Immunomodulatory amide derivatives with improved material properties

Abstract

The present invention relates to a novel thalidomide-based compound derivative in which sugar or a sugar derivative is introduced into thalidomide-based compounds, lenalidomide or pomalidomide, and thus the water solubility is significantly improved. The lenalidomide or pomalidomide derivative according to the present invention has significantly increased water solubility compared to conventional lenalidomide or pomalidomide, and can be formulated as an injectable or eye drop preparation. Therefore, it has the advantage that a high concentration of a therapeutic agent can be administered locally, and it can be easily administered in combination with other therapeutic agents developed as injectable or eye drop preparations.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to immunomodulatory amide derivatives with improved material properties, and more particularly to lenalidomide or pomalidomide derivatives with significantly improved water solubility, which are thalidomide-based compounds, by introducing sugar or a sugar derivative into lenalidomide or pomalidomide. [Background technology]

[0002] Thalidomide was a drug sold from the late 1950s to the 1960s to prevent morning sickness in pregnant women, but due to reports of its teratogenic side effect, it was banned from use or administration by pregnant women, as well as those of childbearing age or who may become pregnant. However, as the effectiveness of thalidomide in treating multiple myeloma and the mechanism of its side effects have recently been clarified, active research is underway to develop multiple myeloma treatments using thalidomide-related compounds.

[0003] Multiple myeloma is a blood cancer that develops when plasma cells differentiate and proliferate abnormally. These abnormal plasma cells are called myeloma cells. Myeloma cells form tumors, dissolve bones, causing pain and increasing bone fractures. They also invade the bone marrow, reducing the number of white blood cells, red blood cells, and platelets, increasing the risk of anemia, infection, and bleeding. Myeloma cells also produce an abnormal immune protein, M protein, which can thicken the blood, causing hyperviscosity syndrome and damaging the kidneys. Multiple myeloma primarily affects black people, men, and those over 65 years old. The incidence of the disease has been gradually increasing in Korea recently. The main treatments for multiple myeloma are bortezomib, thalidomide, lenalidomide, and pomalidomide. Bortezomib, an injectable drug, is steadily maintaining its market share and showing signs of growth, while lenalidomide, an oral drug, has replaced thalidomide in its position and is showing strong growth in the market.

[0004] Lenalidomide is the next generation of thalidomide, demonstrating superior therapeutic effects due to its more potent cancer cell killing and immune modulation. When lenalidomide is combined with dexamethasone for patients who have relapsed or are refractory to conventional treatment, it is known to be highly effective, with a disease-free survival of 13.4 months and an overall survival of 38 months. Side effects, such as peripheral neuropathy, seen with conventional thalidomide, have been largely eliminated, and while bone marrow suppression has become slightly more severe, it is known that this can be mitigated by administering leukocyte-stimulating factors.

[0005] Pomalidomide was approved by the U.S. FDA in 2013 for the treatment of relapsed and refractory multiple myeloma. It is used in patients who have received at least two prior therapies, including lenalidomide and bortezomib, and whose disease progresses within 60 days of completing the last treatment. Pomalidomide directly inhibits angiogenesis and myeloma cell growth, and this dual effect is primarily driven by its activity in myeloma rather than other pathways such as TNFα inhibition. Pomalidomide exhibits antiangiogenic and antimyeloma activity by enhancing the expression of IFN-γ, IL-2, and IL-10, as well as by suppressing IL-6 expression.

[0006] Both lenalidomide and pomalidomide were developed by Celgene as oral capsule formulations and are commercially available in doses of 1 to 25 mg. Lenalidomide is marketed in Korea under the trade name Revlimid® Capsules, and pomalidomide is marketed in Korea under the trade name Pomalyst® Capsules. Both are filled in size 0 capsules, which are quite long and bulky with a major axis of approximately 2.17 cm.

[0007] Therefore, patients, especially elderly patients, may find it somewhat inconvenient to take the drug. In addition, in the case of capsules, even when taken with water, the capsule may stick to the throat or esophagus during the swallowing process, making it difficult to remove even when drinking a large amount of water. In addition, if the drug accidentally sprays out, it can cause pain and, in some cases, inflammation. In response to these various issues, attempts have been made to improve the physical properties of oral formulations (Korean Patent Publication No. 10-2020-0013258).

[0008] However, such prior art was intended to improve the physical properties of lenalidomide or pomalidomide as an oral formulation, and lenalidomide or pomalidomide is insoluble in water, making it difficult to develop it as an injectable formulation. Therefore, when these therapeutic agents are administered in combination with other therapeutic agents (particularly therapeutic agents administered intravenously), unlike other therapeutic agents that are administered intravenously, these therapeutic agents are administered orally, which makes the administration methods complicated as they are administered in different ways, and when administered orally, it is difficult to administer an injectable agent at a high concentration locally.

[0009] Therefore, the inventors have made strenuous efforts to develop novel compounds with improved physical properties that can be used in various dosage forms such as injections, eye drops, sprays, and patches while maintaining efficacy equal to or greater than that of lenalidomide or pomalidomide. As a result, they have found that when a sugar or sugar derivative is introduced into the amino group (NH2) present in the phthalimide moiety of lenalidomide or pomalidomide, the solubility in water is significantly increased and the teratogenic side effects of lenalidomide or pomalidomide can be reduced while maintaining the pharmaceutical efficacy of lenalidomide or pomalidomide, thereby completing the present invention. [Summary of the Invention] [Problem to be solved by the invention]

[0010] An object of the present invention is to provide immunomodulatory amide derivatives having improved water solubility and other material properties so that they can be used in injections, eye drops, and the like. [Means for solving the problem]

[0011] To achieve the above object, the present invention provides a lenalidomide or pomalidomide derivative in which a sugar or a sugar derivative is bound to an amino group (NH2) on the phthalimide moiety of lenalidomide or pomalidomide.

[0012] In the present invention, the sugar or sugar derivative is a triose, tetraose, pentose, or hexose, or a derivative thereof.

[0013] In the present invention, the sugar or sugar derivative is glucose, ribose, glucuronic acid, or glycerin aldehyde.

[0014] In the present invention, the derivative is characterized by being selected from the group consisting of the following formulas III to XIV.

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[0027] In the present invention, the derivative is characterized by having water solubility improved by 50% or more compared to lenalidomide or pomalidomide.

[0028] The present invention further provides a pharmaceutical composition for preventing or treating cancer, which comprises the derivative as an active ingredient.

[0029] The present invention further provides a method for preventing or treating cancer, which comprises the step of administering the derivative to an individual in need thereof.

[0030] The present invention further provides the use of the derivatives for the prevention or treatment of cancer.

[0031] The present invention further provides a use of the derivative for the manufacture of a medicament for the prevention or treatment of cancer.

[0032] In the present invention, the cancer is characterized by being a blood cancer or a solid cancer.

[0033] In the present invention, the blood cancer is characterized by being selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0034] The present invention further provides a pharmaceutical composition for preventing or treating myelodysplastic syndrome, which comprises the above derivative as an active ingredient.

[0035] The present invention further provides a method for preventing or treating myelodysplastic syndrome, which comprises the step of administering the derivative to an individual in need thereof.

[0036] The present invention further provides the use of the derivative for the prevention or treatment of myelodysplastic syndrome.

[0037] The present invention further provides a use of the derivative for the manufacture of a medicament for the prevention or treatment of myelodysplastic syndrome.

[0038] The present invention further provides a pharmaceutical composition for preventing or treating inflammatory diseases, which comprises the above derivative as an active ingredient.

[0039] The present invention further provides a method for preventing or treating an inflammatory disease, comprising administering the derivative to an individual in need thereof.

[0040] The present invention further provides the use of said derivatives for the prevention or treatment of inflammatory diseases.

[0041] The present invention further provides a use of the derivative for the manufacture of a medicament for the prevention or treatment of an inflammatory disease.

[0042] In the present invention, the inflammatory disease is characterized by being selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease.

[0043] The present invention further provides a pharmaceutical composition for preventing or treating brain diseases, which comprises the above-mentioned derivative as an active ingredient.

