubricants include syloid silica gel (Baltimore, Maryland, WR Grace Co., AEROSIL 200), agglomerated aerosol of synthetic silica (Plano, Texas, sold by Degussa Co.), CAB-O -SIL (pyrogenic silicon dioxide product sold by Cabot Co., Boston, Massachusetts), and mixtures thereof, including but not limited to. If any lubricant is used, it is usually used in an amount of less than about 1 weight percent of the pharmaceutical composition or dosage form into which it is incorporated.

(5.5.2 Delayed release dosage form)
The active ingredients provided herein can be administered by controlled release means or delivery devices well known to those skilled in the art. For example, U.S. Pat.Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, all of which are incorporated herein by reference. Examples include, but are not limited to, those described in US Pat. Nos. 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566. Such dosage forms include one or more active ingredients using, for example, hydropropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof. Can be released slowly or in a controlled manner to provide the desired release profile at various ratios. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Accordingly, provided herein are single unit formulations suitable for oral administration such as, but not limited to, tablets, capsules, jarcaps, and caplets adapted for controlled release. .

(5.5.3 Parenteral dosage form)
Parenteral dosage forms are administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. In general, the administration of parenteral dosage forms bypasses the protective measures that patients naturally have, so such dosage forms can be sterilized or are sterilized prior to administration to the patient. Can be. Examples of parenteral dosage forms include, but are not limited to, liquids that can be injected as they are, dry preparations that can be dissolved or suspended as they are in a pharmaceutically acceptable medium for injection, suspensions that can be injected as they are, And emulsions.

  Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include water for injection (United States Pharmacopeia); aqueous media such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; Water miscible media such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate, etc. The non-aqueous medium is not limited to these.

  Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms provided herein. For example, cyclodextrins and their derivatives can be used to increase the solubility of the active ingredients provided herein. See, for example, US Pat. No. 5,134,127, incorporated herein by reference.

(5.6 kits)
In certain embodiments, immunomodulatory compounds (e.g., 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3- (4-amino-1- Oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) and valproic acid, hydroxyurea or trichostatin A are not administered to the patient simultaneously or by the same route of administration. Provided herein are kits that allow a suitable amount of active ingredient to be conveniently administered to a patient when used by a healthcare professional.

  A typical kit provided herein includes: an immunomodulatory compound (eg, 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3- Dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione) or a pharmaceutically acceptable salt, solvate, hydration thereof Product, stereoisomer, prodrug or polymorph container, and valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug or A container containing a polymorphic dosage form.

  The kits provided herein further include a device used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, infusion bags, patches and inhalers.

  The kits provided herein can further comprise CD34 + hematopoietic stem cells or bone marrow for transplantation, and a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. . For example, if the active ingredient is provided in a solid state that must be reconstituted for parenteral administration, the kit is particle free, in which the active ingredient dissolves and is suitable for parenteral administration Includes a sealed container of suitable media to form a sterile solution. Examples of pharmaceutically acceptable vehicles include water for injection (US Pharmacopeia); but are not limited to, sodium chloride injection, Ringer injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer injection Aqueous media such as, but not limited to, water miscible media such as ethyl alcohol, polyethylene glycol and polypropylene glycol; and, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, myristic acid Non-aqueous media such as, but not limited to, isopropyl and benzyl benzoate.

(6. Examples)
Particular embodiments provided herein are illustrated in the following non-limiting examples.

(6.1 Experimental procedure)
(6.1.1 Materials)
Namalva CSN.70 cells were purchased from DSMZ (Brauschweig, Germany). Bone marrow and cord blood CD34 + cells were purchased from Cambrex (Walkersville, MD) and AllCells (Emeryville, CA), respectively. Bone marrow CD34 + cells from sickle cell anemia patients (SCA) were provided by Christopher Morris (Loma Linda University Medical Center, CA).

  Anti-CD34-PE was purchased from BD pharmingen. Valproic acid, trichostatin A and hydroxyurea were from Sigma.

