UA110964C2 - Use of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione for treatment of cancer - Google Patents

Abstract

The invention relates to the use of 3- (5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl) piperidine-2,6-dione or its enantiomer, or a mixture of its enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph for the manufacture of a medicament for the treatment or management of a patient suffering from cancer, including non-Hodgkin's lymphoma.

Description

This application claims priority to prior US patent application Mo. 61/451,995, filed Mar. 11, 2011, and prior US patent application Mo. 61/480,272, filed Apr. 28, 2011, the entire contents of which are incorporated herein by reference. 1. The branch to which the invention belongs

The present invention relates to methods of treatment, prevention and/or management of patients suffering from various forms of cancer, which include administering to the patient 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2 ,6-dione or its enantiomer or mixture of its enantiomers or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph. 2. Background of the invention 2.1 Pathobiology of cancer

Cancer is primarily characterized by an increase in the number of pathological cells originating from a given normal tissue, the invasion of these pathological cells into adjacent tissues, or the spread of malignant cells through the lymphatic or blood system to regional lymph nodes and distant sites (metastasis). Clinical data and molecular biological studies indicate that cancer is a multistage process that begins with small preneoplastic changes that can progress to neoplasia under certain conditions. A neoplastic lesion can arise clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, particularly under conditions in which the neoplastic cells escape immune control by the host. See Voii, I., Vgovioii ) apa Kaiye,

O., Ittipoiiodu, 17.1-17.12 (Zha ed., Mozbu, 51. I otsiv, Mo., 1993).

There is a huge variety of forms of cancer, which are described in detail in the medical literature.

Examples include lung, colon, rectal, prostate, breast, brain, and bowel cancers. Cancer incidence continues to rise as the general population ages, as new forms of cancer develop, and as susceptible populations (such as people infected with HIV or overexposed to the sun) grow. Therefore, there is a great need for new methods and compositions that can be used to treat patients suffering from cancer.

Many types of cancer are associated with the formation of new blood vessels, a process known as angiogenesis.

Several mechanisms involved in tumor-induced angiogenesis have been elucidated. Most

The most direct of these mechanisms is the secretion of cytokines with angiogenic properties by tumor cells. Examples of these cytokines include acidic and basic fibroblast growth factor (a, B-ESF), angiogenin, vascular endothelial growth factor (VEF), and TME-α (tumor necrosis factor-alpha). Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent destruction of the extracellular matrix, where some cytokines accumulate (eg, B-ESPE). Angiogenesis can also be caused indirectly due to the involvement of inflammatory cells (in particular, macrophages) and their subsequent release of angiogenic cytokines (for example, TME-a, B-R).

Lymphoma refers to forms of cancer that develop in the lymphatic system. Lymphoma is characterized by malignant neoplasms of lymphocytes -- B lymphocytes and T lymphocytes (that is, B cells and T cells). Lymphoma generally begins in lymph nodes or accumulations of lymph tissue in organs, including but not limited to the stomach or intestines. Lymphoma can involve the bone marrow and, in some cases, the blood. Lymphoma can spread from one area to other parts of the body.

The treatment of various forms of lymphoma is described, for example, in US patent No. 7,468,363, the full content of which is incorporated herein by reference. Such lymphomas include, but are not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, activated B-cell lymphoma, diffuse large B-cell lymphoma (ALL 0), mantle cell lymphoma (MC), follicular lymphoma (follicular center cell lymphoma), transformed lymphoma, lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma (I-U), diffuse low-differentiated lymphocytic lymphoma (PO), centrocytic lymphoma, diffuse small cleaved cell lymphoma (05SSI), peripheral T-cell lymphomas (PTSI), cutaneous T-cell lymphoma cellular lymphoma and mantle zone lymphoma and poorly differentiated follicular lymphoma.

Non-Hodgkin's lymphoma (NHL) is the fifth most common form of cancer in both men and women in

USA, with an estimated 63,190 new cases and 18,660 deaths in 2007. See Uetai A, ei aiI.,, SA Sapseg 9 Siip 2007; 57(1):43-66. Probability of development of MNI. increases with age, and the incidence of MNI. in the elderly has been steadily increasing over the past decade, raising concerns about the aging US population.

See eat Siagke S A, ei aI. Sapseg 2002; 94(7):2015-2023. because Diffuse large B-cell lymphoma (BCL) accounts for approximately one-third of non-Hodgkin's lymphomas. Although some patients with CI ALL. are cured by traditional chemotherapy, others die from this disease. Anticancer drugs cause rapid and persistent depletion of lymphocytes, possibly by direct induction of apoptosis in mature T and B cells. See K. eappke. yei ai, Viosa 2001, 98:3066-3073. Absolute lymphocyte count (ALC) has been shown to be a prognostic factor in follicular non-Hodgkin lymphoma, and recent results have shown that AL at diagnosis is an important prognostic factor in diffuse large B-cell lymphoma. See Y. Kit ei ai, dWashigpai oi Siiiipisa!

Opsoiodu, 2007 ABSO Appia! Meeiipu Rgoseedipd5 Rai I. Moi 25, Mo. 185 (Shipe 20 Zurrietepi), 2007: 8082.

Leukemia refers to malignant neoplasms of hematopoietic tissues. Various forms of leukemia are described, for example, in US Pat. No. 7,393,862 and US Patent Application No. 60/380,842, filed May 17, 2002, the entire contents of which are incorporated herein by reference. Although viruses are reported to cause several forms of leukemia in animals, the causes of leukemia in humans are largely unknown. See manual Tpe MegsKk Mapiai, 944-952 (1717 ey. 1999). Malignant transformation usually occurs in a single cell through two or more stages followed by proliferation and clonal spread. In some leukemias, specific chromosomal translocations have been identified with corresponding leukemic cell morphology and specific clinical features (for example, translocations 9 and 22 in chronic myelocytic leukemia, and 15 and 17 in acute promyelocytic leukemia). Acute leukemias are mostly undifferentiated cell populations, and chronic leukemias are more mature cell forms.

Acute leukemias are divided into lymphoblastic (AG I) and non-lymphoblastic (AMI I) types. See manual Tpe Megsk Mapmiai, 946-949 (1717 ea. 1999). They can be further subdivided according to their morphological and cytochemical appearance according to the Franco-American-British (EAV) classification or according to their type and degree of differentiation. The use of antigen-specific B- and T-cells and monoclonal antibodies to myeloid antigen helps the most classification. AG. is mainly a disease of childhood, which is diagnosed by laboratory data and bone marrow examination. AMI, also known as acute myelogenous leukemia or acute myeloblastic leukemia (AMI), occurs in humans

Of any age and is the most common form of acute leukemia among adults: it is a form usually associated with radiation as an etiological factor.

Chronic leukemias are described as either lymphocytic (CL) or myelocytic (CM).

See manual Tpe Megsk Mapiai, 949-952 (177 ey. 1999). SI. characterized by the appearance of mature lymphocytes in the blood, bone marrow and lymphoid organs. A distinctive feature of Si! there is persistent absolute lymphocytosis (x5000/μl) and an increase in the number of lymphocytes in the bone marrow. Most patients with CIII also have a clonal proliferation of lymphocytes with B-cell characteristics. SII is a disease of middle or old age. At SM. a characteristic feature is the predominance of granulocytic cells of all stages of differentiation in the blood, bone marrow, liver, spleen, and other organs. In a symptomatic patient at diagnosis, the total white blood cell count (W/BC) is usually approximately 200,000/μL, but may be as high as 1,000,000/μL. SMi is relatively easy to diagnose due to the presence of the Philadelphia chromosome.

In addition to the categories of acute and chronic, neoplasms are also classified based on the division of cells that cause such disorders into progenitors or peripheral. See, for example, published US Patent Application Mo. 2008/0051379, the disclosure of which is incorporated herein by reference in its entirety. Neoplasms from progenitor cells include AII and lymphoblastic lymphomas, and they arise in lymphocytes before they differentiate into T or B cells. Neoplasms from peripheral cells are those that arise in lymphocytes that have differentiated into either T- or B-cells. Such peripheral neoplasms include, without limitation, B-cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma, follicular lymphoma, extranodal

B-cell lymphoma of the marginal zone of lymphoid tissue associated with mucous membranes, nodular marginal zone lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, plasmacytoma, diffuse large B-cell lymphoma, and Burkitt's lymphoma. In more than 95 to 95 cases of SIDS, there is a clonal spread of the B-cell line of differentiation.

See Sapseg: Rgipsiriee5 5 Rgasiise oi Opsoiodu (Zha Eayop) (1989) (year 1843-1847). Less than in 595 cases of SIA. tumor cells have a T-cell phenotype. However, despite these classifications, pathological disruption of normal hematopoiesis is a distinctive feature of all leukemias. because Multiple myeloma (MM) is a malignant disease that develops in the bone marrow and is characterized by an excess number of plasma cells. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infection, and other complications. Multiple myeloma is the second most common hematologic malignancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M-protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin. M-protein, short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.

Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast-stimulating factors (including I-1, I/-6, and TE), which cause calcium leaching from bones, causing lytic lesions; another symptom is hypercalcemia. Osteoclast-stimulating factors, also called cytokines, can reverse apoptosis, or death, of myeloma cells. In 50 to 95 patients, during diagnosis, myeloma-related lesions of the skeletal bones are radiologically detectable. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, increased blood viscosity, infections, and kidney failure.

Solid tumors are pathological bulks of tissue that may contain, but usually do not contain, cysts or areas of fluid accumulation. Solid tumors can be benign (non-cancerous) or malignant (cancerous). Different types of solid tumors are named after the type of cells that form them. Examples of solid tumor types include, but are not limited to, malignant melanoma, adrenal carcinoma, breast carcinoma, renal cell carcinoma, pancreatic carcinoma, non-small cell lung carcinoma (NSCLC), and carcinoma of unknown primary location. Drugs commonly administered to patients with various types or stages of solid tumors include, but are not limited to, Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IM (interferon), tamoxifen,

And -2 (interleukin-2), BM-SZE (a factor that stimulates granulocyte-macrophage colonies) or their

From a combination.

Although patients who achieve complete remission after initial therapy have a reasonable probability of cure, fewer than 1,095 patients in whom initial therapy is ineffective or who experience disease recurrence achieve cure or efficacy of therapy lasting longer than 3 years. See Segpu T, Yeyi AI., App Opsoi 2002; 13 Zirri 4:211-216.

Rituximab is known to cause the deletion of normal B cells in the body. See M. AKIIyM eyii aI,, Appai5 oi Opsoiodu 15:1109-1114, 2004. Long-term immunological deletions of B cells under the influence of rituximab and the characteristics of restoration of the pool of B cells in patients with lymphoma are not well defined, despite the widespread use of this therapy. See Ueppitheg N. ApoiikK ei a!., SiIipisa! Ittypoiodu, my. 122, issue 2, Eerpagu 2007, pages 139-145.

The approach to treating patients with relapsed or refractory disease is largely based on experimental treatments followed by stem cell transplantation, which may not be appropriate for patients with poor functional status or advanced age. Therefore, there is a great need for new methods that can be used to treat patients with MN.

The link between cancer and altered cellular metabolism has been well established. See

Saigp5. V.A., her AI. Mashge Veu., 2011, 11:85-95. Understanding the metabolism of tumor cells and their associated genetic changes may lead to the identification of improved cancer treatments. See same link For example, tumor cell survival and proliferation through increased glucose metabolism has been linked to the phosphatidylinositol 3-kinase (PKZ) signaling pathway, whereby mutations in tumor suppressor genes such as RTEM activate tumor cell metabolism. See same link

ACTI (also known as RKV (protein kinase B)) stimulates glucose metabolism associated with tumor cell growth through various interactions with the genes RECEVZ, EMTRO5, tTokK and 5522 (also known as tuberin). See same link

The transcription factors NIE1 and NIE2 are largely responsible for the cellular response to low oxygen conditions often associated with tumors. See same link After activation, NIE1 stimulates the ability of tumor cells to carry out glycolysis. See same link Thus, inhibition of NIEI can slow down or reverse the development of tumor cell metabolism. The activation of NIRT has been linked to RZK, tumor suppressor proteins such as UNI. (von Hippel-Landau gene), succinate dehydrogenase (ZOH) and fumarate hydratase. See same link

The MUS oncogenic transcription factor was also associated with the metabolism of tumor cells, in particular, with glycolysis. See same link MUS also stimulates cell proliferation through glutamine metabolic pathways. See same link

AMP-activated protein kinase (AMPK) functions as a metabolic checkpoint that tumor cells must overcome to proliferate. See same link Several mutations have been identified that suppress AMRK signaling in tumor cells. See

ZpasKeyinoga, O.V. 6 Zpam, V.)., Have VNeu. Sapseg, 2009, 9:563-575. 5TK11 (serine/greonine kinase 11) was identified as a tumor suppressor gene related to the role of AMRK. See

Saigpv, V.A., Yeyi ai. Mayige Veu., 2011, 11:85-95.

The transcription factor p53, a tumor suppressor, also plays an important role in the regulation of cellular metabolism. See same link Loss of p53 in tumor cells may be a significant factor involved in changes in the metabolism of tumor cells to the glycolytic pathway. See same link The transcription factor OSTI, another potential target for chemotherapeutic agents, may cooperate with p53 in the regulation of tumor cell metabolism. See same link

Pyruvate kinase M2 (PKM2) stimulates changes in cellular metabolism that give cancer cells metabolic advantages by supporting cell proliferation. See same link

For example, it was found that lung cancer cells that express RCM2 more than RCM'I have such an advantage. See same link In the clinical setting, RKMO2 has been identified as overexpressed in a number of cancer types. See same link Thus, RKM2 may be a useful biomarker for the early detection of tumors.

Mutations in isocitrate dehydrogenases IONI and ИН2 have been associated with oncogenesis, in particular, in glioblastoma and acute myeloid leukemia. See Magaev5, E.V. eyi a!., M. Epdi. in). Honey, 2009, 361: 1058-1066; Raggopv, O.MU. and a), Zsieepse, 2008, 321: 1807-1812.

Cancer incidence continues to rise as the general population ages, as new cases of cancer occur, and as susceptible populations (such as people infected with HIV, the elderly, or those exposed to excess sunlight) grow. Therefore, there is a great need for new methods, treatments, and compositions that can be used to treat patients suffering from cancer, including but not limited to patients with lymphoma, MNI, multiple myeloma, AMI, leukemias, and solid tumors.

Accordingly, compounds that can inhibit and/or inhibit unwanted angiogenesis, or inhibit the production of certain cytokines, including TME-a, can be used in the treatment and prevention of various forms of cancer. 2.2 Methods of cancer treatment

Current cancer treatments may include surgery, chemotherapy, hormone therapy, and/or radiation therapy to destroy tumor cells in the patient (see, for example, zZioskaai, 1998, Meadisipe, my. 3, Wyrepvivip apa Redeptap, edv. Sparieg 12, Zesiiop IM ). More recently, cancer treatment may also include biological therapy or immunotherapy. All these approaches can have significant disadvantages for the patient. Surgery may, for example, be contraindicated due to the patient's medical condition or may be unacceptable to the patient. In addition, an incomplete removal of the tumor tissue may be performed during the operation. Radiation therapy is effective only when the tumor tissue shows a higher sensitivity to radiation than healthy tissue. Radiation therapy can also often cause severe side effects. Hormonal therapy is rarely prescribed as a separate agent. Although hormone therapy can be effective, it is often used to prevent or delay the recurrence of cancer after most of the cancer cells have been removed with other treatments. Certain biologic and other types of treatment are limited in number and may cause side effects such as rash or swelling, flu-like symptoms including fever, chills and fatigue, gastrointestinal problems, or allergic reactions.