[0044] The present invention further provides a method for preventing or treating a brain disease, which comprises administering the derivative to an individual in need thereof.

[0045] The present invention further provides the use of the derivative for the prevention or treatment of brain diseases.

[0046] The present invention further provides a use of the derivative for the manufacture of a medicament for the prevention or treatment of a brain disease.

[0047] In the present invention, the brain disease is characterized in that it is selected from the group consisting of traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke, and multiple sclerosis.

[0048] The present invention further provides a pharmaceutical composition for preventing or treating angiogenic diseases, which comprises the above derivative as an active ingredient.

[0049] The present invention further provides a method for preventing or treating angiogenic diseases, comprising the step of administering the derivative to an individual in need thereof.

[0050] The present invention further provides the use of said derivatives for the prevention or treatment of angiogenic diseases.

[0051] The present invention further provides a use of the derivative for the manufacture of a medicament for the prevention or treatment of angiogenic diseases.

[0052] In the present invention, the angiogenic disease is characterized by being selected from the group consisting of corneal transplant angiogenesis, neovascular glaucoma, diabetic retinopathy, macular degeneration, diabetic macular edema, corneal diseases caused by neovascularization, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, hemangioma, angiofibroma, vascular malformation, arteriosclerosis, vascular adhesion, and edematous sclerosis.

[0053] The present invention further provides an injectable liquid preparation containing the derivative.

[0054] The present invention further provides an ophthalmic solution preparation containing the derivative. [Effects of the invention]

[0055] The lenalidomide or pomalidomide derivatives according to the present invention have significantly increased water solubility compared to conventional lenalidomide or pomalidomide and can be formulated as injectable or ophthalmic preparations, which allows for local administration of high concentrations of therapeutic agents and allows for easy co-administration with other therapeutic agents developed as injectable or ophthalmic preparations. Furthermore, they have the effect of reducing teratogenic side effects compared to conventional lenalidomide or pomalidomide. [Brief explanation of the drawings]

[0056] [Figure 1] Figure 1 shows the structural formulas of (A) thalidomide, (B) lenalidomide, and (C) pomalidomide. [Figure 2a] Figure 2a shows the chemical formula of Ribose-Lenalidomide. [Figure 2b] FIG. 2b shows the solubility of Ribose-Lenalidomide in DW. [Figure 2c] Figure 2c shows the CRBN-binding ability of ribose-lenalidomide. [Figure 2d]Figure 2d shows the tumor cell killing effect of ribose-lenalidomide confirmed in the MM.1S cell line, a human multiple myeloma cell line. [Figure 2e] Figure 2e shows the results of confirming the ability of ribose-lenalidomide to degrade Aiolos, Ikaros, and CK1α using the MM.1S cell line, a human multiple myeloma cell line. [Figure 2f] Figure 2f shows the results of confirming the SALL4 degradation ability of ribose-lenalidomide in the HTB-105 cell line, a human embryonic carcinoma Tera-1 cell line. [Figure 2g] Figure 2g shows the results of confirming the anti-inflammatory effect of ribose-lenalidomide at the mRNA level using a PBMC cell line, a human peripheral blood mononuclear cell line. [Figure 2h] Figure 2h shows the results of confirming the anti-inflammatory effect of ribose-lenalidomide at the protein level using a PBMC cell line, a human peripheral blood mononuclear cell line. [Figure 2i] Figure 2i shows the results of confirming the therapeutic effects of ribose-lenalidomide administered directly into the vitreous and as an eye drop in a mouse model of macular degeneration. [Figure 3a] FIG. 3a shows the chemical formula of Glucose-Lenaldiomide. [Figure 3b] FIG. 3b shows the solubility of Glucose-Lenaldiomide in DW. [Figure 3c] Figure 3c shows the CRBN binding ability of Glucose-Lenaldiomide. [Figure 3d] Figure 3d shows the tumor cell killing effect of Glucose-Lenaldiomide confirmed in the MM.1S cell line, a human multiple myeloma cell line. [Figure 3e] Figure 3e shows the results of confirming the SALL4 degradation ability of glucose-lenaldiomide in the HTB-105 cell line, a human embryonal carcinoma Tera-1 cell line. [Figure 3f]Figure 3f shows the therapeutic effect of direct intravitreal administration of Glucose-Lenaldiomide on macular degeneration, confirmed using a mouse model of macular degeneration (*p<0.05 vs CNV(+Vehicle)). [Figure 4a] FIG. 4a shows the chemical formula of Ribose-Pomalidomide. [Figure 4b] Figure 4b shows the solubility of Ribose-Pomalidomide in DW. [Figure 4c] Figure 4c shows the CRBN-binding ability of Ribose-Pomalidomide. [Figure 4d] FIG. 4d shows the tumor cell killing effect of Ribose-Pomalidomide confirmed in the MM.1S cell line, a human multiple myeloma cell line. [Figure 4e] Figure 4e shows the results of confirming the SALL4 degradation ability of Ribose-Pomalidomide in the HTB-105 cell line, a human embryonic carcinoma Tera-1 cell line. [Figure 5a] FIG. 5a shows the chemical formula of Glucose-Pomalidomide. [Figure 5b] FIG. 5b shows the solubility of Glucose-Pomalidomide in DW. [Figure 5c] Figure 5c shows the CRBN-binding ability of Glucose-Pomalidomide. [Figure 5d] FIG. 5d shows the tumor cell killing effect of Glucose-Pomalidomide confirmed in the MM.1S cell line, a human multiple myeloma cell line. DETAILED DESCRIPTION OF THE INVENTION

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory methods described below are well known and commonly used in the art.

[0058] In the present invention, it was confirmed that when a suitable sugar or sugar derivative is introduced into the amino group present on the phthalimide moiety of lenalidomide or pomalidomide, which are thalidomide-based compounds, the solubility of lenalidomide or pomalidomide in water is significantly improved, and the pharmacological effect of the thalidomide-based compound is maintained.

[0059] Thus, in one aspect, the present invention relates to a lenalidomide or pomalidomide derivative in which a sugar or sugar derivative is attached to an amino group (NH2) on the phthalimido moiety of lenalidomide or pomalidomide.

[0060] Lenalidomide is known as (RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and has the following formula (I):

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[0062] Pomalidomide is It is known as (RS)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione and has the following formula (II):

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[0064] Pomalidomide is a compound in which an amino group is added to the phthalimide moiety of thalidomide, while lenalidomide has the same structure as pomalidomide but without the carbonyl group in the phthalimide moiety (see Figure 1). Both compounds are called immunomodulatory drugs (IMiDs) and have been reported to have stronger immunomodulatory activity than thalidomide.

[0065] Lenalidomide and pomalidomide have a phthalimido moiety and a glutarimido moiety, respectively (see Figure 1), and in the present invention, they are characterized in that a sugar or sugar derivative is bound to an amino group present on the phthalimido moiety.

[0066] In the present invention, the sugar or sugar derivative is characterized by being a triose, a tetraose, a pentose, or a hexose, or a derivative of any of these, but is not limited thereto.

[0067] In one embodiment of the present invention, the sugar is glucose, ribose, glucuronic acid, or glycerin aldehyde, but is not limited thereto.

[0068] In the present invention, the derivative is characterized by being selected from the group consisting of the following formulas III to XIV, but is not limited thereto.

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[0081] In the present invention, the derivative represented by Chemical Formula III and the derivative represented by Chemical Formula IV are two types in which glucose is bound to lenalidomide, respectively.

[0082] In the present invention, the derivative represented by formula V or the derivative represented by formula VI is lenalidomide bound to ribose.

[0083] In the present invention, the derivative represented by Formula VII or the derivative represented by Formula VIII are two types in which glucose is bound to pomalidomide.

[0084] In the present invention, the derivative represented by Chemical Formula IX or the derivative represented by Chemical Formula X are two types in which ribose is bound to pomalidomide.

[0085] On the other hand, in the present invention, the derivative represented by Chemical Formula XI is lenalidomide bound to glucuronic acid, the derivative represented by Chemical Formula XII is lenalidomide bound to glycerinaldehyde, the derivative represented by Chemical Formula XIII is pomalidomide bound to glucuronic acid, and the derivative represented by Chemical Formula XIV is pomalidomide bound to glycerinaldehyde.