(6.1.2 Cell culture and treatment)
Namalva was cultured in RPMI-1640 medium (Invitrogen, Carlsbad) supplemented with 10% fetal bovine serum, penicillin (100 u / ml) and streptomycin (100 μg / ml). CD34 + cells were treated with 20% serum replacement BIT (StemCell Technologies, in the presence of SCF (100 ng / ml), Flt3-L (100 ng / ml) and IL-3 (20 ng / ml) (Biosource International, Camarillo, Calif.). It was grown in serum-free conditions in Iscove's DMEM (Invitrogen, Carlsbad, CA) supplemented with Vancouver, BC. Namalva cells and CD34 + cells were cultured for 3 and 6 days, respectively. DMSO 0.1%, Compound 1 or Compound 2, valproic acid (VPA) or trichostatin A (TSA) was added at the indicated concentrations during 3 or 6 days of culture.

  BM-CD34 + cells were cultured in Iscove's MDM with BIT 95000 (StemCell technologies) in the presence of growth factors. Growing CD34 + cells with SCF (100 ng / ml), Flt3-L (100 ng / ml) and IL-3 (20 ng / ml) for the first 6 days, followed by SCF (50 ng / ml) and EPO for 6 days Differentiation toward the erythroid lineage was achieved by culture with (2U or 4U / ml). To study the effects of immunomodulatory compounds, CD34 + progenitor cells were differentiated for 6 days in the presence or absence of Compound 1, Compound 2, or hydroxyurea (HU).

(6.1.3 Cell proliferation and apoptosis analysis)
Namalva and CD34 + cells were plated at 4000 and 2000 cells in 96-well plates, respectively, and treated with compounds. After the specified time, cells were counted and phenotyped by flow cytometry using a FACS array. The percentages of apoptotic cells and CD34 + cells were monitored using propidium iodide staining (BD pharmingen, Chicago, IL) and anti-CD34 antibody (PE conjugate) (BD pharmingen), respectively, according to the manufacturer's experimental procedure.

(6.1.4 Namalva cell proliferation assay using BrDu incorporation)
Namalva cells were plated in 96-well plates at 10,000 cells per well and treated with the indicated concentrations of TSA and Compound 1 for 3 days. The effect of TSA and Compound 1 on cell proliferation was measured using a BrDu uptake kit (Roche, Germany).

(6.1.5 Immunofluorescent staining of fetal hemoglobin)
After 6 days of culture, cells were washed with phosphate buffered saline (PBS), fixed with 2% paraformaldehyde, permeabilized with cytopermeafix (BD-pharmingen), and HbF-PE (BD Pharmingen, San Diego, CA) And analyzed by flow cytometry (FACSAria, BD pharmingen).

(6.2 results)
Using Namalva cells (human Burkitt lymphoma), 10 nM TSA was found to be synergistic to Compound 1 in that it induces cell growth arrest (FIG. 1).

  Using Namalva cells (human Burkitt lymphoma), 10 nM TSA was found to be synergistic to Compound 1 in that it induces apoptosis (FIG. 2).

  Using Namalva cells (human Burkitt lymphoma), VPA was found to be additive and synergistic to Compound 1 in that it induces cell growth arrest (FIG. 3).

  Using Namalva cells (human Burkitt lymphoma), VPA was found to be additive and synergistic to Compound 1 in that it induces apoptosis (FIG. 4).

  Using Namalva cells (human Burkitt lymphoma), it was found that VPA is additive and synergistic to Compound 2 in that it induces cell growth arrest (FIG. 5).

  Using Namalva cells (human Burkitt lymphoma), VPA was found to be additive and synergistic to compound 2 in that it induces apoptosis (FIG. 6).

  The effect of the combination of Compound 1 and TSA was investigated on CD34 + cell proliferation. As shown in FIGS. 7 and 8, Compound 1 alone increased the number and percentage of CD34 + cells after 6 days of culture in a dose-dependent manner. Addition of TSA 10 nM to the proliferation cocktail significantly improved the effect of Compound 1 on CD34 + proliferation. As shown in the tables of FIGS. 7 and 8, VPA is additive to Compound 1, and in some conditions a synergistic effect was observed.