As for chemotherapy, there are a variety of chemotherapy agents available to treat cancer. A number of chemotherapeutic agents act by inhibiting DNA synthesis, either directly or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division. See Sitap ei ai, Soodtap apa Siitap: Tne RNaptasoiodisa! Vaviv oi TPnegareshiisv,

Tepii Es. (Mesdgam of NIII, Mem/MogK).

Despite the availability of various chemotherapy agents, chemotherapy has many disadvantages. See YeIosKaai!e, Medisipe, my. Z, Wyrepvivip apa Eeedeptap, yeav., sn. 12, Zesi. 10, bo 1998. Almost all chemotherapy agents are toxic, and chemotherapy produces significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. In addition, even when combinations of chemotherapy agents are administered, many tumor cells are resistant or develop resistance to chemotherapy agents. Indeed, those cells that are resistant to certain chemotherapeutic agents used in a treatment protocol are often resistant to other drugs, even if these agents act by a mechanism different from that of the drugs used in a particular treatment.

This phenomenon is called multidrug resistance. Due to drug resistance, many forms of cancer are resistant to standard chemotherapy treatment protocols.

There is a significant need for safe and effective ways to treat, prevent, and manage patients suffering from cancer, particularly forms of cancer that are resistant to standard treatments such as surgery, radiation therapy, chemotherapy, and hormone therapy, while at the same time reducing or excluding toxic effects and/or side effects associated with conventional treatments. 2.3 Cereblon

Cereblon protein (SKVM) is a protein consisting of 442 amino acids, evolutionarily conserved from plants to humans. In humans, the SCVM gene was identified as a "candidate" gene, possibly responsible for the development of autosomal recessive non-syndromic mental retardation (ASMD). See Niddipv, in 9. ei aI., MeigoIodu, 2004, 63:1927-1931.

SAVM was initially characterized as a novel protein containing C-protein signaling (regulator of C-protein signaling) that interacted with the calcium-activated potassium channel protein (5I 01) in rat brain and was later shown to interact with the voltage-gated chloride channel (VCL). -2) in the retina with AMRK?7 and bilum SOVI1. See to, 5. eyi a!., U. Meshosnet, 2005, 94: 1212-1224;

Nopbegaeg V. ei aI., REV5 Hey, 2009, 583:633-637; Apdege 5. Yei ai., Mayte, 2006, 443:590-593.

BOVI was originally identified as a nucleotide excision repair protein associated with DNA damage binding protein 2 (0082). Its defective activity causes a repair defect in patients with xeroderma pigmentosum group E (CRE). It is also suggested that OOVI1 functions as a component of numerous individual complexes of ubiquitin-protein ligase OSX (0081-С0О14-Х-roh) EZ, which mediate

From ubiquitination and subsequent proteosomal cleavage of target proteins. SCM has also been identified as a target for the development of therapeutics for cortical diseases. See the published application for the International Patent UMO 2010/137547 A1.

Recently, cereblon has been identified as a key molecular target that binds to thalidomide in causing birth defects. See MO, T. eyi a!I., 5siepse, 2010, 327: 1345-1350. It was found that YUOVI interacts with SCVM and thus was indirectly related to thalidomide. In addition, thalidomide was able to inhibit the auto-ubiquitination of ip migo SCM, indicating that thalidomide is an inhibitor of EZ ubiquitin ligase. Importantly, this activity was inhibited by thalidomide in wild-type cells, but not in cells with mutated SCM binding sites that prevent thalidomide binding. The thalidomide binding site was mapped to the highly conserved C-terminal region, which consists of 104 amino acids, in

SEKVM. Both individual point mutations in SEVM, UZ384A and MUZ86A, were defective in thalidomide binding, with the double point mutant having the lowest thalidomide binding activity. The connection between SCVM and the teratogenic effect of thalidomide was confirmed in experimental models in zebrafish and chicken embryos. Identifying the targets of thalidomide and other drugs will allow the molecular mechanisms of efficacy and/or toxicity to be determined and may lead to drugs with improved efficacy and toxicity profiles. 3. Brief summary of the essence of the invention

The present invention relates to methods of treating and preventing cancer, including primary and metastatic cancer, as well as cancer that is refractory or resistant to conventional chemotherapy, and the methods include administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of 3-(5-amino- 2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione, having the structural formula I:

M z sh Y su

MN" o oso

H (5) or its enantiomer or mixture of its enantiomers, or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph as a single agent or as part of a combination treatment.

The present invention also relates to methods of managing patients suffering from cancer (eg, preventing its recurrence or prolonging remission) comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of 3-(5-amino-2-methyl- 4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione or its enantiomer or mixture of its enantiomers, or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph.

In addition, the present invention also relates to methods of treating, preventing, or managing patients suffering from cancer, comprising administering to a patient in need of such treatment, prevention, or management a therapeutically or prophylactically effective amount of 3-(5-amino-2-methyl- 4-oxo-4H-quinazoline-3-ylpiperidine-2,6-dione, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof in combination with treatment conventionally used for the treatment prevention or management of patients suffering from cancer Examples of such conventional treatments include, but are not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, and immunotherapy.

The present invention relates to methods of treating, preventing, or managing patients suffering from cancer, comprising administering to a patient in need of such treatment, prevention, or management a therapeutically or prophylactically effective amount of 3-(5-amino-2-methyl-4-oxo- 4H-quinazolin-3-yl)upiperidine-2,6-dione or its enantiomer or mixture of its enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, in an amount sufficient to provide a plasma concentration of the compound at steady state from about 0.001 to about 100 µM. In another embodiment, the amount is sufficient to provide a steady-state peak plasma concentration of the compound of about 0.001 to about 100 µM. In another embodiment, the amount is sufficient to provide a steady-state concentration of the compound in the plasma immediately prior to administration of its next dose from about 0.01 to about 100 µM. In another embodiment, the amount is sufficient to provide an area under the curve (AUC)

From the concentration of the compound in the plasma in the range from about 100 to about 100,000 ng"hr./ml.

In certain embodiments, the invention relates to methods of treating or managing patients suffering from lymphoma, multiple myeloma, leukemia, and solid tumors.

In some embodiments, the lymphoma is selected from the group consisting of lymphoma

Hodgkin's, non-Hodgkin's lymphoma, SNiD-related lymphomas, anaplastic large cell lymphoma, angioimmunoblastic lymphoma, blastic MK-cell lymphoma, Burkitt's lymphoma, Burkitt's lymphoma-like lymphoma, small uncleaved cell lymphoma, small cell lymphocytic lymphoma, cutaneous T-cell lymphoma cellular lymphoma, diffuse large B-cell lymphoma, enteropathic T-cell lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, marginal zone lymphoma, nasal

T-cell lymphoma, pediatric lymphoma, peripheral T-cell lymphoma, primary central nervous system lymphoma, transformed lymphoma, treatment-related T-cell lymphoma, and Waldenström's macroglobulinemia.

In some embodiments, the leukemia is selected from the group consisting of acute myeloid leukemia (AMI), T-cell leukemia, chronic myeloid leukemia (CM), chronic lymphocytic leukemia (CL) and acute lymphoblastic leukemia (AL).

In some embodiments, the solid tumor is selected from the group consisting of melanoma, head and neck tumors, breast carcinoma, non-small cell lung carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, colorectal carcinoma, and hepatocellular carcinoma.

In some embodiments, the invention relates to methods of treating or managing patients suffering from non-Hodgkin's lymphomas, including without limitation diffuse large cell

B-cell lymphoma (PI ALL), using prognostic factors.

In some embodiments, the invention relates to methods of using gene and protein biomarkers as a prognostic indicator of clinical sensitivity to lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AMI and/or solid tumors and the effectiveness of treatment of a patient 3-(5-amino-2-methyl- 4-oxo-4H-quinazolin-3-yl)-piperidine-2,b-dione or its enantiomer or a mixture of its enantiomers or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph.

The methods of the present invention include methods for screening or identifying patients suffering from cancer, for example, lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, (c;

AMI. and patients with solid tumors, for the treatment of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)y-piperidin-2,b-dione or its enantiomer or a mixture of its enantiomers or its pharmaceutical an acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph. In particular, the present invention relates to methods of selecting patients with a higher frequency of effectiveness of treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione.

In one embodiment, the present invention relates to a method of predicting the effectiveness of tumor treatment in a patient with lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, AMI, or a solid tumor, the method comprising obtaining tumor tissue from the patient, purifying protein or RNA from the tumor, and determining the presence or in the absence of a biomarker, for example, by analyzing protein or gene expression. The expression monitored can be, for example, mRNA expression or protein expression.

In certain embodiments, the biomarker is a gene associated with an activated B-cell phenotype AND ALL... The genes are selected from the group consisting of IKE4/MOMI, ROCHI1,

ZRIV, SAKO11 and VGIMR/ROCK'I. In one embodiment, the biomarker is ME-kV (nuclear factor kappa b).

In one embodiment, the mRNA or protein is purified from the tumor, and the presence or absence of the biomarker is determined by gene or protein expression analysis. In certain embodiments, the presence or absence of a biomarker is determined by quantitative real-time PCR (PCR (RT-PCR)), microarray, flow cytometry, or immunofluorescence. In other embodiments, the presence or absence of a biomarker is determined by enzyme-linked immunosorbent assay (ELISA) methodologies or other similar methods known in the art.

In another embodiment, the invention relates to a method of predicting the effectiveness of tumor treatment in a patient with non-Hodgkin's lymphoma, and the method includes obtaining tumor cells from the patient, culturing the cells in the presence or in the absence of 3-(5-amino-2-methyl-4-oxo- 4H-quinazolin-3-yl)upiperidine-2,6-dione, purifying protein or RNA (from cultured cells and measuring the presence or absence of a biomarker, e.g. protein or gene expression analysis. The expression being monitored can be,

For example, mRNA expression or protein expression.

In another embodiment, the invention relates to a method of monitoring the effectiveness of tumor treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione in a patient with lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, AMI or solid tumor. The method includes obtaining a biological sample from a patient, measuring the expression of a biomarker in the biological sample, administering 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2,b-dione to the patient, after which obtaining a second biological sample from the patient, measuring the expression of the biomarker in the second biological sample and comparing the expression levels, and an increase in the level of expression of the biomarker after treatment indicates the probability of the effectiveness of the treatment of the tumor. In one embodiment, a reduced level of expression of the biomarker after treatment indicates the likelihood of efficacy of the tumor treatment. The expression monitored can be, for example, mRNA expression or protein expression. The expression in the treated sample can increase, for example, by about 1.5, 2.0, 3, 5 or more times.

In yet another embodiment, the invention relates to a method of monitoring a patient's compliance with a medication treatment protocol. The method includes obtaining a biological sample from a patient, measuring the level of expression of at least one biomarker in the sample and determining whether the level of expression is increased or decreased, compared to the level of expression in the control untreated sample, and increased or decreased expression of the biomarker indicates the patient's compliance with the drug treatment protocol. In one embodiment, the expression of one or more biomarkers is increased. The expression of the biomarker being monitored can be, for example, mRNA expression or protein expression. The expression in the treated sample can be increased, for example, by about 1.5, 2.0, 3, 5 or more times.

In another embodiment, the invention relates to a method of predicting sensitivity to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,b6-dione in a patient with lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, AMI or solid tumor. In one embodiment, the patient is a patient with non-Hodgkin's lymphoma, in particular, a patient with CI ALL. The method includes obtaining a biological sample from a patient, optionally, isolation or purification of mRNA from a biological sample, amplification of mRNA transcripts, for example, CT-RSE, and a higher initial level of a specific biomarker indicates a higher probability that this form of cancer will be sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidin-2,b-dione. In certain embodiments, the biomarker is a gene associated with an activated B-cell phenotype. The genes are selected from the group consisting of IKE4/MYOMI, ROCHRI, 5RIV, SAKOT11 and VGIMR/ROEMTI.

The invention also relates to methods of treatment or management of patients suffering from cancer using 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6b-dione using

SCVM as a prognostic factor. In certain embodiments, the invention relates to methods of screening or identifying cancer patients for treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione using levels of SCVM as a prognostic factor. In some embodiments, the invention relates to methods of selecting patients having a higher frequency of efficacy of treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione using levels of SCVM as a prognostic factor.

In one embodiment, the invention relates to a method of predicting the effectiveness of treatment of a patient suffering from cancer with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione, and the method includes obtaining a biological material in the patient and determining the presence or absence of SEVM.

In one embodiment, the method includes obtaining cancer cells from a patient, culturing the cells in the presence or absence of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6- dione, purifying protein or RNA from cultured cells and determining the presence or absence of a biomarker by protein or gene expression analysis. The expression monitored can be, for example, mRNA expression or protein expression. In one embodiment, the cancer is lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, or melanoma.

In another embodiment, the invention relates to a method of monitoring the effectiveness of drug treatment of a tumor in a patient suffering from cancer. The method includes obtaining a biological sample from a patient, measuring the expression of a biomarker in the biological sample, administering one or more drugs to the patient, then obtaining a second biological sample from the patient, measuring the expression of the biomarker in the second biological sample and comparing the expression levels, with an increased level of expression of the biomarker after treatment

Zo indicates the probability of effectiveness of tumor treatment. In one embodiment, the patient suffering from cancer is a patient with lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, or melanoma.

In one embodiment, a reduced level of expression of the biomarker after treatment indicates the likelihood of efficacy of the tumor treatment. The expression of the biomarker being monitored can be, for example, mRNA expression or protein expression. The expression in the treated sample can be increased, for example, by about 1.5, 2.0, 3, 5 or more times. In one embodiment, the tumor is lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, or melanoma.

In another embodiment, the present invention relates to a method of predicting sensitivity to drug therapy in a patient suffering from cancer, in particular, a patient with multiple myeloma or non-Hodgkin's lymphoma. The method includes obtaining a biological sample from a patient, optionally, isolating or purifying mRNA from the biological sample, amplifying mRNA transcripts, for example, CT-RSE, where a higher baseline level of a specific biomarker indicates a higher probability that the malignant disease will be sensitive to drug treatment. In certain embodiments, the biomarker is a gene or protein associated with multiple myeloma or non-Hodgkin's lymphoma. In one embodiment, the genes are those genes that are associated with SEVM and are selected from the group consisting of 0081, 0082, ZZKZV, SOY 4A, CO AB, KhVR-1, BABI, KAMVRb, BO53I, RNOON, AMRK, IKRA and

MEKV. In another embodiment, the genes are selected from the group consisting of ООВИ1, ООВ2, IRA and

MEKV.

In one embodiment, the invention relates to a method of identifying a patient having lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or melanoma that is sensitive to treatment with 3-(5-amino-2-methyl-4 - oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione; identification of a gene or protein associated with CVVM, wherein the presence of a gene or protein associated with CEVM indicates the presence of lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or melanoma sensitive to treatment of 3-(5-amino-2-methyl-4-oxo-4H-quinazoline-

Z-yl)upiperidine-2,6-dione. In one embodiment, the gene or protein associated with SEBM is selected from the group consisting of OOV1, OOV2, IKE4 and MEKV. bo In one embodiment, identifying a patient having lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, or melanoma that is sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- il)upiperidine-2,6-dione, includes measurement of the level of activity of SCVM in the patient. In another embodiment, measuring the level of SCM activity in a patient includes measuring SOVI1, OB, IKE4 and/or MEKV in cells obtained from the patient.