[0086] In the present invention, the derivative is characterized by having improved water solubility compared to lenalidomide or pomalidomide, and preferably, the water solubility is improved by about 10% or more, preferably about 20% or more, more preferably about 30% or more, and most preferably about 50% or more. In one aspect, the derivative according to the present invention may have improved water solubility by about 100% or more, about 200% or more, about 300% or more, about 400% or more, or about 500% or more compared to lenalidomide or pomalidomide.

[0087] Meanwhile, the present invention has confirmed that the lenalidomide or pomalidomide derivatives bind to cereblon (CRBN) with the same binding strength as lenalidomide or pomalidomide and can degrade cereblon substrates to the same extent as lenalidomide or pomalidomide. It has also been confirmed that the lenalidomide or pomalidomide derivatives can induce multiple myeloma cell death at the same level as lenalidomide or pomalidomide. Furthermore, the present invention has confirmed that the lenalidomide or pomalidomide derivatives of the present invention can induce less degradation of SALL4 and thus reduce side effects compared to lenalidomide or pomalidomide, with regard to teratogenesis, a side effect induced by the degradation of SALL4 during fetal development when lenalidomide or pomalidomide is administered to pregnant women.

[0088] Cereblon is an important direct target of thalidomide, forming an E3 ubiquitin ligase complex with DDB1 (a damaged DNA-binding protein), CUL4A (Cullin-4A), and Roc1 (a cullin 1 modulator). This complex ubiquitinates specific proteins, targeting them for proteolysis. Knockdown of cereblon by RNA interference (RNAi) blocked lenalidomide- or pomalidomide-induced cell growth suppression in various multiple myeloma cell lines. Lenalidomide and pomalidomide exert their anticancer effects by binding to cereblon via the glutarimide moiety and degrading its substrates.

[0089] Recent studies have demonstrated that thalidomide and its analogs (lenalidomide and pomalidomide; collectively referred to as immunomodulatory drugs, or IMiDs) induce degradation of the B cell survival and transcription factors Ikaros and Aiolos, thereby arresting multiple myeloma growth and altering immune cell function. The zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) selectively bind to cereblon via IMiDs. Furthermore, IMiDs directly bind to cereblon and activate E3 ligases, rapidly activating the ubiquitination and degradation of Ikaros and Aiolos (see Science, 343, 305, 2014; Science, 343, 301, 2014). Ikaros and Aiolos are transcription factors involved in B cell and T cell differentiation, and the toxic effect on multiple myeloma cells is due to the loss of these two transcription factors, which leads to decreased expression of transcription factors such as IRF4 and Myc in B cells, thereby inducing myeloma cell death.

[0090] Lenalidomide is the only IMiD approved for the treatment of myelodysplastic syndrome (MDS) with chromosome 5q deletion (5q-). However, its mechanism of action remains unclear. In 2015, in addition to Ikaros and Aiolos, casein kinase alpha (CK1α) was identified as a lenalidomide-dependent CRBN substrate. 5q-MDS cells transmit a chromosomal region containing the deleted CSNK1A1 gene and exhibit haploinsufficient expression of CK1α. Lenalidomide-induced degradation of CK1α in these 5q-MDS cells leads to cell death. Furthermore, lenalidomide-induced degradation of CK1α is significantly stronger than that induced by thalidomide or pomalidomide, suggesting that the degradation depends on the substrate ligand recognized by CRBN.

[0091] Meanwhile, in 2018, two independent groups reported the C2H2 zinc finger transcription factor SALL4 (Spalt-Like Transcription Factor 4) as a thalidomide-dependent neosubstrate for CRBN. First, Fischer's research team used mass spectrometry in human embryonic stem cells (hESCs) to identify substrates that were decreased upon treatment with thalidomide, lenalidomide, or pomalidomide. SALL4 was identified as a causative gene for genetic disorders such as Duane Radial Ray syndrome, Okihiro syndrome, and Holt-Oram syndrome, which partially overlap with thalidomide embryopathy. Chamberlain's group also independently identified SALL4 based on its structural similarity to known zinc finger-type neosubstrates. Both groups concluded that SALL4 is a substrate that induces the teratogenic effects of thalidomide-related compounds.

[0092] Therefore, in another aspect, the present invention relates to a pharmaceutical composition for preventing or treating cancer, which comprises the above-mentioned derivative as an active ingredient.

[0093] In yet another embodiment, the present invention relates to a method for preventing or treating cancer, comprising administering said derivative to an individual in need thereof.

[0094] In yet another aspect, the present invention relates to the use of said derivatives for the prevention or treatment of cancer.

[0095] In yet another aspect, the present invention relates to the use of said derivatives for the manufacture of a medicament for the prevention or treatment of cancer.

[0096] In the present invention, the cancer is characterized as being a blood cancer or a solid cancer, but is not limited thereto.

[0097] In the present invention, the blood cancer is characterized by being acute leukemia, chronic leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, but is not limited thereto.

[0098] In yet another aspect, the present invention relates to a pharmaceutical composition for preventing or treating myelodysplastic syndrome, comprising the above-mentioned derivative as an active ingredient.

[0099] In another embodiment, the present invention relates to a method for preventing or treating myelodysplastic syndrome, comprising administering said derivative to an individual in need thereof.

[0100] In another aspect, the present invention relates to the use of said derivatives for the prevention or treatment of myelodysplastic syndromes.

[0101] In another aspect, the present invention relates to the use of said derivatives for the manufacture of a medicament for the prevention or treatment of myelodysplastic syndrome.

[0102] In yet another aspect, the present invention relates to a pharmaceutical composition for preventing or treating tumors, which contains the above-mentioned derivative as an active ingredient, and the tumors include benign tumors and malignant tumors.

[0103] In another embodiment, the present invention relates to a method for preventing or treating tumors, comprising administering said derivative to an individual in need thereof.

[0104] In another aspect, the present invention relates to the use of said derivatives for the prevention or treatment of tumors.

[0105] In another aspect, the present invention relates to the use of said derivatives for the manufacture of a medicament for the prevention or treatment of tumors.

[0106] Meanwhile, the present invention has confirmed that the lenalidomide or pomalidomide derivatives can exert anti-inflammatory effects similar to or higher than those of lenalidomide or pomalidomide.

[0107] Therefore, in yet another aspect, the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases, which comprises the above-mentioned derivative as an active ingredient.

[0108] In another aspect, the present invention relates to a method for preventing or treating an inflammatory disease, comprising administering said derivative to an individual in need thereof.

[0109] In another aspect, the present invention relates to the use of said derivatives for the prevention or treatment of inflammatory diseases.

[0110] In another aspect, the present invention relates to the use of said derivatives for the manufacture of a medicament for the prevention or treatment of inflammatory diseases.

[0111] In the present invention, the inflammatory disease is characterized by being selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease, but is not limited thereto.

[0112] In yet another aspect, the present invention relates to a pharmaceutical composition for preventing or treating brain diseases, which comprises the derivative as an active ingredient.

[0113] In another aspect, the present invention relates to a method for preventing or treating a brain disease, comprising administering said derivative to an individual in need thereof.

[0114] In another aspect, the present invention relates to the use of said derivatives for the prevention or treatment of brain diseases.

[0115] In another aspect, the present invention relates to the use of said derivatives for the manufacture of a medicament for the prevention or treatment of a brain disease.

[0116] In the present invention, the brain disease is characterized by being selected from the group consisting of traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's dementia, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke, and multiple sclerosis, but is not limited thereto.

[0117] Furthermore, the present invention has confirmed through animal experiments that the lenalidomide or pomalidomide derivatives according to the present invention can effectively treat macular degeneration, which is one of neovascular diseases.

[0118] Therefore, in yet another aspect, the present invention relates to a pharmaceutical composition for preventing or treating angiogenic diseases, which comprises the above-mentioned derivative as an active ingredient.

[0119] In another aspect, the present invention relates to a method for preventing or treating angiogenic diseases, comprising administering said derivative to an individual in need thereof.