  The effect of the combination of Compound 2 and TSA was investigated on CD34 + cell proliferation. As shown in FIGS. 9 and 10, Compound 2 alone increased the number and percentage of CD34 + cells after 6 days of culture in a dose dependent manner. Addition of TSA 1 nM and 10 nM to the proliferation cocktail significantly improved the effect of Compound 2 on CD34 + proliferation. As shown in the tables of FIGS. 9 and 10, VPA is additive to Compound 1, and in some conditions a synergistic effect was observed.

  The effect of the combination of Compound 1 and VPA was investigated on CD34 + cell proliferation. As shown in FIGS. 11 and 12, Compound 1 alone increased the number and percent of CD34 + cells after 6 days of culture in a dose-dependent manner. The addition of VPA 0.1, 0.3, and 1 mM to the proliferation cocktail significantly improved the effect of Compound 1 on CD34 + proliferation. As shown in the tables of FIGS. 11 and 12, VPA is additive to Compound 1, and in some conditions a synergistic effect was observed.

  The effect of the combination of Compound 2 and VPA was investigated on CD34 + cell proliferation. As shown in FIGS. 13 and 14, Compound 2 alone increased the number and percentage of CD34 + cells after 6 days of culture in a dose dependent manner. The addition of VPA 0.1 and 0.3 mM to the proliferation cocktail significantly improved the effect of Compound 2 on CD34 + proliferation. As shown in the tables of FIGS. 13 and 14, VPA is additive to Compound 2, and in some conditions a synergistic effect was observed.

  The effect of the combination of Compound 1 and Compound 2 and hydroxyurea was investigated on fetal hemoglobin expression in CD34 + hematopoietic stem cells from healthy donors differentiated into erythrocytes. As shown in FIG. 15, Compound 1 and Compound 2 alone increased the percentage of HbF expressing cells after 6 days of culture in a dose dependent manner. By adding 10 μM HU to the proliferation cocktail, the effects of Compound 1 and Compound 2 on HbF expression were significantly improved in a synergistic manner.

  The effect of the combination of Compound 1 and hydroxyurea was investigated on fetal hemoglobin expression in CD34 + hematopoietic stem cells from sickle cell anemia patients (SCA) differentiated into red blood cells. As shown in FIG. 16, Compound 1 alone increased the percentage of HbF expressing cells after 6 days of culture in a dose dependent manner. Addition of 10 μM HU to the growth cocktail significantly improved the effect of Compound 1 on HbF expression in a synergistic manner.

  All cited references are incorporated herein by reference in their entirety. Although the present disclosure has been described in terms of particular embodiments, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the disclosure as defined by the appended claims. It will be obvious to you.

  The embodiments provided herein are intended to be illustrative only and one of ordinary skill in the art will recognize, with routine experimentation, many equivalents of specific compounds, materials, and procedures, or You will be able to confirm. All such equivalents are considered to be within the scope of the present disclosure and are encompassed by the appended claims.

Claims (27)