In one embodiment, the invention relates to a method of treating or managing a patient suffering from non-Hodgkin lymphoma, comprising: (i) identifying a patient who has lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, AMI. or a solid tumor sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazoline-

C-yl)piperidine-2,6b-dione, and (i) administering to the patient a therapeutically effective amount of 3-(5-amino-2-methyl-4-oxo-4|H-quinazolin-3-yl)upiperidine-2, 6-dione or a pharmaceutically acceptable salt or solvate (eg, hydrate) thereof.

In one embodiment, the patient is suffering from non-Hodgkin's lymphoma. In one embodiment, the non-Hodgkin lymphoma is a diffuse large B-cell lymphoma. In another embodiment, the non-Hodgkin lymphoma involves an activated B-cell phenotype.

In one embodiment, identifying a patient having non-Hodgkin's lymphoma responsive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione comprises identifying of a gene associated with an activated B-cell phenotype. In one embodiment, the gene associated with an activated B-cell phenotype is selected from the group consisting of IKE4/MOMI, EOHRI, ZRIV, SAKOT11, and VHIMP/ROEMI.

In one embodiment, identifying a patient having non-Hodgkin's lymphoma responsive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione comprises measuring the level of ME-KV activity in the patient. In another embodiment, measuring the level of ME-kV activity in a patient includes measuring the baseline level of ME-kV activity in tumor cells obtained from the patient.

The invention also relates to kits used to predict the likelihood of effective treatment of lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AMI- or solid tumor or to monitor the effectiveness of treatment 3-(5-amino-2-methyl-4-oxo-4H-quinazoline -3-yl)/piperidine-2,6-dione. The kit includes a solid substrate and means for detecting protein expression of at least one biomarker in a biological sample. An indicator strip, membrane, chip, disk, test strip, filter, microsphere, glass slide, multiwell plate, or optical fiber can be used in such a kit. The solid substrate of the kit can be, for example, a plastic, silicone, metal, resin, glass, membrane, particle, sediment, gel, polymer, sheet, sphere, polysaccharide, capillary, film, plate, or glass slide. A biological sample can be, for example, a cell culture, cell line, tissue, oral cavity tissue, gastrointestinal tract tissue, organ, organelle, biological fluid, blood sample, urine sample, or skin sample. A biological sample can be, for example, a lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells.

In a further embodiment, the present invention relates to a kit used to predict the likelihood of effective treatment or to monitor the effectiveness of treatment 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl/upiperidin-2,6- The kit includes a solid substrate, nucleic acids in contact with the substrate, wherein the nucleic acids are complementary to at least 20, 50, 100, 200, 350 or more bases of mRNA, and a means for detecting mRNA expression in a biological sample.

In another embodiment, the present invention relates to a kit used to predict treatment efficacy or to monitor treatment efficacy of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl/upiperidin-2,6- The kit includes a solid substrate, at least one nucleic acid in contact with the substrate, wherein the nucleic acids are complementary to at least 20, 50, 100, 200, 350, 500 or more mRNA bases, and means for detecting mRNA expression in a biological sample.

In certain embodiments, the kits of the present invention use a means to detect the expression of a biomarker by quantitative real-time PCR (PCR), microarray, flow cytometry, or immunofluorescence. In other embodiments, the expression of the biomarker is measured by methodologies based on EGISA or other similar methods known in the art.

The present invention also relates to pharmaceutical compositions containing from about 1 to 1000 mg of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-ylpiperidine-2,6-dione or its enantiomer or a mixture thereof enantiomers or its pharmaceutically acceptable salt, solvate, hydrate,

co-crystal, clathrate or polymorph.

The present invention additionally relates to pharmaceutical compositions containing from about 1 to 1000 mg of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,b-dione or its enantiomer or mixture its enantiomers or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph; and one or more additional active ingredients. In certain embodiments, one or more additional active ingredients are selected from oblimersen, melphalan, 5-C5E (granulocyte colony-stimulating factor), CM-

CE (granulocyte-macrophage colony-stimulating factor), ERO, soh-2 (cyclooxygenase-2) inhibitor, topotecan, pentoxifylline, ciprofloxacin, taxotere, irinotecan, dexamethasone, doxorubicin, vincristine, IC 2, IEM, dacarbazine, Aga-C ( arabinofuranosyllucytidine), vinorelbine and isotretinone.

The present invention also relates to kits used to predict the likelihood of effective treatment of lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma or melanoma or to monitor the effectiveness of treatment with one or more drugs, for example, 3-(5 -amino-2-methyl-4-oxo-4H-quinazolin-3-yl)ipiperidine-2,6-dione. The kit includes a solid substrate and means for detecting protein expression of at least one biomarker in a biological sample. An indicator strip, membrane, chip, disk, test strip, filter, microsphere, glass slide, multiwell plate, or optical fiber can be used in such a kit.

The solid substrate of the kit can be, for example, a plastic, silicone, metal, resin, glass, membrane, particle, sediment, gel, polymer, sheet, sphere, polysaccharide, capillary, film, plate, or glass slide. A biological sample can be, for example, a cell culture, cell line, tissue, oral cavity tissue, gastrointestinal tract tissue, organ, organelle, biological fluid, blood sample, urine sample, or skin sample. A biological sample can be, for example, a lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells.

In another embodiment, the kit includes a solid substrate, nucleic acids in contact with the substrate, wherein the nucleic acids are complementary to at least 20, 50, 100, 200, 350 or more bases of mRNA, and means for detecting mRNA expression in a biological

From the sample.

In certain embodiments, the kits of the present invention use a means to detect the expression of a biomarker by quantitative real-time PCR (PCRA (RT-PCR)), microarray, flow cytometry, or immunofluorescence. In other embodiments, the expression of the biomarker is measured by methodologies based on EGISA or other similar methods known in the art.

The present invention also relates to a kit including (i) a pharmaceutical composition containing 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione or its enantiomer or a mixture of its enantiomers or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof; and (i) a pharmaceutical composition containing a hematopoietic growth factor, a cytokine, an anticancer agent, an antibiotic, a soh-2 inhibitor, an immunomodulatory agent, an immunosuppressive agent, a corticosteroid or a pharmacologically active mutant or derivative thereof, or a combination thereof.

In one embodiment, the present invention relates to a kit that includes: (Its) a pharmaceutical composition containing 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6 -dione or its enantiomer or mixture of its enantiomers or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph; and (ii) a pharmaceutical composition containing oblimersen, melphalan, 5-C5E, 4M-C5ZE, EPO, soh-2 inhibitor, topotecan, pentoxifylline, taxotere, iritocan, ciprofloxacin, dexamethasone, doxorubicin, vincristine, I. 2, IEM, dacarbazine, Aga-C, vinorelbine or isotretinone.

In another embodiment, the present invention relates to a kit comprising: (ii) a pharmaceutical composition containing 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6 -dione or its enantiomer or mixture of its enantiomers or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph; and (i) umbilical cord blood, placental blood, peripheral blood stem cells, peripheral blood or bone marrow hematopoietic stem cell preparation. 4. Brief description of drawings

Fig. from TA to 10: inhibitory effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione (compound of formula I) on the activity of MEKV in cells of OSI VSI.

Fig. 2: Antiproliferative effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidinbo-2,6-dione (compound of formula I) in the analysis of ip migo based on SI VS cells .

Fig. 3: 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2,b-dione (compound of formula 1) co-stimulates T cells and increases cytokine production.

Fig. 4: Antiangiogenic effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione in the analysis of human umbilical cord explants.

Fi. 5A and 58: Antiproliferative effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6-dione in an IP assay based on multiple myeloma (MM) cells.

Fig. 6: Inhibition of IP migo tumor under the action of antiproliferative effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione in the MO29 xenograft model.

Fig. 7A-7C: Cereblon expression modulates the effects of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6b-dione on ABC-OI VS cell line.

Fig. 8: SCM knockout eliminates C1 arrest induced by 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione.

Fig. 9: SKVM knockout eliminates the effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione on the phosphorylation of RK and IKE-4 in HO29 cells.

Fi. 10: Antiproliferative activity of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6b-dione is inhibited in SEVM-sensitive myeloma cells.

Fig. 11: Cereblon expression modulates the anti-invasive activity of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6b-dione.

Fig. 12A-121I: 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6b-dione inhibits hypoxia-induced expression of NIE1-a in solid tumor cell lines.

Fig 13A and 138: 3-(5-amino-2-methyl-4-oxo-4H-quinazoline-3-ylpiperidine-2,6b-dione inhibits the formation of a colony of breast cancer cells.

Fig. 14: 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6b-dione inhibits the growth of tumor cells of glioblastoma 87. 5. Detailed description of the invention

The present invention relates to methods of treating, managing patients, or preventing cancer, which include administering to a patient in need of such treatment, managing, or preventing a therapeutically or prophylactically effective amount of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl) )upiperidine-2,6-dione or its enantiomer or a mixture of enantiomers or its pharmaceutical

Of an acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph as a single agent or as part of a combination therapy.

In certain embodiments, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6-dione or an enantiomer or mixture of enantiomers thereof or a pharmaceutically acceptable salt, solvate, hydrate thereof , co-crystal, clathrate, or polymorph is administered in combination with one or more additional drugs (or "second active agents") for use in the treatment, management, or prevention of cancer. Second active agents include small molecules and large molecules (eg, proteins and antibodies), some examples of which are provided herein, as well as stem cells. Methods or treatments that may be used in combination with administration of a compound of the present invention include, but are not limited to, surgery, blood transfusion, immunotherapy, biological therapy, radiation therapy, and other non-drug treatments currently in use for the treatment, prevention, and management of patients suffering from cancer. In certain embodiments, a compound of the present invention may be used as a vaccine adjuvant.

In some embodiments, the methods of the present invention are based in part on the discovery that certain expressed genes or proteins associated with certain cancer cells can be used as biomarkers to indicate the effectiveness or course of disease treatment.

Such forms of cancer include, but are not limited to, lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, acute myeloid leukemia (AML), and solid tumors. In certain embodiments, the malignancy relates to an activated B-cell phenotype in non-Hodgkin's lymphoma. In particular, these biomarkers can be used to predict, evaluate and monitor the effectiveness of treatment of patients with 3-(5-amino-2-methyl-4-oxo-4|H-quinazolin-3-yl)/piperidine-2,b-dione.

In some embodiments, the methods of the present invention are based in part on the discovery that cereblon (SCVM) is related to the antiproliferative activity of certain drugs, such as 3-(5-amino-2-methyl-4-oxo-4- quinazolin-3-yl)ipiperidin-2,b-dione..- In some embodiments, SCM can be used as a biomarker to indicate the effectiveness or success of a 3-(5-amino-2-methyl-4-oxo-4H) disease treatment -quinazoline-3-yl-piperidine-2,6-dione Without being bound by a particular theory, CEBM binding may contribute to or even be required for the antiproliferative or other activities of certain 60 compounds such as 3-(5-amino-2-methyl -4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione.

Without being limited by theory, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-ylpiperidine-2,6-dione may mediate growth inhibition, apoptosis, and inhibition of angiogenic factors in certain types of cancer, such as lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia,

AMI and solid tumors. After examining the expression of several cancer-related genes in several cell types before and after treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione, it was found that the expression levels of several cancer-related genes or proteins can be used as biomarkers to predict and monitor cancer treatments.

It was also found that the level of ME-KV activity is increased in cells of the activated B-cell phenotype in non-Hodgkin lymphoma, relative to other lymphoma cells, and that such cells may be sensitive to treatment with 3-(5-amino-2-methyl-4- oxo-4H-quinazolin-3-yl)piperidine-2,6-dione. This indicates that the initial activity of ME-kV in lymphoma cells can be a prognostic biomarker for the treatment of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6- dionoma in patients with non-Hodgkin's lymphoma.

Therefore, in certain embodiments, the present invention relates to methods of predicting the effectiveness of tumor treatment in a patient with non-Hodgkin's lymphoma. In one embodiment, the present invention relates to a method of predicting the effectiveness of tumor treatment in a patient with non-Hodgkin's lymphoma, the method comprising obtaining tumor tissue from the patient, purifying protein or RNA from the tumor, and determining the presence or absence of a biomarker, for example, by analyzing protein or gene expression. The expression to be monitored can be, for example, mRNA expression or protein expression. In certain embodiments, the biomarker is a gene associated with an activated B-cell phenotype of OI ALL. Genes are selected from the group consisting of IKE4/MOM'I1, EOHRI, 5RIV,

SAKOT11 and VGIMR/ROEMIT. In one embodiment, the biomarker is ME-kV.

In another embodiment, the method includes obtaining tumor cells from a patient, culturing the cells in the presence or absence of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6- dione, purifying RNA or protein from cultured cells and determining the presence or absence of a biomarker, for example, by analyzing gene or protein expression.

In certain embodiments, the presence or absence of a biomarker is determined

With real-time quantitative PCR (QRT-PCR), microarray, flow cytometry or immunofluorescence. In other embodiments, the presence or absence of a biomarker is determined by methodologies based on EGISA or other similar methods known in the art.

Methods of the present invention include methods of screening or identifying cancer patients, such as patients with non-Hodgkin's lymphoma, for treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2 ,6-dione. In particular, the present invention relates to methods of selecting patients who have, or who are likely to have a higher frequency of treatment efficacy 3-(5-amino-2-methyl-4-oxo-4-quinazolin-3-yl)/upiperidine-2, 6-dione.

In one embodiment, the method comprises identifying patients with potential treatment efficacy by obtaining tumor cells from the patient, culturing the cells in the presence or absence of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl) of piperidine-2,6-dione, purification of RNA or protein from cultured cells and determination of the presence or absence of a specific biomarker. The expression to be monitored can be, for example, mRNA expression or protein expression. The expression in the treated sample can increase or in some cases decrease, for example, about 1.5, 2.0, 3, 5 or more times. In certain embodiments, the biomarker is a gene associated with an activated B-cell phenotype. Genes selected from the group consisting of IKE4A/MOMI,

EOHRI, BRIV, SAKOT11 and VGIMR/ROKMI. In one embodiment, the biomarker is

ME-KkV. Baseline expression levels of these genes may be predictive of cancer sensitivity to 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione treatment.

In one embodiment, the expression of IKE4/MOMI in cancer cells, for example ABC subtype lymphoma cells, can be reduced by treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazoline-

Z-yl)piperidine-2,6-dione. In some embodiments, the inhibitory regulation of IKE4 by 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione may represent a potential pharmacodynamic biomarker.

In another embodiment, the present invention relates to a method of monitoring the effectiveness of tumor treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione in a patient with lymphoma, non-Hodgkin's lymphoma , multiple myeloma, leukemia, AMI. or with a solid tumor. The method includes obtaining a biological sample from a patient, measuring the expression of one or more biomarkers in the biological sample, administering to the patient 3-(5-amino-2-methyl-4-

oxo-4H-quinazolin-3-yl/piperidine-2,6-dione, then obtaining a second biological sample from the patient, measuring the expression of the biomarker in the second biological sample, and comparing the expression levels of the biomarker, with an increased level of biomarker expression after treatment indicating the likelihood effectiveness of tumor treatment. In one embodiment, a reduced level of expression of the biomarker after treatment indicates the likelihood of efficacy of the tumor treatment. In certain embodiments, the biomarker is a gene associated with an activated B-cell phenotype of non-Hodgkin lymphoma. Genes selected from the group consisting of IKE4A/MOMI,

EOHRI, BRIV, SAKOT11 and VGIMR/ROKMI. In one embodiment, the biomarker is

ME-kV.