[0120] In another aspect, the present invention relates to the use of said derivatives for the prevention or treatment of angiogenic diseases.

[0121] In another aspect, the present invention relates to the use of said derivatives for the manufacture of a medicament for the prevention or treatment of angiogenic diseases.

[0122] In the present invention, the angiogenic disease is characterized by being selected from the group consisting of corneal transplant angiogenesis, neovascular glaucoma, diabetic retinopathy, macular degeneration (e.g., exudative age-related macular degeneration or wet age-related macular degeneration), diabetic macular edema, corneal neovascularization, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, hemangioma, angiofibroma, vascular malformation, arteriosclerosis, vascular adhesion, and edema-induced sclerosis, but is not limited thereto.

[0123] In a preferred embodiment, the neovascular disease may be macular degeneration, and the derivative may be administered by intravitreal injection or injected into the eye in the form of eye drops.

[0124] The lenalidomide or pomalidomide derivatives according to the present invention may exhibit their pharmaceutical effects by cleaving the sugar or sugar derivative in response to a change in pH, resulting in the formation of lenalidomide or pomalidomide, respectively. In one embodiment, the lenalidomide or pomalidomide derivatives are preferably prepared from a composition having a pH of about 7 to 8. The pH is then adjusted to 7 or below, e.g., 6.5 or below, preferably 6 or below, prior to infusion into the body, and then the derivatives can be injected into the body. In another embodiment, the lenalidomide or pomalidomide derivatives may be prepared from a composition having a pH of about 7 to 8, and then injected into the body. The sugar or sugar derivative may be cleaved in response to a change in the pH in the body (e.g., a decrease in pH in an organ such as the stomach) to 7 or below, e.g., 6.5 or below, preferably 6 or below. However, the pharmacological mechanism of the derivatives is not limited thereto.

[0125] In a preferred embodiment, the present invention includes a pharmaceutical composition comprising an effective amount of a lenalidomide derivative or pomalidomide derivative according to the present invention as an active ingredient. In one embodiment, the pharmaceutical composition is useful for treating blood cancers (e.g., multiple myeloma, non-Hodgkin's lymphoma, etc.), solid cancers, myelodysplastic syndromes, inflammatory diseases (e.g., psoriasis, rheumatoid arthritis, Crohn's disease, etc.), brain diseases (e.g., traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, and glaucoma). and multiple sclerosis) or angiogenic diseases (e.g., corneal transplant angiogenesis, neovascular glaucoma, diabetic retinopathy, wet age-related macular degeneration, wet age-related macular degeneration, diabetic macular edema, neovascular corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, hemangiomas, angiofibromas, vascular malformations, arteriosclerosis, vascular adhesions, and scleredema).

[0126] As used herein, the term "pharmaceutical composition" or "pharmaceutical formulation" refers to a mixture comprising a novel compound of the present invention and a pharmaceutically acceptable excipient, such as a diluent or carrier, that is particularly suited for in vivo or in vitro diagnostic or therapeutic use. According to one embodiment, a pharmaceutical composition comprising a composition of the present invention may be provided in a manner that allows it to be administered to a subject as needed. In one embodiment, the composition of the present invention may be administered to a human.

[0127] As used herein, "combination administration" or "co-administration" refers to the administration of a composition according to the present invention simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapy, inflammatory disease, or brain disease treatments). The compounds of the present invention may be administered singly or co-administered to a patient. Co-administration refers to the simultaneous or sequential administration of compounds, either individually or in combination (one or more compounds or agents). Thus, the preparation may be combined with other active substances, if desired.

[0128] As used herein, an "effective amount" or "therapeutically-effective amount" refers to an amount of a compound or composition (e.g., a compound or composition of the invention) sufficient to achieve a beneficial or desired result. An effective amount may be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0129] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions for administration to humans, one of ordinary skill in the art will understand that these compositions are generally suitable for administration to any type of animal. That is, pharmaceutical compositions according to the present invention may be administered to animals requiring veterinary treatment, such as other mammals, including livestock (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Variations of pharmaceutical compositions for administration to various animals are well understood, and skilled veterinary pharmacologists may design and / or perform such variations, as necessary, through simple routine experimentation.

[0130] The pharmaceutical compositions described herein may be prepared by any of the methods known in the art of pharmacology or described herein below. Generally, such methods for preparation include the step of bringing the active ingredient(s) into association with an excipient and / or one or more other accessory ingredients, and then, if necessary or desired, shaping and / or packaging the product in the desired single- or multi-dose unit.

[0131] The pharmaceutical compositions of the present invention may be prepared, packaged, and / or sold unpackaged in single unit doses and / or multiple single unit doses. As used herein, a "unit dose" is a discrete amount of pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of active ingredient is generally equal to the dose of the active ingredient administered to a subject and / or a convenient fraction of such a dose, e.g., one-half or one-third of the dose.

[0132] The relative amounts of active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or disorder of the subject being treated, and on the route by which the composition is administered. For example, the composition may contain from 0.001% to 100% (w / w) of the active ingredient.

[0133] As used herein, pharmaceutically acceptable excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surfactants, isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the purpose of a particular dosage form. Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006) discloses various excipients used in the preparation of pharmaceutical compositions and known techniques for their manufacture. The use of any conventional carrier medium is considered within the scope of the present invention, except that it is incompatible with the substance or its derivatives, for example, by providing any undesired biological effect or interacting in a deleterious manner with any other component of the pharmaceutical composition. Pharmaceutically acceptable excipients are at least 95%, 96%, 97%, 98%, 99%, or 100% pure.

[0134] The excipients are approved for human and veterinary use. In one embodiment, the excipients are approved by the U.S. Food and Drug Administration. In one embodiment, the excipients are pharmaceutical grade. In one embodiment, the excipients meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia (EP).

[0135] In one embodiment, the excipient is approved for human and veterinary use. In one embodiment, the excipient is approved by the U.S. Food and Drug Administration. In one embodiment, the excipient is pharmaceutical grade. In one embodiment, the excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia (EP).

[0136] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils.

[0137] Such excipients may optionally be included in the formulations of the present invention. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may be present in the composition, according to the discretion of the formulator.

[0138] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and combinations thereof.

[0139] Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and combinations thereof.

[0140] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acids, and the like. Esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Mills 45], polyoxyethylene hydrogenated castor oil, poly Ethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether [Breeze 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laureth, sodium lauryl sulfate, Fluronic F68, poloxamer 188,Including, but not limited to, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or combinations thereof.

[0141] Exemplary binders include, but are not limited to, starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, breadwort gum, chatty gum, mucilage of isapol fuscus, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (veegum), and lachtarabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and combinations thereof.

[0142] Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium dibisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxymethylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glidant Plus, fenonib, methylparaben, low molar 115, germaben II, neolon, katone, and euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0143] Exemplary buffering agents include, but are not limited to, citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof.

[0144] Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

[0145] Exemplary oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, and ritzel. Exemplary oils include, but are not limited to, air cubeba, macadamia nut, mallow, mango seed, meadowsweet, mink, nutmeg, olive, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquat, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary oils include, but are not limited to, butyl stearate, glyceryl tricaprylate, glyceryl tricaprate, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0146] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, sprout, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes. In certain embodiments for parenteral administration, the novel compounds of the present invention are mixed with a solubilizing agent, such as cremophor, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and combinations thereof.

[0147] The lenalidomide or pomalidomide derivatives according to the present invention have significantly improved water solubility compared to their parent compounds, lenalidomide or pomalidomide, and in one embodiment may be used as an injectable liquid formulation.

[0148] Therefore, in yet another aspect, the present invention relates to an injectable liquid formulation containing the derivative.

[0149] In the present invention, the term "injection liquid preparation" may be used interchangeably with "injection dosage form," "injection," or "injectable preparation."

[0150] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be prepared using dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution are used. Sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic mono- or diglycerides, may be used. Fatty acids, such as oleic acid, are also used in the preparation of injectable preparations.

[0151] Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by containing sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0152] Furthermore, the lenalidomide derivatives or pomalidomide derivatives according to the present invention have significantly improved water solubility compared to their parent compounds, lenalidomide or pomalidomide, and in one embodiment may be used as an eye drop preparation.