  A composition comprising an effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt thereof, and an effective amount of valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt thereof.   Effective amounts of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro- Isoindole-2-yl) -piperidine-2,6-dione or a pharmaceutically acceptable salt thereof and an effective amount of valproic acid, hydroxyurea or trichostatin A or a pharmaceutically acceptable salt thereof. The composition according to 1.   Effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or a pharmaceutically acceptable salt thereof, and an effective amount of valproic acid or a pharmaceutical thereof A composition according to claim 2 comprising an acceptable salt as   An effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or a pharmaceutically acceptable salt thereof, and an effective amount of trichostatin A or a thereof The composition of claim 2 comprising a pharmaceutically acceptable salt.   Effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or a pharmaceutically acceptable salt thereof, and an effective amount of hydroxyurea or a pharmaceutical thereof A composition according to claim 2 comprising an acceptable salt as   Effective amount of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione or a pharmaceutically acceptable salt thereof, and an effective amount of valproic acid Or the composition of Claim 2 containing the pharmaceutically acceptable salt thereof.   Effective amount of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione or a pharmaceutically acceptable salt thereof, and an effective amount of trichostatin The composition of claim 2 comprising A or a pharmaceutically acceptable salt thereof.   Effective amount of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione or a pharmaceutically acceptable salt thereof, and an effective amount of hydroxyurea Or the composition of Claim 2 containing the pharmaceutically acceptable salt thereof.   The composition according to claim 1 or 2, further comprising a pharmaceutically acceptable carrier.   A unit dosage form comprising the composition of claim 1 or 2.   The substantially pure (S) enantiomer of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1 The composition of claim 2 comprising -oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione.   A method of increasing CD34 + hematopoietic stem cell proliferation, wherein CD34 + hematopoietic stem cells are treated with an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline-1,3-dione or 3 -(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, and an effective amount of valproic acid, hydroxy Contacting said urea or trichostatin A, or a pharmaceutically acceptable salt thereof.   13. The method of claim 12, wherein the CD34 + hematopoietic stem cells are contacted in vitro.   13. The method of claim 12, wherein the CD34 + hematopoietic stem cells are contacted in vivo.   A method of treating, preventing, or managing a blood disease or disorder, wherein an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl) -isoindoline- 1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, and Administering the effective amount of valproic acid, hydroxyurea or trichostatin A, or a pharmaceutically acceptable salt thereof.   The method of claim 15, wherein the blood disease or disorder is blood cancer.   The blood cancer is multiple myeloma, β-hemoglobin abnormality, leukemia, myeloma, lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia or acute bone marrow The method according to claim 16, which is blastic leukemia.   16. The method of claim 15, wherein the blood disease or disorder is myelodysplastic syndrome or myeloproliferative disorder.   A method of transplanting bone marrow, wherein the bone marrow is treated with an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino -1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, and an effective amount of valproic acid, hydroxyurea or trichostatin A Or in vitro contact with a pharmaceutically acceptable salt thereof, followed by implantation into a patient in need thereof.   A method of reconstructing bone marrow, wherein an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, and an effective amount of valproic acid, Said method comprising administering hydroxyurea or trichostatin A or a pharmaceutically acceptable salt thereof.   21. The method of claim 20, wherein the patient has received or is undergoing chemotherapy and / or radiation therapy.   A method of treating, preventing or managing a solid tumor, wherein a patient in need thereof has an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1, 3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt, and an effective amount of Administering the valproic acid, hydroxyurea or trichostatin A, or a pharmaceutically acceptable salt thereof.   Multiple myeloma, beta hemoglobinopathy, leukemia, myeloma, lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, or acute myeloblastic leukemia For a patient in need thereof in an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3 -Dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, and an effective amount of Administering the valproic acid, hydroxyurea or trichostatin A, or a pharmaceutically acceptable salt thereof.   A method of treating, preventing or managing myelodysplastic syndrome or myeloproliferative disorder, wherein an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl) is administered to a patient in need thereof. ))-Isoindoline-1,3-dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or pharmaceutically acceptable thereof And administering an effective amount of valproic acid, hydroxyurea or trichostatin A, or a pharmaceutically acceptable salt thereof.   A method of increasing fetal hemoglobin expression in a cell, wherein the fetal hemoglobin-expressing cell is treated with an effective amount of 4- (amino) -2- (2,6-dioxo (3-piperidyl))-isoindoline-1,3- Dione or 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, and an effective amount of valpro Contacting said acid, hydroxyurea or trichostatin A, or a pharmaceutically acceptable salt thereof.   26. The method of claim 25, wherein the cell is a sickle cell anemia cell.   26. The method of claim 25, wherein the cell is a normal cell.

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