In certain embodiments, the method includes measuring the expression of one or more biomarker genes associated with an activated B-cell phenotype. The genes are selected from the group consisting of IKE4A/MOMI, EEOHRI, 5RIV, SAKO11 and VGIMR/ROCMI1. The expression to be monitored can be, for example, mRNA expression or protein expression. The expression in the treated sample can be increased, for example, by about 1.5, 2.0, 3, 5 or more times.

In yet another embodiment, the invention relates to a method of monitoring a patient's compliance with a drug therapy protocol. The method includes obtaining a biological sample from a patient, measuring the expression level of at least one biomarker in the sample, and determining whether the expression level in the sample obtained from the patient is increased or decreased compared to the expression level in a control untreated sample, wherein the increased or decreased expression indicates the patient's compliance with the drug therapy protocol. In one embodiment, the expression of one or more biomarkers is increased. The expression to be monitored can be, for example, mRNA expression or protein expression.

The expression in the treated sample can be increased, for example, by about 1.5, 2.0, 3, 5 or more times. In certain embodiments, the biomarker is a gene associated with an activated B-cell phenotype. Genes selected from the group consisting of IKE4A/MOMI,

EOHRI, BRIV, SAKOT11 and VGIMR/ROKMI. In one embodiment, the biomarker is

ME-kV.

In another embodiment, the invention relates to a method of predicting sensitivity to

From treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,b6-dione in a patient with lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AMI, or a solid tumor. In one embodiment, the patient is a patient with non-Hodgkin's lymphoma, in particular, a patient with CI ALL. The method includes obtaining a biological sample from a patient, optionally, isolating or purifying mRNA from the biological sample, amplifying an mRNA transcript, for example, KET-RSC, and a higher baseline level of one or more specific biomarkers indicates a higher probability that the cancer is will be sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione. In one embodiment, the biomarker is a gene associated with activated

B-cell phenotype selected from the group consisting of IKE4/MOMI, RBOHRI, 5RIV,

SAKOT11 and VGIMR/ROEMTI.

In another embodiment, a method of predicting responsiveness to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione in a patient with MNI, e.g., a patient with pI VS, includes obtaining a sample from the patient, pouring the tumor sample into a paraffin-embedded, formalin-fixed block and staining the sample with antibodies to CO20, CO10, bBeii-6,

IVEA/MOMTIT, bsi-2, cyclin 02 and/or EOHRI, as described in the publication Naps5 ei ai, Viosa, 2004, 103: 275-282, which is fully incorporated herein by reference. In one embodiment, CO10, rcI-6, and IEE4/MOM-1 staining can be used to stratify ALL CIs into CVD and non-CVD subgroups to predict outcome.

In one embodiment, the present invention relates to a method of predicting the effectiveness of tumor treatment in a patient with non-Hodgkin's lymphoma, comprising: () obtaining a biological sample from the patient; (i) measuring the activity of the ME-kV pathway in a biological sample and (ii) comparing the level of ME-kV activity in a biological sample with the level of ME-kV activity in a biological sample of a lymphoma subtype from non-activated B cells; and the increased level of ME-kV activity relative to the non-activated B-cell lymphoma subtype indicates the probability of tumor treatment effectiveness in a patient treated with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine -2,6-dione.

In one embodiment, measuring ME-kV pathway activity in a biological sample includes measuring the level of ME-kV in the biological sample. In one embodiment, the present invention relates to a method of monitoring the effectiveness of tumor treatment in a patient with non-Hodgkin's lymphoma, which includes: () obtaining a biological sample from the patient: (i) measuring the level of activity of ME-KkV in the biological sample; (ii) administering to the patient a therapeutically effective amount of 3-(5-amino-2-methyl-4-oxo-4|H-quinazolin-3-yl)piperidine-2,6b-dione, or its solvate or hydrate; (im) obtaining a second biological sample from the patient; (m) measuring the level of ME-KkV activity in the second biological sample; and (m) comparing the activity level of ME-KkV in the first biological sample with the activity level

ME-KV in the second biological sample; and the reduced level of ME-KV activity in the second biological sample relative to the first biological sample indicates the probability of the effectiveness of tumor treatment in the patient.

In one embodiment, the present invention relates to a method of monitoring a patient's compliance with a medical treatment protocol, which includes: () obtaining a biological sample from the patient; (its) measuring the level of ME-KV activity in a biological sample; and (iii) comparison of the ME-kV activity level in a biological sample with a control untreated sample; and the reduced level of ME-kV activity in the biological sample relative to the control indicates the patient's compliance with the drug treatment protocol.

In one embodiment, the non-Hodgkin lymphoma is diffuse large cell

B-cell lymphoma.

In another embodiment, the level of ME-kV activity is measured by enzyme-linked immunosorbent assay.

In one embodiment, the present invention relates to a method of predicting the effectiveness of tumor treatment in a patient with non-Hodgkin's lymphoma, comprising: () obtaining a biological sample from the patient; (iii) cultivation of cells from a biological sample; (ii) purification of RNA from cultured cells; and (im) identification of increased gene expression associated with activated B-cell

With the phenotype of non-Hodgkin's lymphoma relative to the control non-activated B-cell phenotype of non-Hodgkin's lymphoma; and increased expression of a gene associated with an activated B-cell phenotype of non-Hodgkin's lymphoma indicates the likelihood of a patient being treated with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine -2,6-dione.

In one embodiment, the increased expression is an increase of about 1.5, 2.0, 3, 5 or more times.

In one embodiment, the gene associated with an activated B-cell phenotype is selected from the group consisting of IENE4/MOMI, GOHRI, 5RIV, SAKOT11, and VHIMP/ROEMI.

In one embodiment, identification of gene expression associated with an activated B-cell phenotype of non-Hodgkin lymphoma is performed by quantitative PCR in real chow.

The present invention also relates to a method of treating or managing a patient with non-Hodgkin's lymphoma, comprising: () identifying a patient having non-Hodgkin's lymphoma sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)upiperidine-2,6-dione; and (i) administering to the patient a therapeutically effective amount of 3-(oxo-4-quinazolin-3-yl)-piperidin-2,6-dione or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In one embodiment, the non-Hodgkin lymphoma is diffuse large cell

B-cell lymphoma.

In another embodiment, the non-Hodgkin lymphoma involves an activated B-cell phenotype.

In another embodiment, diffuse large B-cell lymphoma is characterized by the expression of one or more biomarkers overexpressed in cell lines KIMA, 02932, TMO8, OSI-I uZ or OSI-I ut.

In another embodiment, diffuse large B-cell lymphoma is characterized by the expression of one or more biomarkers overexpressed in KIMA, 02932, TMO8 or OSI-I ut0 cell lines.

In one embodiment, identifying a patient having lymphoma responsive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,b-dione comprises determining lymphoma phenotype of the patient. bo In one embodiment, the lymphoma phenotype is characterized as activated B-

cell subtype.

In one embodiment, the lymphoma phenotype is characterized as an activated B-cell subtype of diffuse large B-cell lymphoma.

In certain embodiments, identifying a lymphoma phenotype includes obtaining a biological sample from a patient having lymphoma. In one embodiment, the biological sample is a cell culture or a tissue sample. In one embodiment, the biological sample is a sample of tumor cells. In another embodiment, the biological sample is a lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells. In one embodiment, the biological sample is a blood sample.

In one embodiment, identifying a patient having non-Hodgkin's lymphoma responsive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione comprises identifying of a gene associated with an activated B-cell phenotype. In one embodiment, the gene associated with an activated B-cell phenotype is selected from the group consisting of IKE4/MOMI, EOHRI, ZRIV, SAKOT11, and VHIMP/ROEMI.

In one embodiment, identifying a patient having non-Hodgkin's lymphoma responsive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione comprises measuring the level of ME-KV activity in the patient. In another embodiment, measuring the level of activity of ME-KV in a patient includes measuring the level of baseline activity of ME-KV in tumor cells obtained from the patient.

In another embodiment, diffuse large B-cell lymphoma is characterized by one or more of the following features: () overexpression of 5RIV, a hematopoiesis-specific family of Eiv5 transcription factors required for the survival of cells of the activated B-cell subtype; (i) higher constitutive expression of IKE4/MOMI than in cells of the SWR subtype; (iii) higher constitutive expression of EOHRI1 stimulated by trisomy 3; (im) higher constitutive expression of Vytr!1, that is, RKOM'I; and (m) higher constitutive expression of the SAKO11 gene; and (m) increased level of activity of ME-kV relative to the cells of the ALL axis. non-activated B-cell

From the subtype.

Additional prognostic factors that may be used concurrently "(with those presented in this description are prognostic factors: severity of disease (tumor), absolute lymphocyte count (ALC), time since last treatment with rituximab for lymphoma, or all of the above factors.

The present invention also relates to a method of selecting a group of patients suffering from cancer, based on the expression level of SEVM or the expression levels of ОООВ1, ООВ2, IKE4 or MEКВ within a given form of cancer for the purpose of predicting the clinical effectiveness of treatment, monitoring the clinical effectiveness of treatment or monitoring the patient's adherence to the scheme introduction of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione, its stereoisomer or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph; wherein the cancer patients are selected from patients with multiple myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, melanoma, and solid tumors. Baseline expression levels of these genes may predict cancer sensitivity to 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione treatment.

In one embodiment, the expression of IKE4/MOMI in cancer cells, such as ABC subtype lymphoma, can be reduced by treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2, 6-dione. In some embodiments, the inhibitory regulation of IKE4 by 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione may represent a potential pharmacodynamic biomarker.

In one embodiment, the cancer patients are multiple myeloma patients.

In one embodiment, the cancer patients are non-Hodgkin lymphoma patients.

In one embodiment, the method of selecting a group of patients suffering from cancer is based on the level of expression of OBI1 within a given form of cancer.

In one embodiment, the method of selecting a group of patients suffering from cancer is based on the level of expression of OOB2 within a given form of cancer.

In one embodiment, the method of selecting a group of patients suffering from cancer is based on the level of expression of IKE4 within a given form of cancer. In one embodiment, the method of selecting a group of patients suffering from cancer is based on the level of MEKV expression within a given form of cancer.

In another embodiment, the method comprises selecting a group of cancer patients responsive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione, its stereoisomer or its pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph, based on the expression level of SEVM or the expression levels of roBvI1, roV2, IR4 or MEKV within the patient's T cells, B cells or plasma cells, in order to predict the clinical effectiveness of the treatment, monitoring the clinical effectiveness of the treatment or monitoring the patient's compliance with the administration scheme of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione, its stereoisomer or its pharmaceutically acceptable salt, solvate , hydrate, co-crystal, clathrate or polymorph.

In one embodiment, the cancer patients are selected from patients with multiple myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, melanoma, and solid tumors.

The present invention also relates to methods of treating cancers such as lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, acute myeloid leukemia (AMI) and solid tumors that result in increased overall patient survival. In some embodiments, an increase in overall patient survival is observed in a patient population sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione. In some embodiments, the patient population sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)ipiperidin-2,6-dione is characterized by one or more of the biomarkers specified in this description.

In other embodiments, the present invention relates to methods of treating cancer, e.g., lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, acute myeloid leukemia (AMI), and solid tumors, resulting in disease-free patient survival. In some embodiments, disease-free patient survival is observed in a patient population sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione. In some embodiments, the patient population sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione is characterized by one or more of the biomarkers specified in this description.

In other embodiments, the present invention relates to methods of treating cancer, e.g., lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia, acute myeloid leukemia (AMI), and solid tumors, which result in an increased frequency of objective treatment efficacy in a patient population. In some embodiments, disease-free patient survival is observed in a population of patients sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione. In some embodiments, the patient population sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is characterized by one or more of the biomarkers indicated in this description.

In other embodiments, the present invention relates to methods of treating cancers such as lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, acute myeloid leukemia (AMI) and solid tumors that result in increased time to progression or progression-free survival of patients. In some embodiments, an increase in time to progression or progression-free survival of patients is observed in a population of patients sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2 ,6-dione. In some embodiments, the patient population sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is characterized by one or more of the biomarkers indicated in this description.

The present invention also relates to kits used to predict the probability of effective treatment of lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia. AMI- or solid tumor 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)ipiperidin-2,6-dione. The kit includes a solid substrate and means for detecting the expression of a biomarker in a biological sample. An indicator strip, membrane, chip, disk, test strip, filter, microsphere, glass slide, multiwell plate, or optical fiber can be used in such a kit. The solid substrate of the kit can be, for example, a plastic, silicone, metal, resin, glass, membrane, particle, sediment, gel, polymer, sheet, sphere, polysaccharide, capillary, film, plate, or glass slide. A biological sample can be, for example, a cell culture, cell line, tissue, oral cavity tissue, gastrointestinal tract tissue, organ, organelle, biological fluid, blood sample, urine sample, or skin sample.

A biological sample can be, for example, a lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells. 60 In one embodiment, the kit comprises a solid substrate, nucleic acids in contact with the substrate, wherein the nucleic acids are complementary to at least 20, 50, 100, 200, 350 or more bases of the mRNA of a gene associated with an activated B-cell phenotype in MNI ., a tool for detecting mRNA expression in a biological sample. In one embodiment, the gene associated with an activated B-cell phenotype is selected from the group consisting of IEE4/MOM'I, EOHRI, 5RIV, SAKO11, and VHIMP/ROEMI.

In one embodiment, the invention relates to a kit used to predict the likelihood of effective treatment of lymphoma, non-Hodgkin's lymphoma, multiple myeloma, leukemia, AMI, or a solid tumor or to monitor the effectiveness of treatment of 3-(5-amino-2-methyl-4-oxo- 4H-quinazolin-3-yl)upiperidine-2,b-dione. The kit includes a solid substrate and a means for detecting ME-kV expression in a biological sample. In one embodiment, the biological sample is a cell culture or a tissue sample. In one embodiment, the biological sample is a sample of tumor cells. In another embodiment, the biological sample is a lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells. In one embodiment, the biological sample is a blood sample. In one embodiment, the MNI. is ORI ALL.

In certain embodiments, the kits of the present invention use a means to detect biomarker expression by real-time quantitative PCR (RT-PCR), microarray, flow cytometry, or immunofluorescence. In other embodiments, the expression of the biomarker is measured by EGISA-based methodologies or other similar methods known in the art. Additional methods of determining mRNA and protein expression can be used in connection with the methods and kits of the present invention, for example, methods of SOMA hybridization and cytometric analysis based on fluorescence of microparticles.

In one embodiment, the present invention relates to a kit for predicting the effectiveness of tumor treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione in a patient suffering from non-Hodgkin's lymphoma , comprising: (i) a solid substrate and (i) a means for detecting the expression of a biomarker of an activated B-cell phenotype of non-Hodgkin's lymphoma in a biological sample.

In one embodiment, the biomarker is ME-kV.

In one embodiment, the biomarker is a gene associated with an activated B-cell phenotype and is selected from the group consisting of IKE4/MOM'I, ROCHRI, 5RIV, SAKO11, and VHIMP/ROEM'I.

In certain methods of the invention, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6-dione is administered in combination with a therapy conventionally used to treat, prevent, or manage patients suffering from cancer. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, and immunotherapy.

The present invention also relates to pharmaceutical compositions, separate standard dosage forms, administration schemes and kits containing 3-(5-amino-2-methyl-4-oxo-4H-quinazoline-

C-yl)upiperidine-2,6-dione or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof and a second or additional active agent. Second active agents include certain combinations or "cocktails" of drugs.

In some embodiments, the methods of treating, preventing and/or managing lymphoma patients of the present invention may be used in patients who have not responded to standard treatment. In one embodiment, the lymphoma is relapsed, refractory, or resistant to conventional therapy.