[0153] Therefore, in yet another aspect, the present invention relates to an ophthalmic solution preparation containing the above-mentioned derivative.

[0154] In the present invention, the term "ophthalmic solution preparation" may be used interchangeably with "ophthalmic dosage form," "eye drops," "eye drop preparation," "ophthalmic dosage form," or "eye drops."

[0155] On the other hand, in order to prolong the effect of a drug, it is generally desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This is accomplished by using a liquid suspension of crystalline or amorphous material with low water solubility. The absorption rate of the drug then ultimately depends on the dissolution rate, which may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of parenterally administered drugs can be achieved by dissolving or suspending the drug in an oil vehicle.

[0156] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with one or more inert pharmaceutically acceptable excipients or carriers, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as calcium carbonate, jasmine, maltodextrin, niacin, niacin, niacinamide, niacinamide, niacinamide-containing cellulose acetate ... Mixed with potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof.

[0157] In the case of capsules, tablets and pills, dosage forms may contain buffering agents. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules, using not only lactose or milk sugar, but also high molecular weight polyethylene glycols and the like as such excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulating art. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules, using not only lactose or milk sugar, but also high molecular weight polyethylene glycols and the like as such excipients.

[0158] The active ingredient may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient may be mixed with one or more inert diluents, such as sucrose, lactose, or starch. These dosage forms may contain additional substances other than inert diluents, as is common practice, such as refined lubricants and other refinement aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, dosage forms may also contain buffering agents. These may optionally contain opacifying agents and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0159] Dosage forms for topical and / or transdermal administration of the novel compounds of the present invention or pharmaceutical compositions containing them may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterilization conditions with a pharmaceutically acceptable carrier and / or any necessary preservatives and / or buffers that may be required. Furthermore, the present invention generally contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms may be prepared, for example, by dissolving and / or dispersing the active ingredient in a suitable medium. Alternatively, or additionally, the rate may be controlled by providing a rate-controlling membrane or by dispersing the active ingredient in a polymer matrix and / or gel.

[0160] Formulations for topical administration include, but are not limited to, liquid and / or semi-liquid formulations, such as salves, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments and / or pastes, and / or solutions and / or suspensions. The concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent, but a topically administrable formulation may contain, for example, about 1% to about 10% (w / w) active ingredient. Formulations for topical administration may further include one or more additional ingredients described herein.

[0161] For example, topical formulations may be prepared in dosage forms known in the art for administration to the eye.

[0162] The novel compounds of the present invention or pharmaceutical compositions containing the same described herein are typically prepared in dosage unit form for ease of administration and uniformity of dosage. However, it will be understood that the daily dosage regimen of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on various factors, including the disease, disorder, or disorder being treated and the severity of the disorder, the activity of the specific active ingredient selected, the specific composition selected, the subject's age, weight, general health, sex, and diet, the administration time, route of administration, and excretion rate of the specific active ingredient selected, the duration of treatment, drugs combined with or used concomitantly with the specific active ingredient selected, and factors well known in the medical field.

[0163] The novel compounds of the present invention, their salts, or pharmaceutical compositions thereof may be administered by any route. In one embodiment, the novel compounds, their salts, or pharmaceutical compositions thereof are administered by various routes, including oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (by powder, ointment, cream, and / or liquid drops), mucosal, nasal, oral, enteral, sublingual, intratracheal instillation, bronchial instillation, and / or inhalation, and / or oral spray, nasal spray, and / or aerosol. Specific contemplated routes are systemic intravenous injection, topical administration via the blood and / or lymphatic supply, and / or direct administration to the affected area. Generally, the most appropriate route of administration will depend on various factors, including the properties of the agent (e.g., its stability in the gastrointestinal environment) and the subject's disorder (e.g., whether the subject can tolerate oral administration).

[0164] In certain embodiments, the novel compounds of the present invention, their salts, or pharmaceutical compositions thereof are administered at a dosage level sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 25 mg / kg of a subject's body weight daily, one or more times per day, to achieve the desired therapeutic effect. Target dosages may be delivered three times per day, twice per day, daily, every two days, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered through multiple administrations (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0165] It will be understood that the dosage ranges described herein provide guidance for administering pharmaceutical compositions to adults. For example, the amount administered to children or adolescents may be determined by a specialist or a person skilled in the art and may be less than or the same as that administered to adults. The exact amount of the peptides of the present invention required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and overall disorder, side effects or severity of the disorder, the identity of the specific compound, and the mode of administration.

[0166] It will be appreciated that the novel compounds and pharmaceutical compositions of the present invention can be used in combination therapy. The particular combination of therapies (therapeutic agents or procedures) to employ in combination therapy will take into account the desired therapeutic effect to be achieved and the compatibility of the desired therapeutic agents and / or procedures.

[0167] The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more therapeutically active agents. While the following delivery methods fall within the scope of the present invention, the term "combination" is not intended to imply that the agents must be administered at the same time, administered, or formulated for simultaneous delivery. The compositions may be administered simultaneously with, before, or after, one or more other therapeutic agents or medical procedures. Generally, each agent is administered at a dose and / or time schedule designated for that agent. Furthermore, the present invention encompasses the delivery of pharmaceutical compositions of the present invention in combination with agents that can improve their bioavailability, reduce and / or modify their metabolism, inhibit their secretion, and / or modify their distribution in the body. It will be appreciated that the novel compounds of the present invention and the therapeutically active agents used in this combination may be administered simultaneously in a single composition or separately in different compositions.

[0168] The particular combination to be used in combination therapy will take into account the desired therapeutic effect to be achieved and / or the compatibility of the procedures and / or therapeutically active agents, including the peptides of the invention. It will be understood that the combinations used may achieve the desired effect for the same disorder (e.g., the novel compounds of the invention may be administered in combination with yet another therapeutically active agent (e.g., a second therapeutic agent) used to treat the same disorder) and / or they may achieve a different effect (e.g., control of any side effects).

[0169] As used herein, the term "therapeutically active agent" refers to any substance used medicinally to treat, prevent, delay, reduce or ameliorate a disorder, including substances used in treatment, including prophylactic and curative treatment.

[0170] In one embodiment, the other therapeutically active agent for co-administration is for treating multiple myeloma. In one embodiment, the other therapeutically active agent may be a proteasome inhibitor and / or an immune-modifying drug. In the present invention, the other therapeutically active agent may be selected from the group consisting of, but not limited to, dexamethasone, bortezomib, carfilzomib, melphalan, doxorubicin, and cyclophosphamide.

[0171] In one example, the pharmaceutical compositions of the present invention may be administered in combination with any therapeutically active agent or procedure (e.g., surgery, radiation therapy) useful in treating, alleviating, ameliorating, palliating, delaying the onset of, inhibiting the progression of, reducing the severity of, and / or reducing the incidence of one or more symptoms or characteristics of the disease.

[0172] In various embodiments, the present invention provides kits for treating multiple myeloma in a subject suffering from multiple myeloma. In one embodiment, the kit includes i) instructions for administering a lenalidomide or pomalidomide derivative composition or pharmaceutical composition according to the present invention to a subject suffering from multiple myeloma, and ii) a lenalidomide or pomalidomide derivative composition or pharmaceutical composition according to the present invention. In one embodiment, the kit may include one or more unit dosage forms containing a dose of the lenalidomide or pomalidomide derivative composition or pharmaceutical composition described herein effective to treat multiple myeloma in the subject. In one embodiment, the subject is a human patient.

[0173] In one embodiment, the kit further comprises at least one selected from the group comprising a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.

[0174] The term "about" as used herein may be interpreted to mean approximately, roughly, roughly, or to a certain extent. When the term "about" is used in conjunction with a numerical range, it is interpreted to modify that range by extending the boundaries above and below the specified numbers. In general, the term "about" is used herein to modify numerical values ​​above and below the stated value by a variance of 10%.

[0175] The terms "individual," "patient," and "subject" are used interchangeably and include any animal, including a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, including a human.

[0176] Example The present invention will be described in more detail below through examples. It will be obvious to those skilled in the art that these examples are merely for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention.

[0177] Example 1. Ribose-Lenalidomide 1-1.Synthesis A solution of 100 mg (0.386 mmol) lenalidomide in 1.00 mL of dimethylformamide (DMF) and 1.00 mL of ethanol (EtOH) was mixed with a solution of 290 mg (1.93 mmol) ribose in 0.500 mL of water and 53.0 μL (0.926 mmol) of acetic acid (AcOH). The mixture was stirred at 60 °C overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silicon dioxide (SiO2) (dichloromethane (DCM):methanol (MeOH) = 9:1 to 8:1) and then purified by C 18The resulting product was purified by column chromatography on SiO2 (100% water to methanol (MeOH):HO = 3:1) to synthesize ribose-lenalidomide (type 1, Figure 2a, compound V).

[0178] [ka]

[0179] 1-2.Solubility in water Lenalidomide (Combi-Block, Inc., San Diego, CA, USA) and ribose-lenalidomide (3 mg each) were weighed and placed in a 1.5 mL Eppendorf tube. 0.03 mL of water was added, followed by vortexing for 1 minute and centrifugation at 15,000 rpm for 1 minute to precipitate any insoluble compounds. When a precipitate was observed, 0.03 mL of water was added and the process was repeated.

[0180] The solubility was determined according to Table 1 as defined in USP23 (United States Pharmacopeia 23).

[0181] [Table 1]

[0182] As a result, as shown in Figure 2b, it was confirmed that ribose-lenalidomide (type 1) exhibits a solubility of 100 mg / ml or more in water (freely soluble according to USP23), but lenalidomide is completely insoluble in water.

[0183] 1-3.CRBN bond strength Immunomodulatory amide compounds such as lenalidomide are known to bind to the cereblon (CRBN) protein. We therefore compared the binding affinity of ribose-lenalidomide to the cereblon (CRBN) protein with that of its parent compound, lenalidomide (Combi-Block, Inc. San Diego, CA, USA).

[0184] To this end, we used a fluorescence-based Alpha assay kit (PROTAC Optimization kit for BET Bromodomain-Cereblon Binding (BPS Bioscience, #79770)) according to the manufacturer's instructions to evaluate the competitive inhibition of CRBN and dBET1 binding by lenalidomide and ribose-lenalidomide. For this experiment, we used AlphaLISA anti-FLAG acceptor beads, 5 mg / ml (PerkinElmer #AL112C), Alpha Glutathione donor beads, 5 mg / ml (PerkinElmer #6765300), Optiplate 384 (PerkinElmer #6007290), and L-Glutathione reduced (G4251, Sigma-Aldrich).

[0185] As a result, as shown in Figure 2c, ribose-lenalidomide (type 1) showed improved binding ability to the Cereblon (CRBN) protein compared to lenalidomide.

[0186] 1-4.Tumor cell killing effect Lenalidomide is an FDA-approved treatment for multiple myeloma patients as maintenance therapy after autologous stem cell transplantation, and we investigated whether ribose-lenalidomide also exerts a multiple myeloma cell death effect.

[0187] For this purpose, human multiple myeloma cell line MM.1S (CRL-2974) was purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured in RPMI 1640 medium (Corning, MD, USA) supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U / ml penicillin (Corning, MD, USA), and 100 μg / ml streptomycin (Corning, MD, USA) in a 5% CO incubator at 37°C for 24 hours. 1 × 10 cells were cultured. 4 The cells were plated into a 96-well plate at 100 cells / well and cultured for 24 hours. After 24 hours, the cells were treated with ribose-lenalidomide dissolved in DMSO or DW at 0, 0.005, 0.014, 0.041, 0.123, 0.37, 1.111, 3.333, or 10 μM. After further culture for 3 days, the cells were analyzed using a CCK assay kit (Dojindo, Japan) according to the manufacturer's instructions.

[0188] As a result, as shown in Figure 2d, it was confirmed that when ribose-lenalidomide (type 1) was dissolved in DMSO or DW, both effectively killed the human multiple myeloma cell line MM.1S.

[0189] 1-5.Aiolos, Ikaros, and CK1α degradation effects Thalidomide-related compounds are known to regulate immune cell function by binding to the E3 ligase Cerebolone (CRBN) and degrading the transcription factors Aiolos and Ikaros as their substrates. Therefore, to confirm whether ribose-lenalidomide still maintains its immunomodulatory function, we compared its effects on Aiolos and Ikaros degradation with those of its parent compound, lenalidomide.

[0190] In addition, CK1α, another substrate of cereblon (CRBN), promotes stress-related signals that help to sustain oncogenic cascades such as PI3K / AKT, JAK / STAT, and NF-κB in multiple myeloma, and help to counter various adverse effects. Therefore, we investigated whether ribose-lenalidomide could exert its therapeutic effect on multiple myeloma by degrading CK1α in the same way as lenalidomide.

[0191] To this end, human multiple myeloma cell line MM.1S (CRL-2974) was purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured in DMEM medium (Corning, MD, USA) supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U / ml penicillin (Corning, MD, USA), and 100 μg / ml streptomycin (Corning, MD, USA) in a 5% CO2 incubator at 37°C.

[0192] Cells were aliquoted and cultured for 24 hours, then treated with 1 μM or 10 μM of each compound and cultured for another 24 hours. Cells were disrupted in RIPA buffer containing a protease inhibitor cocktail (Thermo Fisher Scientific) and centrifuged at 14,000 rpm for 15 minutes at 4°C to obtain cell extracts. Equal volumes of cell extracts were loaded, separated by SDS-PAGE, and transferred to PVDF membranes. The membranes with transferred proteins were blocked with skim milk, incubated overnight with primary antibodies at 4°C, and then incubated with HRP-conjugated secondary antibodies for 1 hour at 4°C. Between each step, the membranes were washed three times with TBS-T. Detection was performed using chemoluminescence reagent (Thermo Fisher Scientific) and confirmed using a Chemidoc (iBright CL1000, Invitrogen, CA, USA). The primary antibodies used were Aiolos (#15103), Ikaros (#9034), GAPDH (#2118S), and β-actin (#3700S) antibodies, purchased from Cell Signaling Technology (Danvers, MA, USA). The CK1α (PA5-17536) antibody was purchased from Invitrogen (Waltham, Massachusetts, USA).

[0193] As a result, as shown in Figure 2e, the Aiolos, Ikaros, and CK1α degradation effect of ribose-lenalidomide (type 1) was confirmed to be at a level almost similar to that of lenalidomide, and no difference was observed in the Aiolos, Ikaros, and CK1α degradation effect of ribose-lenalidomide depending on the solvent.

[0194] 1-6.SALL4 decomposition effect Cereblon (CRBN)-binding therapeutics can cause severe congenital malformations, such as shortened forelimbs or brachydactyly, which have been reported to be closely related to the degradation of SALL4. Therefore, we compared the SALL4 degradation effects of ribose-lenalidomide with those of lenalidomide.

[0195] For this purpose, human embryonal carcinoma Tera-1 cell line (HTB-105) was purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured in DMEM medium (Corning, MD, USA) supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U / ml penicillin (Corning, MD, USA), and 100 μg / ml streptomycin (Corning, MD, USA) in a 37°C, 5% CO2 incubator.

[0196] Cells were aliquoted and cultured for 24 hours, then treated with 1 or 10 μM lenalidomide dissolved in DMSO, ribose-lenalidomide dissolved in DMSO, or water, and cultured for another 24 hours. Cells were lysed in RIPA buffer containing a protease inhibitor cocktail (Thermo Fisher Scientific) and centrifuged at 14,000 rpm for 15 minutes at 4°C to obtain cell extracts. Equal volumes of cell extracts were loaded, separated by SDS-PAGE, and transferred to PVDF membranes. The membranes with transferred proteins were blocked with skim milk, incubated overnight with primary antibodies at 4°C, and then incubated with HRP-conjugated secondary antibodies for 1 hour at 4°C. Washes were performed three times with TBS-T between each step. Detection was performed using chemoluminescence reagent (Thermo Fisher Scientific) and confirmed using a Chemidoc (iBright CL1000, Invitrogen, CA, USA). The primary antibodies used, SALL4 (#5850) and GAPDH (#2118S), were purchased from Cell Signaling Technology (Danvers, MA, USA).