In other embodiments, the methods of treatment, prevention and/or management of lymphoma patients according to the present invention can be used in the treatment of intact patients, that is, patients who have not yet received treatment.

In certain embodiments, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6-dione or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate thereof, hydrate, co-crystal, clathrate or polymorph is administered in combination or alternately with a therapeutically effective amount of one or more additional active agents. Second active agents include small molecules and large molecules (eg, proteins and antibodies), examples of which are provided herein, as well as stem cells. Treatment methods that can be used in combination with administration of a compound of the present invention include, without limitation, surgery, blood transfusion, immunotherapy, biological therapy, radiation therapy, and other non-drug treatments currently used for treatment, prevention or management of patients with diseases or conditions associated with or characterized by adverse angiogenesis.

In one embodiment, the additional active agent is selected from the group consisting of an alkylating agent, glucocorticoid, kinase inhibitor, BUK inhibitor, ROEZ inhibitor, ROE7 inhibitor, doxorubicin, chlorambucil, vincristine, bendamustine, forskolin, rituximab, or a combination thereof.

In one embodiment, the additional active agent is rituximab.

In one embodiment, the glucocorticoid is hydrocortisone or dexamethasone.

In one embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is administered in an amount of from about 5 to about 50 mg per day.

In one embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is administered in an amount of from about 5 to about 25 mg per day.

In another embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6b-dione is administered in an amount of about 5, 10, 15, 25, 30 or 50 mg per day.

In another embodiment, 10 or 25 mg of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6b-dione is administered per day.

In one embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is administered twice daily.

The present invention relates to pharmaceutical compositions (for example, individual standard dosage forms) that can be used in the methods described in this application. In certain embodiments, the pharmaceutical compositions contain 3-(5-amino-2-methyl-4-oxo-4H-quinazoline-

C-yl)upiperidine-2,6-dione or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, and a second active agent.

In one embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is administered orally.

In one embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is administered in a capsule or tablet.

In one embodiment, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-2,6-dione is administered for 21 days followed by seven days off in a 28-day cycle . 5.1 Definition

To facilitate the understanding of the presented description, a number of terms are defined below.

The term "subject" or "patient" refers to an animal, including without limitation a mammal, including a primate (eg, a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "individual" and "patient" are used interchangeably herein when referring, for example, to a mammalian individual such as a human.

As used herein and unless otherwise defined, the terms "treat," "treatment," and "treatment" refer to the elimination or amelioration of a disease or disorder or one or more symptoms associated with a disease or disorder. In certain embodiments, these terms refer to minimizing the spread or exacerbation of a disease or disorder as a result of administration of one or more prophylactic or therapeutic agents to a patient with such disease or disorder. In some embodiments, these terms refer to the administration of a compound of the present invention with or without another additional active agent after the onset of symptoms of a particular disease.

As used herein and unless otherwise defined, the terms "prevent," "prevent," and "prophylaxis" refer to preventing the onset, recurrence, or spread of a disease or disorder or one or more of its symptoms. In certain embodiments, these terms refer to treatment with or prior to the administration of a compound of the invention, with or without an additional active compound, prior to the onset of symptoms, in particular, to patients at risk for the diseases or disorders described herein. These terms include the inhibition or reduction of a symptom of a particular disease. In certain embodiments, patients with a family history of the disease are, in particular, candidates for preventive treatment regimens. In addition, patients with a history of recurrent symptoms are also potential candidates for prophylaxis. In this regard, the term "prophylaxis" can be used interchangeably with the term "prophylactic treatment".

As used herein and unless otherwise defined, the terms "managing a patient with a disease or disorder" and "managing a patient with a disease or disorder" refer to preventing or slowing the progression, spread, and aggravation of a disease or disorder or one or more of its symptoms. Often, the beneficial effects that occur in a patient as a result of the use of a prophylactic and/or therapeutic agent do not lead to a cure for the disease or disorder. Accordingly, the term "treatment of a patient with a particular disease or disorder" includes the treatment of a patient who has suffered from a particular disease in an attempt to prevent or minimize the recurrence of the disease, or to prolong the time during which the disease or disorder is in remission.

As used herein and unless otherwise defined, the term "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in the treatment or management of a patient with a disease or disorder, or to delay or minimize one or more symptoms associated with associated with a disease or disorder.

A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutically beneficial effect in the management of a patient with a disease or disorder. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or eliminates symptoms or causes of a disease or disorder, or increases the therapeutic effectiveness of another therapeutic agent.

As used herein and unless otherwise defined, the term "prophylactically effective amount" of a compound refers to an amount sufficient to prevent or prevent the recurrence of a disease or disorder. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic beneficial effect in disease prevention. The term "prophylactically effective amount" may include an amount that improves prevention overall, or increases the prophylactic effectiveness of another prophylactic agent.

The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or base, such as a liquid or solid excipient, diluent, excipient, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with a human or animal tissue or organ without undue toxicity, irritation, allergic reaction, immunogenicity or other problems or complications , which corresponds to an appropriate benefit/risk ratio. See manuals Netipdiop: Tye 5siepse apa Rgasiise oi Ripaptasu, 2151 Eayop; Iirripsoi UMiShatve 5 MUMKip5: Rpyaaadei!rnia, RA, 2005; Naparook oi Rpaptaseshisai

Zo Ekhsiriepiye, BIJ Eyyop; Noume eyi aiYi. Ea5.,, Te RnaptaseshisaI! Rgebz5 apii She Apteegisap

Rpaptaseshisai! Avzosiyaop: 2005; and Naparook oi Rpaptaseshisa! Adayimevs, Zha Eayop; A5y apa Avp

Eavz., Somzheg Rybiizpipa Sotrapu: 2007; Rnaptaseciisa! Rgegogtiiaynyop apa ERoptshiayop, sirvop

Ea., SAS Rgezz II S: Vosa Naip, NI, 2004).

As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, malignant or benign, and all precancerous and cancerous cells and tissues.

As used in this description, the term "neoplastic" refers to any form of malignant or benign cellular growth with its impaired or absent regulation, which leads to pathological tissue growth. Thus, "neoplastic cells" include malignant and benign cells that have cellular growth with its impaired or absent regulation.

The term "recurrent" refers to a situation where an individual or mammal that has had cancer in remission after treatment has a return of cancer cells.

As used herein, the term "tumor treatment efficacy in a patient" refers to any increase in a beneficial therapeutic effect for the patient. "Effectiveness of tumor treatment in a patient" can be, for example, a decrease in

B c, 10 U, 25 Uo, 50 95 or 100 95 physical symptoms of cancer. "Effectiveness of treating a tumor in a patient" can also be, for example, an increase of 5 95 , 10 95 , 25 U , 50 o , 100 9 , 200 95 in the effectiveness of the treatment of the patient, as measured by any suitable means, such as gene expression , number of cells, results of quantitative analysis, etc.

The term "probability" generally refers to an increase in the likelihood of an event. The term "probability" when used in relation to the effectiveness of tumor treatment in a patient as a whole implies an increased probability that the rate of tumor progression or tumor cell growth will decrease. The term "probability" when used in relation to the effectiveness of treatment of a tumor in a patient can also generally mean an increase in indicators, such as mRNA or protein expression, which may indicate an increase in success in the treatment of a tumor.

The term "predict" generally means to determine or announce in advance. When used, for example, to "predict" the effectiveness of a cancer treatment, the term "predict" can mean that the probability of the outcome of the cancer treatment can be determined at an early stage, before the treatment has begun, or before the treatment period has significantly progressed.

As used herein, the term "control" generally refers to the monitoring, surveillance, regulation, tracking, surveillance, or supervision of an activity.

For example, the term "monitoring the efficacy of a compound" refers to the monitoring of efficacy in the treatment of cancer in a patient or in a culture of tumor cells. Similarly, the term "monitoring" when used in connection with a patient's compliance with a proposed treatment, either individually or in a clinical trial, refers to tracking or confirming that the patient is actually taking the tested immunomodulatory compound as intended. Monitoring can be done, for example, by observing expression

mRNA or protein biomarkers.

The effect of treatment of cancer or related disease can be characterized as full or partial effectiveness of the treatment. "Complete response" refers to the absence of clinically detectable disease with normalization of any previously abnormal X-ray, bone marrow and cerebrospinal fluid (CSF) or protein abnormalities. "Partial treatment efficacy" refers to a reduction of at least about 10 95 , 20 95 , ZO Us , 40 90 , 50 Ob , bos , 7095 , 8095 , or 9095 of the total measured tumor burden (ie, the number of malignant cells present in an individual, or the measured the volume of tumor formations or the amount of pathological monoclonal protein) during the absence of new lesions. The term "treatment" implies both full and partial effectiveness.

The term "refractory or resistant" refers to the condition where an individual or mammal has residual cancer cells in the body, even after invasive treatment.

The term "drug resistance" refers to a condition where a disease does not respond to treatment with a drug or drugs. Drug resistance can be either endogenous, meaning that the disease has never responded to treatment with the drug or drugs, or it can be acquired, meaning that the disease ceases to respond to treatment with the drug or drugs to which the disease previously reacted In certain embodiments, drug resistance is endogenous. In certain embodiments, drug resistance is acquired.

The term "sensitivity" and "sensitive" when referring to treatment with a compound is a relative term that refers to the degree of effectiveness of the compound in reducing or reducing the progression of a treatable tumor or disease. For example, the term "increased sensitivity" when used with reference to the treatment of a cell or tumor in connection with the compound refers to an increase in the effectiveness of the treatment of the tumor by at least 5 95 or more.

The term "expressed" or "expression" as used herein refers to transcription from a gene to produce an RNA nucleic acid molecule of at least a partially complementary region of one of the two nucleic acid strands of the gene. The term "expressed" or "expression" as used herein refers to translation from an RNA molecule to produce a protein, polypeptide, or portion thereof.

The content of mRNA that is "up-regulated" generally increases after a given treatment or condition. An mRNA that is "down-regulated" generally refers to a decrease in the level of mRNA expression in response to a given treatment or condition. In some situations, mRNA levels may remain unchanged after a given treatment or condition.

mRNA from a sample obtained from a patient can be "up-regulated" when treated with an immunomodulatory compound, compared to an untreated control. This boost regulation can be, for example, an increase of about 5 95, 10 9, 2095, 30 90, 40 В, 50 95, 60 95, 70 95, 90 95, 100 95, 200 95, З00 о, 500 95, 1000 U, 5000 95 or greater level of comparative control mRNA.

Alternatively, the mRNA may be "down-regulated" or expressed at a lower level in response to the administration of certain immunomodulatory compounds or other agents. The "down-regulated" mRNA may, for example, be present at a level of approximately 99 95, 95 9, 90 Fo, 80 90, 70 Zo, 60 95, 50 U, 40 FU, ZO Uo, 20 90, 10 Ov, 1 U or less of the comparative control mRNA level.

Similarly, the level of a polypeptide or protein biomarker from a patient sample may be increased by treatment with an immunomodulatory compound, compared to an untreated control. This increase can be approximately 5 95, 10 95, 20 Zo, 3 Zo, 40 Zo, 50 о, 60 о, 7095, 90 96, 100 95, 200 95, З00 95, 500 95, 1000 95, 5000 95 or more. level of the comparative control protein. Alternatively, the level of a protein biomarker may decrease in response to the administration of certain immunomodulatory compounds or other agents. This reduction may, for example, be present at about 99 95, 95 95, 90 95, 80 Zo, 70 Us, 60 Us, 50 Fo, 40 Fo, 30 90, 20 o, 10 Or, 1 95 or less than the level of the comparative control protein.

As used herein, the terms "determination," "measurement," "estimation," and "quantification" generally refer to any form of measurement and include determining whether or not an element is present. These terms include both quantitative and/or qualitative definitions. The assessment can be relative or absolute. "Assessing the presence of something" can include determining the amount of something present as well as determining whether it is present or absent.

As used herein and unless otherwise specified, the term "pharmaceutically acceptable salt" includes non-toxic acid- and base-addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids known in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid , succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid and the like.

Compounds that are acidic in nature are capable of forming salts with various pharmaceutically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable base-addition salts of such acid compounds are those that form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations, such as, but not limited to, alkali metal or alkaline earth metal salts and , in particular, calcium, magnesium, sodium or potassium salts. Suitable organic bases include, without limitation, M, M-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, megluamine (M-methylglucamine), lysine, and procaine.

As used herein and unless otherwise indicated, the term "solvate" means a compound of the present invention or a salt thereof, which additionally includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.

When the solvent is water, the solvate is a hydrate.

As used herein and unless otherwise specified, the term "prodrug" means a derivative of a compound that can be hydrolyzed, oxidized, or otherwise interacted under biological conditions (ip migo or ip mimo) to produce a compound. Examples of prodrugs include, without limitation, derivative compounds of formula | according to the present invention, which contain biohydrolyzed moieties, such as biohydrolyzed amides, biohydrolyzed esters, biohydrolyzed carbamates, biohydrolyzed carbonates, biohydrolyzed ureides, and biohydrolyzed phosphate analogs. Other examples of prodrugs include derivatives of compounds of formula I according to the present invention that contain -MO, -MO", -OMO or -OMO" moieties. Prodrugs can be obtained using such methods as described in the Vygdeg5 Medicipa manuals! Spetivigu apa Ogid Oivsomegu, 172-178, 949-982 (Mapitei E. Umoii 5 ey. 1995) and Oezidp oi Rgodgydz (N. Vypddaaga eed., EIzeimieg, Mem/ MOgK 1985).

As used herein and unless otherwise specified, the terms "biohydrolyzed amide," "biohydrolyzed ester," "biohydrolyzed carbamate," "biohydrolyzed carbonate," "biohydrolyzed ureide," and "biohydrolyzed phosphate" mean, respectively, amide, ester, carbamate, a carbonate, ureide, or phosphate of a compound that either: 1) does not interfere with the biological activity of the compound, but may add to that compound advantageous properties such as uptake, duration of action, or onset of action; or 2) is biologically inactive, but is rapidly converted into a biologically active compound. Examples of biohydrolyzable esters include, without limitation, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters ( such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and acylaminoalkyl esters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, c-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyetheramines.

As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that contains one stereoisomer of a compound and is essentially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be essentially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be essentially free of other diastereomers of the compound. In certain embodiments, the stereomerically pure compound contains more than about 80 95 wt. of one stereoisomer of the compound and less than about 20 95 wt. of other stereoisomers of the compound, more than about 90 95 wt. of one stereoisomer of the compound and less than about 10 95 wt. of other stereoisomers of the compound, more than about 95 95 wt. of one stereoisomer of compound i and less than about 5 95 wt. of other stereoisomers of the compound, or more than about 97 95 wt. of one stereoisomer of the compound and less than about 3 95 wt. other stereoisomers of the compound. As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition that contains more than about 60 95 wt. of one stereoisomer of the compound, more than about 70 95 wt. or more than about 80 95 wt. one stereoisomer of the compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having a single chiral center. Similarly, the term "stereomerically enriched" means a stereomerically enriched composition of a compound having one chiral center.

The term "about" or "about" means an acceptable error for a particular quantity as determined by one of ordinary skill in the art, which depends in part on how that quantity is measured or determined. In certain embodiments, the term "about" or "about" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "about" means within 50 95, 20 95, 15 Fo, 10 9", 9 Ob, 890, 7 o, 6 95, 5 o, 4 o, Z o, 2 o, 1 o, 0.5 V or 0.05 95 of a given value or range. 5.2 Endpoints of clinical trials for registration as an anticancer drug "Overall survival" is defined as the time from randomization to death from any cause and is measured in the population included in the initially intended treatment group. Overall survival should be evaluated in randomized controlled trials. Demonstration of statistically significant an increase in overall survival can be considered clinically meaningful if the toxicity profile is acceptable, and this has often supported the registration of new drugs.