[0197] As a result, as shown in Figure 2f, ribose-lenalidomide (type 1) was shown to suppress the SALL4 degradation effect compared to lenalidomide, and ribose-lenalidomide was found to have improved teratogenic side effects compared to lenalidomide.

[0198] 1-7. Anti-inflammatory effect The anti-inflammatory effects of ribose-lenalidomide were compared with those of lenalidomide.

[0199] For this purpose, PBMCs, a human peripheral blood mononuclear cell line, were purchased from Stemexpress (2.5 million, PBMNC025C, #1909040034) and used. They were stabilized for 24 hours in RPMI-1640 (Corning, MD, USA) supplemented with 10% fetal bovine serum (Corning, MD, USA), 100 U / ml penicillin (Corning, MD, USA), and 100 μg / ml streptomycin (Corning, MD, USA) in a 5% CO2 incubator at 37°C.

[0200] Each cell was 1 x 10 6 The cells were plated onto a 96-well plate at 100 cells / well and cultured for 24 hours. After 24 hours, the cells were treated with 0.1 or 1 μM ribose-lenalidomide or lenalidomide. After 1 hour, the cells were treated with PHA (25 μg / ml). After 6 hours, RNA expression levels were confirmed by real-time PCR, and after 24 hours, changes in inflammation-related cytokines were confirmed by ELISA.

[0201] RNA was isolated using an RNA prep kit (Monarch Total RNA Miniprep Kit, NEB) according to the manufacturer's instructions, cDNA was synthesized using the LunaScript RT SuperMix kit (NEB), and RT-PCR was performed using the following primer set:

[0202] [Table 2]

[0203] The products used in the experiments were the same as those used in the experiments: RT-PCR cyber-green: Luna® Universal qPCR Master Mix (M3003), Real-time PCR plate (48 well): MicroAmp® Fast Optical 48-well Reaction Plate (4375816, Applied Biosystems), Real-time PCR sealing film (48 well): MicroAmp™ 48-well Optical Adhesive Film (4375323, Applied Biosystems), and the experiments were performed according to the manufacturer's instructions.

[0204] Meanwhile, the cell culture medium was separated by centrifugation and then analyzed for TNF-α protein content using a Human TNF alpha uncoated ELISA kit (88-7346-22, Invitrogen) according to the manufacturer's instructions.

[0205] As a result, as shown in Figures 2g and 2h, we confirmed that ribose-lenalidomide (type 1) exerted anti-inflammatory effects similar to or slightly improved than those of lenalidomide at the mRNA and protein levels.

[0206] 1-8.Treatment effect on macular degeneration The efficacy of this drug in healing lesions was confirmed in the mouse CNV model, a model of wet age-related macular degeneration (wet AMD).

[0207] To perform this study, 7-week-old male C57BL / 6 mice (Koatech, Korea) were used, with five mice per group. After a one-week acclimation period, 8-week-old mice were anesthetized with ketamine hydrochloride (100 mg / kg, IP) and a drop of mydriacyl (tropicamide) eye drops was placed in the right eye to dilate the pupil. After 3 minutes, the mouse was placed on a platform attached to a slit lamp, and a coverslip was placed over the right eye to act as a contact lens. After illuminating the optic nerve head with the slit lamp, four laser spots (200 mW, 50 μm spot size, 100 ms duration) were projected around the optic nerve head using a 532 nm laser (Irdiex Oculight Tx, USA) attached to the slit lamp.

[0208] After creating the choroidal neovascular lesions, a solution of ribose-lenalidomide dissolved in PBS was administered into the lesion. For intravitreal administration, 1.5 μl of a 0.2 μg / ml solution was administered once immediately after laser irradiation using a 25 μl Hamilton syringe with a 33G gauge needle. Ribose-lenalidomide was also dissolved in PBS to a concentration of 2 mg / ml, and prepared as eye drops. The solution was administered four times daily. The efficacy of the solution was confirmed by fluorescent staining of blood vessels after 7 and 14 days.

[0209] Fluorescence staining was performed using a Heidelberg Spectralis HRA+OCT device (Heidelberg, Germany). After anesthesia with ketamine hydrochloride (100 mg / kg, IP) and xylazine (10 mg / kg, IP), the right eye was dilated with a drop of Mydriacyl eye drops (tropicamide), and 0.05 ml of fluorescite 10% (Alcon, USA) was administered IP to stain blood vessels. Fluorescence images were taken 10 minutes after fluorescite injection.

[0210] As a result, as can be seen from Figure 2i, a significant tendency toward a reduction in lesions was confirmed in both the intravitreal administration group of ribose-lenalidomide (type 1) and the eye drop administration group compared to the control group.

[0211] Example 2. Glucose-Lenalidomide 2-1.Synthesis 100 mg (0.386 mmol) lenalidomide was dissolved in 1.00 mL of dimethylformamide (DMF) and 1.00 mL of ethanol (EtOH), followed by the addition of 208 mg (1.16 mmol) glucose dissolved in 0.50 mL of water (HO) and 53.0 μL (0.926 mmol) of acetic acid (AcOH). The mixture was stirred at 60 °C overnight and concentrated under reduced pressure. The residue was purified by C18-SiO2 (100% water to methanol (MeOH) = 3:1) column chromatography to synthesize glucose-lenalidomide (type 1, formula III, Figure 3a).

[0212] [ka]

[0213] Separately, 200 mg (0.772 mmol) lenalidomide and 167 mg (0.926 mmol) glucose were dissolved in 2.00 mL of dimethylformamide (DMF) and 0.500 mL of water (HO), and 53.0 μL (0.926 mmol) acetic acid (AcOH) and 58.2 mg (0.926 mmol) sodium cyanoborohydride (NaBHCN) were added. The mixture was stirred overnight at 65 °C. 1N HCl was added to adjust the pH of the mixture to pH 1-2. The mixture was diluted with 5.00 mL of water and washed five times with 5.00 mL of dimethylformamide (DMF). The aqueous layer was concentrated under reduced pressure. The residue was collected by C 18- After purification by SiO2 (100% water to methanol (MeOH) = 1:5) column chromatography, another form of glucose-lenalidomide (type 2, compound IV, Figure 3a) was synthesized.

[0214] [ka]

[0215] 2-2.Solubility in water The solubility of glucose-lenalidomide in water was confirmed in the same manner as in Example 1-2.

[0216] As a result, as shown in Figure 3b, it was confirmed that lenalidomide was hardly soluble in DW, but that both types of glucose-lenalidomide exhibited solubilities of 100 mg / ml or more in DW (freely soluble according to USP23 standard).

[0217] 2-3.CRBN bond strength The CRBN binding ability of glucose-lenalidomide was confirmed in the same manner as in Examples 1-3.

[0218] As a result, as shown in Figure 3c, glucose-lenalidomide was found to have a slightly weaker or similar level of CRBN binding affinity than lenalidomide.

[0219] 2-4. Tumor cell death effect The tumor cell killing effect of glucose-lenalidomide was confirmed by the same method as in Examples 1-4.

[0220] As a result, as shown in Figure 3d, it was confirmed that glucose-lenalidomide (type 1) exhibited the same effect as lenalidomide in killing the human multiple myeloma cell line MM.1S.

[0221] 2-5.SALL4 decomposition effect The SALL4 decomposition effect of glucose-lenalidomide was confirmed in the same manner as in Examples 1-6.

[0222] As a result, as shown in Figure 3e, glucose-lenalidomide significantly reduced the SALL4 degradation effect compared to lenalidomide, confirming a reduced possibility of teratogenic side effects.

[0223] 2-6.Treatment effect for macular degeneration The therapeutic effect of glucose-lenalidomide on macular degeneration was confirmed by administering it once intravitreally to a mouse CNV model, which is a wet age-related macular degeneration (wet AMD) model, in the same manner as in Example 1-8.

[0224] As a result, as shown in Figure 3f, the therapeutic effect of glucose-lenalidomide (type 1) administration on macular degeneration was confirmed.