Several endpoints are based on tumor assessment. These endpoints include survival

OS without clinically evident signs of disease (OE5), objective frequency of treatment effectiveness (OCC), time to disease progression (TPR), survival without disease progression (PE) and time to detection of treatment ineffectiveness (TTE). Data collection and analysis for these time-dependent endpoints is based on indirect assessments, calculations, and metrics (eg, tumor measurements).

In general, "disease-free survival" (OE5) is defined as the time from randomization to tumor recurrence or to death from any cause. Although overall survival is the usual end point for most adjuvant studies, pRES may be an important end point in situations where survival may be prolonged, making the survival end point impractical. OE5 can be a surrogate endpoint of clinical efficacy, or it can be direct evidence of clinical efficacy. This definition is based on the magnitude of the effect, its risk-benefit ratio, and the type of pathology. Definition

ESR can be complex, especially when deaths are reported without prior documentation of disease progression. These events can be scored either as disease recurrences or as censored events. Although all methods of statistical analysis of deaths have some limitations, counting all deaths (deaths from all causes) as recurrences can minimize error. OE5 may be overestimated using this definition, particularly in patients who die after a long period without follow-up. Error may be introduced if the frequency of visits during long-term follow-up is not the same in different groups of study patients, or if the cases of withdrawal from the study are not random due to toxicity. "Objective response rate" (OBR) is defined as the proportion of patients with a reduction in tumor size by a given amount and within a minimum period of time.

The duration of treatment effectiveness is usually measured from the time of initial manifestation of treatment effectiveness to documented tumor progression. In general, the FDA (US Food and Drug Administration) defined the ORC as the sum of cases of partial treatment efficacy plus cases of complete treatment efficacy. With this method of determination, OKC is a direct indicator of the antitumor activity of the drug, which can be evaluated in a single-group study. Standardized criteria, if available, should be used to confirm treatment efficacy. Various criteria of treatment effectiveness were considered appropriate (for example, KESI5T criteria (criteria for evaluating the effectiveness of treatment in solid tumors)) (TPegazze ei ai., (2000) In May. Sapseg Ipvi, 92:205-16). The significance of OCC is assessed by its size and duration, and the percentage of cases of complete treatment effectiveness (absence of detectable evidence of the presence of a tumor). Time to disease progression (TPR) and progression-free survival (PE5) served as primary endpoints for drug registration. TTR is defined as the time from randomization to objective tumor progression; TTR does not include deaths.

RES is defined as the time from randomization to objective tumor progression or death. Compared to TTR, PE5 is the preferred regulatory endpoint. PE5 includes deaths and thus may correlate better with overall survival. PE5 assumes that patient deaths are coincidentally related to tumor progression. However, in situations where the majority of deaths are not related to cancer, TTR may represent an acceptable end point.

As an end point to justify the registration of a drug, RES can reflect tumor growth and be evaluated before determining a beneficial effect on survival. Its definition is not distorted by subsequent treatment. For a given sample size, the magnitude of the effect on PE5 may be greater than the effect on overall survival. However, formal validation of REb5 as a surrogate for survival in many different existing malignancies may be difficult. Data are sometimes insufficient to allow a proper assessment of the correlation between effects on survival and PE5. Trials of cancer treatments are often small, and the number of proven beneficial effects on survival of existing drugs is generally small. The role of PE5 as an endpoint to justify registration of licensure varies in different forms of cancer. Whether an improvement in ESR represents a direct clinical effect or a surrogate for a clinical effect depends on the magnitude of the effect and the risk-benefit of the new treatment compared to available treatments. "Time to failure" (TTE) is defined as a composite endpoint measuring the time from randomization to treatment discontinuation for any reason, including disease progression, treatment toxicity, and death. TTE is not recommended as a regulatory endpoint for drug registration. TTE does not adequately differentiate efficacy from these additional parameters. The regulatory endpoint should be clear

To distinguish the effectiveness of the medicinal product from toxicity, termination of participation in a clinical trial for reasons related to the patient or the doctor or the patient's intolerance of the tested medicinal product. 5.3 Compound

The compound suitable for use in the methods of this invention is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6b-dione having the structural formula I :

M

5 th

I know about Mo

H () or its enantiomer or a mixture of enantiomers; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof.

A compound of formula I may be prepared according to the methods described in the Examples section of this specification, or as described in US Pat. No. 7,635,700, which is fully incorporated herein by reference. This compound may also be synthesized according to methods apparent to those skilled in the art based on the provisions of this specification.

The compound of formula I significantly inhibits TME-a, I--1rD and other inflammatory cytokines in stimulated I P5 (lipopolysaccharide) PRVMS (human peripheral blood mononuclear cells) and in human whole blood. TME-4 is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TME-α is responsible for a diverse range of signaling events within cells. TME can play a pathological role in cancer. Without being bound by theory, one of the biological effects provided by the immunomodulatory compound of formula I is the reduction of TME-a synthesis. Immunomodulatory compound of the formula | enhances the destruction of TME-a mRNA. The compound of formula I also potently inhibits I/-1rD and stimulates 11-10 under these conditions.

In addition, without being limited by theory, the compound of formula I is a potent costimulator of T cells and increases cell proliferation in a tightly dependent manner under appropriate conditions.

In certain embodiments, without being limited by theory, the biological effects provided by an immunomodulatory compound of Formula 1 include, without limitation, antiangiogenic and immunomodulatory effects.

In certain embodiments, the compound of formula I is a solid. In certain embodiments, the compound of formula I is hydrogenated. In certain embodiments, the compound of formula I is solvated. In certain embodiments, the compound of formula I is anhydrous. In certain embodiments, the compound of formula I is non-hygroscopic.

In certain embodiments, the solid compound of formula I is amorphous. In certain embodiments, the solid compound of formula I! is crystalline. In certain embodiments, the solid compound of formula I! presented in the crystalline form described in the previous patent application

US Mo. 61/451,806, filed Mar. 11, 2011, which is fully incorporated herein by reference.

Solid forms of the compound of formula I can be obtained according to the methods described in the description of the preliminary application for the US patent Mo 61/451,806. Solid forms may also be prepared according to other methods apparent to those skilled in the art.

In certain embodiments, the compound of formula I is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidin-2,6-dione hydrochloride or its enantiomer or mixture of enantiomers; or a pharmaceutically acceptable solvate, hydrate, co-crystal, clathrate or polymorph thereof. In certain embodiments, the hydrochloride is a solid. In certain embodiments, the hydrochloride is anhydrous. In certain embodiments, the hydrochloride is non-hygroscopic. In certain embodiments, the hydrochloride is amorphous. In certain embodiments, the hydrochloride is non-hygroscopic. In certain embodiments, the hydrochloride is amorphous. In certain embodiments, the hydrochloride is crystalline. In certain embodiments, the hydrochloride is presented in crystalline form A.

The hydrochloride compound of formula I and its solid forms can be obtained according to the methods described in the description of the preliminary application for the US patent Mo 61/451,806. The hydrochloride and its solid forms may also be prepared according to other methods apparent to those skilled in the art.

The compound of formula I according to the present invention contains one chiral center and can exist in the form of a mixture of enantiomers, for example, a racemic mixture. This description includes the application

From stereomerically pure forms of such a compound, as well as the use of mixtures of these forms. For example, mixtures containing equal or unequal amounts of enantiomers of a compound of formula I according to the present invention can be used in the methods and compositions described in this application. These isomers can be synthesized asymmetrically or separated using standard techniques such as chiral columns or chiral resolving agents. See, for example, the publications of Dasdiev, «., ei ai., Epapioteg5, Nasetaieez apa VNezoishiopv (U/Peu-Ipiegzsiepse, Mem

UoKk, 1981); Mep, 5. N., yei ai, Teiganedgop 33:2725 (1977); Eiiei, E. I. Yeegeospetivighu oi Sagrop

Sotrotspavz (Medgham, MM, 1962); and M/Pep, 5. N., Tabiez oi Vezoimipd Adepiz apa Oriisa!

Vezo!shiopz, p. 268 (E.I... Eiei, Ea., Opim. oi Moige Oate Rgezv, Moige bate, IM, 1972).

It should be noted that if there is a discrepancy between the depicted structure and the name assigned to that structure, the depicted structure takes precedence. In addition, if the stereochemistry of a structure or part of a structure is not indicated, for example, by bold or dashed lines, then the structure or part of a structure should be interpreted as including all stereoisomers of that structure. 5.4. Other active means

A compound of the present invention, for example, a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may be combined with one or more other pharmacologically active compounds ("second active agents") in the methods and compositions of the present invention.

Certain combinations are believed to work synergistically in the treatment of specific types of cancer and certain diseases and conditions associated with or characterized by unwanted angiogenesis. A compound of formula I of the present invention may also work to alleviate side effects associated with certain second active agents, and certain second active agents may be used to alleviate side effects associated with a compound of formula I of the present invention.

One or more second active ingredients or agents may be used in the methods and compositions of the present invention with a compound of formula I of the present invention. Second active agents can be large molecules (eg proteins) or small molecules (eg synthetic, inorganic, organometallic or organic molecules).

Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. In certain embodiments, the macromolecular active agents are biological molecules, such as artificially obtained naturally occurring proteins. Proteins that can particularly be used in the present invention include proteins that stimulate the survival and/or proliferation of hematopoietic progenitor cells and immunologically active ip myo or ip mimo cells. Others stimulate the division and differentiation of committed erythroid progenitors in IP migo or IP mimo cells. Specific proteins include, but are not limited to: interleukins such as 1-2 (including recombinant I-II (I 2") and canarypox virus I--2), I-- 10, 17-12 and 1--18; interferons, such as interferon alfa-g2a, interferon alfa-2p, interferon alfa-p1, interferon alfa-p3, interferon beta-ia and interferon gamma-Ib; CM-SE (granulocyte-macrophage colony-forming factor) and ZM-C5E ( granulocyte-macrophage colony-stimulating factor and EPO (erythropoietin).

Specific proteins that can be used in the methods and compositions of the invention include, without limitation: filgastrim, which is sold in the United States under the trade name

MEOROSEME! (Atdep, Tpoizapa Oak5, SA); sargramostim, which is sold in the USA under the trade name IGESHOKIMEF (Ittipeh, Beashe, MMA); and recombinant ERO, which is sold in the USA under the trade name ERSEMO (Atdep. Tpoizapa bakb, SA).

Inhibitors of АСсиКИИЙ receptors or inhibitors of activin-АСиККИ! can be used in the methods and compositions of this invention. AsciKIi receptors! include ACE inhibitors and ACE inhibitors. Inhibitors of АССИКИИ receptors can be polypeptides containing activin-binding domains of АСССИКИИ. In certain embodiments, the binding activin domain containing polypeptides are linked to the Es portion of the antibody (ie, a conjugate is generated containing the binding activin domain containing polypeptide of the ASCKII receptor and the Es portion of the antibody). In certain embodiments, the binding activin domain is linked to the Es portion of the antibody through a linker, for example, a peptide linker. Examples of such non-antibody proteins selected to bind activin or AsSIKIA and methods for their design and selection can be found in International Patent Applications UMO/2002/088171, UUO/2006/055689, UMO/2002/032925,

UMO/2005/037989 and US patent applications C 2003/0133939 and 05 2005/0238646, each of which is fully incorporated herein by reference.

Recombinant and mutated forms of CM-C5E can be obtained as described in US Pat

MoMo 5391485; 5393870 and 5229496, the description of each of which is fully incorporated into this application by reference. Recombinant and mutated forms of 5-C5E (granulocyte colony-stimulating factor) can be obtained as described in US Pat. No. 4,810,643; 4999291; 5528823 and 5580755, the description of each of which is fully incorporated into this application by reference.

This specification includes the use of native, naturally occurring and recombinant proteins. The description further includes mutants and derivatives (eg, modified forms) of naturally occurring proteins that exhibit at least some of the pharmacological activity of the proteins on which they are based. Examples of mutants include, without limitation, proteins that have one or more amino acid residues that differ from the corresponding residues in naturally occurring protein forms. The term "mutants" also includes proteins that lack the hydrocarbon moiety normally present in their naturally occurring forms (eg, non-glycosylated forms). Examples of derivatives include, without limitation, pegylated derivatives and fusion proteins, such as proteins formed by fusion of Ids1 or Ids3 with the protein or active portion of the protein of interest. See, for example, the publication of Repispei, M.S. apa Mottizop, 5.I.., U. Ittipoi. Medicine 248:91-101 (2001).

Antibodies that can be used in combination with a compound of formula I according to the present invention include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (HERCEPTIN?U), rituximab (RITUXANE), bevacizumab (AVASTIN'M), pertuzumab (OMMITACO'M), tositumomab (VEHHAKF), edrecolomab (PANOREX-), panitumumab and 5250. A compound of formula I of this invention can also be combined or used in combination with antibodies to TME-a.

Large molecular active agents can be administered in the form of anticancer vaccines.

For example, vaccines that secrete or cause the secretion of cytokines, such as II -2, CSE,

SCH14 (platelet factor 4), 5-C5E and ZM-C5E can be used in the methods, pharmaceutical compositions and kits of the invention. See, for example, the publication of Etepv, G.A., eiaii, Sit. Oriope Moi. Tag. 3(1):77-84 (2001).

Second active agents, which are small molecules, can also be used to alleviate the side effects associated with the administration of a compound of formula I according to the present invention.

However, it is believed that, like some large molecules, they are able to provide a synergistic effect when administered with a compound of formula I (for example, before, after or simultaneously with it). Examples of a small molecule second active agent include, but are not limited to, anticancer agents, antibiotics, immunosuppressive agents, and steroids.

Examples of anticancer agents include without limitation: abraxan; ACE-11; acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesinaldesleukin; altretamine; ambomycin; amethantrone acetate; amrubicin; amsacrine; anastrozole; Anthramycin; aspraginase; asperlin; azacitidine; azetep; azotomycin; batimastat; Benzodepa; bicalutamide; bisanthrene hydrochloride; bisnafid dimesylate: biselesin; bleomycin sulfate; sodium brequinar; bropyrimine; busulfan; actinomycin; calusterone; caracemid; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelicin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemicin; cisplatin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; desaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; Dromostanolone propionate; Duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromat; epipropidine; epirubicin hydrochloride; erbulozol; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fasarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; sodium forstriecin; gemcitabine; gemcitabine hydrochloride; Herceptin; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; lapatinib; letrozole; leuprolide acetate; liarozol hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; mass puncture; Maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; methotrexate sodium; methoprine; meturedepa; mithindomide; mitocarcinoma; mitocromin; mitogyline; mitomalcin; mitomycin; mitospore; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plikamycin; plomestan; sodium porfimer; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; uromycin hydrochloride; pyrazofurin; Riboprine; romidepsin; safingol; safingol hydrochloride; semustine; symptrazen; sodium sparphosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; therapeutic means with

From stem cells, such as ROA-001; streptonigrin; streptozocin; sulofenur; talisomycin; thekogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprin; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribin phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosol hydrochloride; uraciliprite; uredepa; vapreotide; verteporfin; synblastin sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; winglycinate sulfate; vinleurosin sulfate; vinorelbine tartrate; vinrosidine sulfate; winzolidin sulfate; vorozol; Zeniplatin; zinostatin and zurobicin hydrochloride.

Other anticancer drugs include, but are not limited to: 20-epi-1,25-dihydroxyvitamin

OZ; B5-ethinyluracil; abiraterone; aclarubicin; acylfulvene; alecipenol; adozelesin; aldesleukin; AGI/TC antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; an antagonist of OY; antagonist with; Antarelix; anti-dorsalizing morphogenic protein-1; antiandrogen, carcinoma of the prostate gland; anti-estrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; modulators of apoptosis genes; regulators of apoptosis; apuric acid; aga-SOR-OY-RTVA (1-beta-0-Arabinofuranosylcytosine-5'-diphosphate-rac-1-5-octadecyl-2-O-palmitoyl-1-thioglycerol); arginine deaminase; asulacrine; atamestan; atrimustine; Axinastatin 1; axinastatin 2; Axinastatin 3; azhasetron; azatoxin; azatyrosine; derivatives of bakatin Ii; balanol; batimastat; VSE/AVI oncoprotein antagonists; benzochlorins; benzoylstaurosporine; beta-lactam derivatives; beta-alletin; betaclamycin B; betulinic acid; an inhibitor of B-ESE (the main growth factor of fibroblasts); bicalutamide; bisanthrene; bisaziridinylsospermine; bisnafid; Bistraten A; Bizelesin; breflat; bropyrimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; SakKevbhi M3; SAKM 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (ISO5); castanospermine; cecropin B; cetrorelix; chlorine; chloroquinoxaline sulfonamide; cicaprost; Cisiporphyrin; cladribine; analogues of clomiphene; clotrimazole; colismycin A; colismycin B; combretastatin Ai; analogue of combretastatin; conagenin; crambescidin 816; chrysnathol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; 60 deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin

IN; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxyfluridine; doxorubicin; droloxifene; dronabinol; duocarmycin 5A; ebselen; ecomustin; edelfosine; edrecolomab; eflornithine; element; emitefur; epirubicin; epristeride; analogue of estramustine; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fasarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastin; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; hydramanton; ilmofosine; ilomastat; imatinib (e.g., Glivec), imiquimod; immunostimulating peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; yobenguan; iodoxorubicin; 4-ipomeanol; iroplakt; irsogladin; isobenzazole; isohomohalichondrin B; itasetron; jasplakinolide; kagalalide E; lamellarin-M triacetate; lanreotide; Leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha-interferon; leuprolidestrogen and progesterone; leuprorelin; levamisole; liarozol; analogue of linear polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lisoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysophyllin; lytic peptides; Maytansine; manostatin A; marimastat; mass puncture; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbaron; meterelin; methioninase; metoclopramide; MIR (migration inhibitory factor) inhibitor; mifepristone; miltefosine; measurable; mitohuason; mitolactol; mitomycin analogues; mitonafid; mitotoxin-fibroblast growth factor-saporin; mitoxantrone; mofarotene; thunderous; Erbitux, human chorionic gonadotropin; monophosphoryl lipid AK (streptokinase) of the mycobacterial cell wall; mopidamol; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; miriapron; M-acetyldinalin; M-substituted benzamides; nafarelin; nagrestype; naloxonepentazocine; Napavin naphtherpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nizamycin; nitric oxide modulators; nitroxide antioxidant; nitrulin; oblimersen (ZEMABEM5ZEF); O9-benzylguanine; octreotide;

Zo oxycenone; oligonucleotides; onapristone; ondansetron; oracin; oral cytokine inducer; ormaplatin; osateron; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panoxytriol; panomifen; parabactin; pazeliptin; pegaspargase; peldesin; sodium pentosan polysulfate; pentostatin; Pentrozol; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; pizzabanil; pilocarpine hydrochloride; pirarubicin; pyritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; sodium porfimer; porfiromycin; prednisone; propyl bis-acridone; prostaglandin 42; proteasome inhibitors; immunomodulator based on protein A; protein kinase C inhibitor; inhibitors of protein kinase C, microalgae; protein-tyrosine-phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; conjugate of pyridoxylated hemoglobin and polyoxyethylene; antagonists of gaia (recombinant activated factor); raltitrexed; ramosetron; inhibitors of farnesyl protein ha5 transferase; Gaia inhibitors; GAB5-SAP (glyceraldehyde phosphate) inhibitor; demethylated reteliptin; Rhenium etidronate Ke 186; rhizoxin: ribozymes; retinamide KII; rogitukin; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; seintopin; orders; Sarcophytol A; sarliterate; mimetics 5ai 1; semustine; senescence-related inhibitor 1, sense oligonucleotides; signaling inhibitors; Sizofiran; sobuzoxan; sodium borcaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermin; sparphosic acid; spicamycin O; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; overactive vasoactive intestinal peptide antagonist; suradist; suramin; swainsonine; talismustine; tamoxifen methiodide; tauromustine; tazarotene; thekogalan sodium; tegafur; tellurapyryllium; telomerase inhibitors: temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfazin; thymopoietin receptor agonist; timotrynan; thyroid-stimulating hormone; tin ethylthiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosterid; tyrosine kinase inhibitors; tyrphostin; OBS inhibitors; ubenimex; growth inhibitory factor originating from the urogenital sinus; urokinase receptor antagonists; vapreotide; variolin B; velarezol; veramin; Verdins; verteporfin; vinorelbine; Vinxaltine; vitaxin; vorozol; zanoterone; Zeniplatin; zilascorb and 60 zinostatin stimalamer.

Certain second active agents include without limitation oblimersen (GENACENS-), Remicade, docetaxel, celecoxib, melphalan, dexamethasone (DECADRONE), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, ACIBAF, taxol, taxotere, fluorouracil, leucovorin, irinotecan, Xeloda, CRT-11, interferon alfa, pegylated interferon alfa (eg, PEG INTRO-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxel, pacilitaxel, vinblastine, 1-2, YAM-C5E, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (DOXILEU), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (EMCITU"), sulindac and etoposide. 5.5 Biomarkers

The present invention relates to methods associated with the use of mRNA or proteins as biomarkers for establishing the effectiveness of cancer treatment. Levels of mRNA or protein can be used to determine whether a particular agent is likely to be successful in treating a particular type of cancer, such as non-Hodgkin lymphoma.

A biological marker or "biomarker" is a substance whose detection indicates a certain biological condition, such as, for example, the presence of cancer. In some embodiments, biomarkers can be determined either individually, or the content of several biomarkers can be measured simultaneously.

In some embodiments, the "biomarker" indicates a change in the level of mRNA expression that may be correlated with the risk or progression of a disease, or with the susceptibility of a disease to a given treatment. In some embodiments, the biomarker is a nucleic acid such as mRNA or cDNA.

In additional embodiments, a "biomarker" indicates a change in the level of expression of a polypeptide or protein that may be correlated with risk, susceptibility to treatment, or disease progression. In some embodiments, the biomarker may be a polypeptide or protein or a fragment thereof. The relative level of certain proteins can be determined by methods known in the field. For example, antibody-based methods such as immunoblotting, enzyme-linked immunosorbent assay (ELISA) or other methods can be used.

From 5.6 Methods of treatment and prevention

In one embodiment, the present invention relates to a method of treating and preventing cancer, which comprises administering to a patient a compound of the present invention, for example, a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph.

In another embodiment, the present invention relates to a method of managing patients suffering from cancer, which comprises administering to the patient a compound of the present invention, for example, a compound of formula | or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof. The present invention relates to methods of treating or managing patients with lymphoma, in particular, non-Hodgkin's lymphoma. In some embodiments, the present invention relates to methods of treating or managing patients with non-Hodgkin's lymphoma (NHL), including without limitation diffuse large B-cell lymphoma (0 ALL), using prognostic factors.

The present invention also relates to methods of treating patients who have previously received treatment for cancer, but in whom standard treatments are ineffective, as well as those who have not previously received treatment. The invention also includes methods of treating patients regardless of the patient's age, although some diseases or disorders are more common in certain age groups. The invention further includes methods of treating patients who have undergone surgical treatment in an attempt to treat the disease or condition in question, as well as those who have not undergone surgical treatment. Because patients with cancer have heterogeneous clinical presentations and variable clinical outcomes, the treatment given to a patient may vary depending on the patient's prognosis. An experienced clinician will be able to readily identify, without undue experimentation, certain secondary agents, types of surgery, and types of non-pharmacological standard of care that may be effective in the treatment of an individual patient with cancer.

As used herein, the term "cancer" includes, without limitation, solid tumors and hematologic tumors. The term "cancer" refers to diseases of the skin tissues, organs, blood and vessels, including without limitation cancers of the bladder, bones, blood, brain, breast, cervix, chest, colon, endometrium, eye, head, kidney, liver , lymph nodes, lungs, oral cavity, neck, ovaries, pancreas, prostate gland, rectum, stomach, testicles, throat and uterus. Certain forms of cancer include, without limitation, advanced malignancies, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumor with an unfavorable prognosis, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, adenocarcinoma of the rectum, colorectal cancer of stages C or O according to the Dukes classification, inoperable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B -cell lymphoma, diffuse large B-cell lymphoma, poorly differentiated follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant mesothelioma syndrome with pleural effusion, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma tissue, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, progressive ossifying fibrodysplasia, hormone-refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenström macroglobulinemia, indolent myeloma, slow-growing myeloma developing, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent non-metastatic stage IM prostate cancer, insensitive to hormone therapy prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary carcinoma of the thyroid gland and leiomyoma.

In certain embodiments, the cancer is a hematologic tumor. In certain embodiments, the hematologic tumor is metastatic. In certain embodiments, the hematologic tumor is resistant to drug therapy. In certain embodiments, the cancer is myeloma or lymphoma.

In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is resistant to drug therapy. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or glioblastoma.

In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0 .01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day or from about 0.05 to about 10 mg per day.

In a particular embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0, 01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, or from about 0.05 to about 10 mg every other day.

In certain embodiments, a therapeutically or prophylactically effective amount of the compound is about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70 , about 80, about 90, about 100 or about 150 mg per day.

In one embodiment, the recommended daily dose range of a compound of formula | for the conditions described in this application is within the range of about 0.5 mg to about 50 mg per day, preferably administered as a single dose once a day or in divided doses throughout the day. In some embodiments, the dosage is in the range of about 1 mg to about 50 mg per day. In other embodiments, the dosage is in the range of about 0.5 to about 5 mg per day. Certain daily doses include 1, 2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 , 49 or 50 mg per day. 60 In a particular embodiment, the recommended initial dosage may be 0.5, 1,

2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4 or 5 mg per day. The dose can be increased to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In a particular embodiment, the compound can be administered in an amount of about 25 mg/day to patients with INI. (for example, ALL AXES). In a specific embodiment, the compound can be administered in an amount of about 10 mg/day to patients with IBD. (for example, ALL AXES).

In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, from about 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, about 0.01 to about 6 mg/kg/day, about 0.01 to about 5 mg/kg/day, about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, or from about 0.01 to about 1 mg/kg/day.

The administered dose may also be expressed in units other than mg/kg/day.

For example, doses for parenteral administration may be expressed as mg/m-/day.

An average person skilled in the art is well aware of how to convert doses from mg/kg/day to mg/m?/day for a given individual's height or body weight or both (see the Internet site, mly da.dom/sdeg/ sapseg/apitaytate.yt). For example, a dose of 1 mg/kg/day for a person with a body weight of 65 kg is approximately equal to 38 mg/m"/day.

In certain embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound in the range of from about 0.001 to about 500 µM, from about 0.002 to about 200 µM, from about 0.005 to about 100 µM, from about 0 .01 to about 50 µM, from about 1 to about 50

MKM, from about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM.

In other embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound in the range of about 5 to about

Co) 100 nM, about 5 to about 50 nM, from about 10 to about 100 nM, from about 10 to about 50 nM, or from about 50 to about 100 nM.

As used herein, the term "steady-state plasma concentration" refers to the concentration achieved after a period of administration of a compound of the present invention, for example, a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate thereof, hydrate, co-crystal, clathrate or polymorph. After steady state is reached, there are small peaks and valleys in the plasma concentration-time curve of the compound.

In certain embodiments, the amount of compound administered is sufficient to provide a maximum concentration (peak concentration) of the compound in plasma in the range of about 40 0.001 to about 500 μM, from about 0.002 to about 200 μM, from about 0.005 to about 100 μM, from about 0.01 to about 50 µM, from about 1 to about 50 µM, from about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM or from about 1 to about 20 µM. 45 In certain embodiments, the amount of compound administered is sufficient to provide a trough concentration (concentration immediately before administration of the next dose) of the compound in the plasma in the range of about 0.001 to about 500 μM, from about 0.002 to about 200 μM, from about 0.005 to about 100 µM, from about 0.01 to about 50 µM, from about 1 to about 50 µM, from about 0.01 to about 25

BO MKM, from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, from about 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of compound administered is sufficient to provide an area under the concentration-time curve (AUC) of the compound in the range of about 100 to about 100,000 ng"hr/mL, from about 1,000 to about 50,000 ng"hr ./ml, from about 5,000 to about 55 to about 25,000 ng"h/ml or from about 5,000 to about 10,000 ng"h/ml.

In certain embodiments, the patient to be treated by one of the methods of the present invention has not received anticancer therapy prior to administration of the compound of Formula I. In certain embodiments, the patient to be treated by one of the methods of the present invention has received anticancer therapy prior to administration of the compound of formula I. In certain embodiments 60 implementation, the patient to be treated by one of the methods according to the present invention has developed resistance to anticancer therapy.

The methods of the present invention include treating a patient regardless of the patient's age, although some diseases or disorders are more common in certain age groups. In addition, the present invention relates to a method of treating a patient who has undergone surgical treatment in an attempt to treat the disease or condition in question, as well as a patient who has not undergone surgery. Because patients with cancer have heterogeneous clinical presentations and variable clinical outcomes, the treatment given to a patient may vary depending on the patient's prognosis. An experienced clinician will be able to easily identify, without undue experimentation, certain secondary agents, types of surgery, and types of non-pharmacological standard treatments that may be effective in the treatment of an individual patient with cancer.

Depending on the disease to be treated and the condition of the individual, a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenous, CIM (continuous intravenous infusion), intracisternal injection or infusion, subcutaneous injection or implant), inhalation, intranasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) routes of administration.

The compound of the formula | or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may be formulated alone or together in an acceptable standard dosage form with pharmaceutically acceptable excipients, carriers, adjuvants and bases appropriate for each input path.

In one embodiment, a compound of formula ! or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may be administered orally. In another embodiment, a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may be administered parenterally. In yet another embodiment, a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or an enantiomer thereof

A pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph is administered intravenously.

A compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may be delivered as a single dose, such as, for example, a single bolus injection, or oral tablet or pills; or over time, such as by continuous infusion over time or fractional bolus doses over time. If necessary, the compound can be re-administered, for example, until the patient stabilizes or reverses the disease, or until the patient has disease progression or unacceptable toxicity. For example, a stable disease course for solid tumors generally means that the perpendicular diameter of the measurable lesions has not increased by 25 95 or more since the last measurement. See Instructions on the criteria for evaluating the effectiveness of treatment in solid tumors "Nezropbze Emainayop Styepa ip bod Titogv (VESI5T)

Spcydeipev", Chopa! oi She Maiyyopa! Sapseg Ipvziyshe 92(3): 205-216 (2000). Stable course of the disease or its absence is determined by methods known in the art, such as assessment of the patient's symptoms, physical examination, imaging of the tumor, the image of which was obtained using the X-ray method, CAT (computed tomography), PET (positron emission tomography) or MVI scanning (magnetic resonance imaging) and other generally accepted methods.