[0225] Example 3. Ribose-Pomalidomide 3-1.Synthesis 300 mg (1.16 mmol) of pomalidomide, 1.74 g (11.6 mmol) of ribose, and 9.00 mL of dioxane were dissolved in 0.75 mL of water, followed by the addition of 53.0 μL (0.926 mmol) of acetic acid (AcOH). The mixture was stirred at 100 °C overnight. The residue was diluted with 5.0 mL of water and washed four times with 10.0 mL of dimethylformamide (DMF). The aqueous layer was concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 (dichloromethane (DCM):methanol (MeOH) = 9:1) to yield 247 mg of ribose-pomalidomide (Type 1, Compound IX, Figure 4a).

[0226] 247 mg of ribose-pomalidomide (type 1) was dissolved in 4.0 mL of water, and 53.0 μL (0.926 mmol) of acetic acid (AcOH) and 76.6 mg (1.22 mmol) of sodium cyanoborohydride (NaBH3CN) were added. The mixture was stirred at room temperature for 4.5 hours. 1N HCl was added to adjust the pH of the mixture to pH 1-2. The mixture was washed three times with 5.00 mL of dimethylformamide (DMF). The aqueous layer was concentrated under reduced pressure. The residue was purified by column chromatography on silicon dioxide (SiO2) (dichloromethane (DCM):methanol (MeOH) = 8:2) and then purified by C 18-The product was purified by column chromatography on SiO2 (100% water to methanol (MeOH):HO = 1:3 to 1:1). The fractions containing ribose-pomalidomide were collected, concentrated, and treated with n-hexane to yield 74.2 mg of ribose-pomalidomide (Type 2, Compound X, Figure 4a).

[0227] [ka]

[0228] 3-2.Solubility in water The solubility of the two types of ribose-pomalidomide in water was confirmed in the same manner as in Example 1-2.

[0229] As a result, as shown in Figure 4b, ribose-pomalidomide (Type 1) continued to precipitate even at concentrations of 0.1 mg / ml or less (Practically Insoluble or Insoluble level according to USP 23), while ribos-pomalidomide (Type 2) was confirmed to dissolve without visible precipitation at a concentration of 11 mg / ml (Sparringly soluble level according to USP 23).

[0230] 3-3.CRBN bond strength The CRBN binding ability of ribose-pomalidomide was confirmed in the same manner as in Examples 1-3.

[0231] As a result, as shown in Figure 4c, the two types of ribose-pomalidomide exhibited CRBN-binding avidity that was similar to or slightly improved compared to pomalidomide.

[0232] 3-4. Tumor cell killing effect The tumor cell killing effect of ribose-pomalidomide was confirmed by the same method as in Examples 1-4.

[0233] As a result, as shown in Figure 4d, it was confirmed that ribose-pomalidomide (Type 1) reduced the viability of the human multiple myeloma cell line MM.1S, but that ribose-pomalidomide (Type 2) did not significantly reduce the cell viability of the human multiple myeloma cell line MM.1S.

[0234] 3-5.SALL4 decomposition effect The SALL4 decomposition effect of ribose-pomalidomide was confirmed in the same manner as in Examples 1-5.

[0235] As a result, as shown in Figure 4e, ribose-pomalidomide (type 2) significantly reduced the SALL4 degradation effect compared to pomalidomide, confirming a reduced possibility of teratogenic side effects.

[0236] Example 4. Glucose-Pomalidomide 4-1.Synthesis 300 mg (1.16 mmol) of pomalidomide, 2.09 g (11.6 mmol) of glucose, and 9.00 mL of dioxane were dissolved in 0.75 mL of water, followed by the addition of 53.0 μL (0.926 mmol) of acetic acid (AcOH). The mixture was stirred overnight at 100 °C and concentrated under reduced pressure. The residue was diluted with 10.0 mL of water and washed four times with 10.0 mL of dimethylformamide (DMF). The aqueous layer was concentrated under reduced pressure. The residue was purified by C18-SiO2 (100% water to methanol (MeOH):HO = 3:1) column chromatography to obtain 96.8 mg of glucose-pomalidomide (Type 1, Chemical Formula VII, Figure 5a).

[0237] 96.8 mg of glucose-pomalidomide (type 1) was dissolved in 1.5 mL of water, and 3 drops of acetic acid (AcOH) and 27.9 mg (0.445 mmol) of sodium cyanoborohydride (NaBHCN) were added. The mixture was stirred at room temperature for 4.5 hours. 1N HCl was added to adjust the pH of the mixture to pH 1-2. The mixture was washed three times with 3.00 mL of dimethylformamide (DMF). The aqueous layer was concentrated under reduced pressure. The residue was purified by column chromatography on silicon dioxide (SiO2) (dichloromethane (DCM):methanol (MeOH) = 8:2). Fractions containing glucose-pomalidomide (type 2) were collected, concentrated, and treated with n-hexane to yield 68.6 mg of glucose-pomalidomide (type 2, chemical formula VIII, Figure 5a).

[0238] [ka]

[0239] 4-2.Solubility in water The solubility of glucose-pomalidomide in water was confirmed in the same manner as in Example 1-2.

[0240] As a result, as shown in Figure 5b, it was confirmed that the aqueous solubility of the two types of glucose-pomalidomide was significantly improved compared to pomalidomide.

[0241] 4-3.CRBN bond strength The CRBN binding ability of glucose-pomalidomide was confirmed in the same manner as in Examples 1-3.

[0242] As a result, as shown in Figure 5c, the binding ability of glucose-pomalidomide to CRBN was confirmed.

[0243] 4-4. Tumor cell killing effect The tumor cell killing effect of glucose-pomalidomide was confirmed by the same method as in Examples 1-4.

[0244] As a result, as shown in Figure 5d, it was confirmed that glucose-pomalidomide (Type 1) reduced the viability of the human multiple myeloma cell line MM.1S, but glucose-pomalidomide (Type 2) did not significantly reduce the cell viability of the human multiple myeloma cell line MM.1S.

[0245] Although the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents.

Claims

1. A lenalidomide or pomalidomide derivative, wherein the lenalidomide or pomalidomide derivative is selected from the group consisting of the following formulas III to XIV: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 , and 【Chemistry 12】 Lenalidomide or pomalidomide derivatives.

2. A pharmaceutical composition for preventing or treating cancer, comprising the lenalidomide or pomalidomide derivative of claim 1 as an active ingredient.

3. The composition according to claim 2 , wherein the cancer is a blood cancer or a solid cancer.

4. 4. The composition of claim 3, wherein the blood cancer is selected from the group consisting of acute leukemia, chronic leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

5. A pharmaceutical composition for preventing or treating myelodysplastic syndrome, comprising the lenalidomide or pomalidomide derivative of claim 1 as an active ingredient.

6. A pharmaceutical composition for preventing or treating an inflammatory disease, comprising the lenalidomide or pomalidomide derivative of claim 1 as an active ingredient.

7. 7. The composition of claim 6, wherein the inflammatory disease is selected from the group consisting of psoriasis, rheumatoid arthritis, and Crohn's disease.

8. A pharmaceutical composition for preventing or treating a brain disease, comprising the lenalidomide or pomalidomide derivative according to claim 1 as an active ingredient.

9. 9. The composition of claim 8, wherein the brain disease is selected from the group consisting of traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy dementia, ischemic stroke, hemorrhagic stroke, and multiple sclerosis.

10. A pharmaceutical composition for preventing or treating angiogenic diseases, comprising the lenalidomide or pomalidomide derivative according to claim 1 as an active ingredient.

11. The composition of claim 10, wherein the angiogenic disease is selected from the group consisting of corneal transplant angiogenesis, neovascular glaucoma, diabetic retinopathy, macular degeneration, diabetic macular edema, neovascular corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, hemangioma, angiofibroma, vascular malformation, arteriosclerosis, vascular adhesions, and edema sclerosis.

12. An injectable liquid formulation comprising the lenalidomide or pomalidomide derivative of claim 1.

13. An ophthalmic solution formulation comprising the lenalidomide or pomalidomide derivative of claim 1.

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