A compound of formula I or its enantiomer or a mixture of enantiomers; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may be administered once daily (00) or divided into multiple daily doses such as twice daily (TIV), three times daily (TIV) and four times a day (010). In addition, the administration can be continuous (ie, once a day for consecutive days or every day), intermittent, for example, in cycles (ie, including days, weeks or months of interruption without administration of the drug).

As used herein, the term "daily" is intended to mean that a therapeutic compound, such as a compound of formula I, is administered once or more than once daily, for example, over a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as a compound of formula I, is administered daily for a continuous period of at least 10 days to 52 weeks. As used herein, the term "periodic" or "periodically" is intended to refer to termination and initiation at equal or unequal intervals. For example, intermittent administration of a compound of formula I is administration for a period of one to six days per week, administration in cycles (eg, daily administration for two to eight consecutive weeks followed by a period of no administration for a period of up to one week), or administration in a day.

As used herein, the term "cyclic administration" is intended to mean that a therapeutic compound, such as a compound of formula I, is administered daily or continuously, but with a break period.

In some embodiments, the frequency of administration ranges from about one dose per day to about one dose per month. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once a week, once every two weeks, once every three weeks or once every four weeks. In one embodiment, a compound of formula I or an enantiomer or mixture of enantiomers or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered once daily. In another embodiment, a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof is administered twice daily. In yet another embodiment, a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered three times a day. In yet another embodiment, a compound of the formula or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered four times per day.

In certain embodiments, a compound of formula | or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered once daily from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks or from one week to two weeks. In certain embodiments, a compound of formula | or a pharmaceutically acceptable salt or solvate thereof is administered once daily for one week, two weeks, three weeks, or four weeks. In one embodiment, a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof,

The solvate, hydrate, co-crystal, clathrate, or polymorph is administered once daily for one week. In another embodiment, a compound of formula I or an enantiomer thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered once daily for two weeks. In yet another embodiment, a compound of formula I or an enantiomer or mixture of enantiomers or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered once daily for three weeks. In yet another embodiment, a compound of formula I or an enantiomer or mixture of enantiomers or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered once daily for four weeks. 5.6.1 Combined treatment with a second active agent 40 Compound of the formula | or an enantiomer thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof may also be combined or used in combination with other therapeutic agents used in the treatment and/or prevention of the forms of cancer described in this application.

In one embodiment, the present invention relates to a method of treating, preventing, or managing a patient suffering from cancer, comprising administering to the patient 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2 ,6-dione or an enantiomer thereof, or a mixture of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof in combination with one or more other active agents and, optionally, in combination with radiation therapy, hemotransfusions or surgical treatment. Examples of the second active agent 50 are described in this application (see, for example, section 5.3).

As used herein, the term "in combination" includes the use of more than one therapeutic agent (eg, one or more prophylactic and/or therapeutic agents). However, the use of the term "in combination" does not limit the order in which therapeutic agents (eg, prophylactic and/or therapeutic agents) are administered to a patient having a disease or disorder. A first therapeutic agent (e.g., a prophylactic or therapeutic agent, such as a compound of the present invention, e.g., a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) may be administered before (eg in 5 minutes, 15 minutes, minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 60 hours, 96 hours, 1 week, 2 weeks, From week, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks),

at the same time or after (eg after 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks

C week, 4 weeks, 5 weeks, b weeks, 8 weeks, or 12 weeks) of administering to the individual a second therapeutic agent (eg, prophylactic or therapeutic agent). The present invention also provides treatment with three therapeutic agents.

Administration of the compound of formula I and one or more other active agents can occur simultaneously or sequentially by the same or different routes of administration. The suitability of the particular route of administration used for a particular active agent will depend on the active agent itself (eg, whether it can be administered orally without destruction before entering the bloodstream) and the type of cancer being treated.

The route of administration of the compound of formula I does not depend on the route of administration of the second therapeutic agent. In one embodiment, the compound of formula I is administered orally. In another embodiment, the compound of formula I is administered intravenously. Thus, according to these embodiments, the compound of formula I is administered orally or intravenously, and the second therapeutic compound can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, by local delivery by catheter or stent, subcutaneously, into adipose tissue, into joints, submucosally, or in a slow-release dosage form. In one embodiment, a compound of formula I! and the second therapeutic agent are administered by the same route of administration, orally or intravenously. In another embodiment, the compound of the formula is administered by one route of administration, for example, intravenously, while the second agent (anticancer agent) is administered by another route, for example, orally.

In one embodiment, the second therapeutic agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1,000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The particular amount of the second active agent will depend on the particular agent employed, the type of disease being treated or the manner of management of the patient with that disease, the severity and stage of the disease, and the amount of the compound of formula I of the present invention and any optional additional active agents. which are simultaneously administered to the patient. In certain embodiments, the second active agent is oblimersen (ZEMABZEMZEF), ZM-C5E, C2-C5E, ZSE, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX inhibitor -2, II 2, II 8, II 18, IM, Aga-S, vinorelbine or their combination.

In certain embodiments, ZM-C5E, C2-C5E, ZSE, or EPO is administered subcutaneously for about five days in a four- or six-week cycle in an amount ranging from about 1 to about 750 mg/m-/day, from about 25 to about 500 mg/m2/day, from about 50 to about 250 mg/m2/day, or from about 50 to about 200 mg/m2/day. In certain embodiments, ZM-C5ZE can be administered in an amount from about 60 up to about 500 mcg/me IV over 2 hours or from about 5 to about 12 mcg/mg/day subcutaneously.In certain embodiments, 5-C5E can be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on an increase in the total number of granulocytes. A maintenance dose of C-C5E can be administered in an amount of approximately 300 mcg (in patients with a lower body weight) or 480 mcg subcutaneously. In certain embodiments, EPO can be administered subcutaneously in an amount of 10,000 Units C times per week.

In certain embodiments, a compound of the present invention, for example, a compound of the formula or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with melphalan and dexamethasone to patients with amyloidosis. In certain embodiments, a compound of the present invention, for example, a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and steroids may be administered to patients with amyloidosis.

In certain embodiments, a compound of the present invention, e.g., a compound of the formula or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with gemcitabine and cisplatin to patients with locally advanced or metastatic transitional cell bladder cancer.

In certain embodiments, a compound of the present invention, e.g., a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof is administered in combination with a second active ingredient as follows : temozolomide in pediatric patients with recurrent or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide, and cyclophosphamide for recurrent or progressive CNS (central nervous system) cancer; temodar - for patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, recurrent brain tumors or newly diagnosed glioblastoma multiforme; irinotecan - for patients with recurrent glioblastoma; carboplatin - for pediatric patients with brain stem glioma; procarbazine - for pediatric patients with progressive malignant gliomas; cyclophosphamide - for patients with malignant brain tumors with an unfavorable prognosis, newly diagnosed or recurrent glioblastoma multiforme; Gliadelo - for highly differentiated recurrent malignant gliomas; temozolomide and tamoxifen - for anaplastic astrocytoma; or topotecan - for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma.

In certain embodiments, a compound of the present invention, e.g. a compound of formula Y, or an enantiomer or mixture of enantiomers thereof or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin , aromatase inhibitors, selective modulators of estrogen receptors, antagonists of estrogen receptors and/or RI X3397 (Riechhikop) - to patients with metastatic breast cancer.

In certain embodiments, a compound of the present invention, for example, a compound of formula Y, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof is administered with temozolomide to patients with neuroendocrine tumors.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with gemcitabine to patients with recurrent or metastatic head cancer and neck

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof is administered with gemcitabine to patients with pancreatic cancer.

In certain embodiments, a compound of the present invention, e.g., a compound of the formula or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to colon cancer patients in combination with AKIZAF, avastatin , taxol and/or taxotere.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with capecitabine and/or RI X4032 (Riechhikop) to patients with refractory colorectal cancer or patients in whom first-line therapy has failed or this treatment is poorly effective for adenocarcinoma of the colon or rectum.

In certain embodiments, a compound of the present invention, e.g., a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to a patient with colorectal cancer stages C and O according to classification

Dukes or patients previously treated for metastatic colorectal cancer.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to a patient with refractory colorectal cancer in combination with capecitabine , xelodo and/or SRT-11.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or patients with unresectable or metastatic colorectal carcinoma.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered alone or in combination with interferon-alpha or capecitabine in patients with inoperable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa - in patients with primary or metastatic liver cancer.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with pegylated interferon-alpha to patients with Kaposi's sarcoma.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof is administered in combination with fludarabine, carboplatin, and/or topotecan in high-risk patients with refractory or relapsed or acute myelogenous leukemia.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with liposomal daunorubicin, topotecan, and /or cytarabine in patients with acute myeloblastic leukemia of unfavorable karyotype.

In certain embodiments, a compound of the present invention, for example, a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof is administered in combination with gemcitabine, abraxane, erlotinib, gefetinib and/or irinotecan in patients with non-small cell lung cancer.

In certain embodiments, a compound of the present invention, e.g., a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer

In certain embodiments, a compound of the present invention, e.g., a compound of Formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with doxetaxol to patients with non-small cell lung cancer who previously received treatment with carboplatin/UR-16 and radiation therapy.

In certain embodiments, a compound of the present invention, e.g., a compound of formula II,

Zo or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and/or taxotere, or in combination with carboplatin, paclitaxel, and/or thoracic radiation therapy patients with non-small cell lung cancer.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with taxotere to a patient with non-small cell cancer light stages of PIV or MI.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with oblimersen (Genasensf) to patients with non-small cell lung cancer.

In certain embodiments, a compound of the present invention, for example, a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof is administered in combination with ABT-737 (ABroi! And arogayogiev) or obatoklaxom (5X15-070) to patients with lymphoma and other forms of hematological malignancies.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof is administered alone or in combination with a second active ingredient, such as vinblastine or fludarabine, in patients with various types of lymphoma, including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, or relapsed or refractory low-differentiated follicular lymphoma.

In certain embodiments, a compound of the present invention, for example, a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate or polymorph thereof is administered in combination with taxotere, II -2, IEM, M-

C5E, RICH4032 (Riechhikop) and/or dacarbazine in patients with different types or stages of melanoma.

In certain embodiments, a compound of the present invention, e.g., a compound of formula II, 60 or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate thereof,

hydrate, cocrystal, clathrate, or polymorph is administered alone or in combination with vinorelbine to patients with malignant mesothelioma or stage PV non-small cell lung cancer with pleural implants or mesothelioma syndrome with malignant pleural effusion.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of multiple myeloma in combinations with dexamethasone, zoledronic acid, palmitronate,

CM-C5E, biaxin, vinblastine, melphalan, busulfan, cyclophosphamide, IEM, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG

INTRONOMA, vincristine or their combination.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (DoxylomU), vincristine IL or dexamethasone (Decardron).

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of ovarian cancer, such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone or a combination thereof.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, is administered to patients with various types or stages of prostate cancer in combination with Xeloda, 5-ESH/L M (5-fluorouracil with leucovorin), gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, C-M-C5E, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine , Emcyt, Denderon or their combination.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of renal cell disease. cancer in combination with capecitabine, IEM, tamoxifen, I/-2, CM-C5BE,

Celebrex? or their combination.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of sarcoma and cancer female genital organs, uterus or soft tissue in combination with IEM, an inhibitor

COX-2, such as Celebrex?", and/or sulindac.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of solid tumors in combinations with Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IEM, tamoxifen, 1-2, YAM-C5E, or their combination.

In certain embodiments, a compound of the present invention, e.g., a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to a patient with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IEM, tamoxifen, 1-2, YAM-C5E or their combination.

The present invention also includes a method of increasing the dosage of an anticancer drug or agent that can be safely and effectively administered to a patient, the method comprising administering to the patient (eg, a human) a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof , solvate, hydrate, co-crystal, clathrate or polymorph. Patients in whom this method may show a beneficial effect are those who are likely to develop side effects associated with anticancer drugs for the treatment of a certain type of cancer of the skin, subcutaneous tissue, lymph nodes, brain, lungs, liver, bones, intestines , colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal cancer, or combinations thereof. Administration of a compound of the present invention, for example, a compound of the formula !/, or its enantiomer or a mixture of enantiomers or its pharmaceutical

Addition of an acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph alleviates or reduces side effects that are so severe that it would otherwise limit the amount of the anticancer drug.

In one embodiment, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof is administered orally and once daily in an amount of in the range of from about 0.1 to about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, before, during, or after the occurrence of a side effect associated with the administration of the anticancer drug to the patient. In certain embodiments, a compound of the present invention, e.g., a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof is administered in combination with certain agents, such as heparin , aspirin, coumadin, or α-C5E to avoid side effects associated with anticancer drugs, such as, but not limited to, neutropenia or thrombocytopenia.

In one embodiment, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with diseases and disorders associated with associated with or characterized by unwanted angiogenesis, in combination with additional active ingredients, including but not limited to anticancer drugs, anti-inflammatory drugs, antihistamines, antibiotics, and steroids.

In another embodiment, the present invention includes a method of treating, preventing and/or managing patients suffering from cancer, which comprises administering a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal thereof, clathrate or polymorph in combination (e.g., before, during, or after) with conventional treatment including, without limitation, surgical treatment, immunotherapy, biological therapy, radiation therapy, or other non-drug therapy currently used to treat, prevent, or manage patients , who suffer from cancer.

The combined use of a compound of the present invention and conventional therapy can provide a treatment regimen that has no analogues, which has shown unexpected effects in certain patients. Without

Without being limited by theory, it is believed that a compound of formula I may provide additive or synergistic effects when administered concurrently with conventional treatment.

As discussed elsewhere herein, the present invention includes a method of reducing, treating, and/or preventing side effects or unwanted effects associated with conventional treatment, including, but not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, and immunotherapy. A compound of the present invention, e.g., a compound of formula !/, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof and the other active ingredient may be administered to a patient before, during or after side effect associated with conventional treatment.

In one embodiment, a compound of Formula I can be administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg orally and once daily alone or in combination with with a second active agent described in this application (see, for example, section 4.3), before, during or after the use of conventional treatment.

In certain embodiments, a compound of the present invention, e.g., a compound of formula Y, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, and doxetaxel is administered to a patient with non-small cell lung cancer who previously received treatment with sagro/L/R 16 (carboplatin with vepeside) and radiation therapy. 5.6.2 Application with transplantation therapy

The compound of the formula | according to this invention can be used to reduce the risk of graft-versus-host disease (GVHD). Therefore, the present invention includes a method of treating, preventing and/or managing a patient suffering from cancer, which comprises the administration of a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof in combination with transplantation therapy.

As those skilled in the art understand, cancer treatment is often based on the stages and mechanism of the disease. For example, since leukemic transformation inevitably develops at certain stages of cancer, it may be necessary to transplant stem cells from peripheral blood, or a preparation of hematopoietic stem cells or bone marrow. The combined use of the compound of formula I according to the present invention and transplantation therapy provides an unexpected synergism that has no analogues. In particular, the compound of the formula | exhibits immunomodulatory activity that may provide additive or synergistic effects when administered concurrently with transplant therapy in cancer patients.

A compound of formula I may act in combination with transplant therapy to reduce complications associated with an invasive transplant procedure and the risk of TMD. The present invention includes a method of treating, preventing, and/or managing a patient suffering from cancer, which includes administering to the patient (eg, a human) a compound of formula I! or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof before, during, or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cells, a hematopoietic stem cell preparation, or bone marrow . Some examples of stem cells suitable for use in the methods of this invention are described in US Patent No. 7,498,171, the disclosure of which is fully incorporated herein by reference.

In one embodiment, a compound of formula | administered to patients with multiple myeloma before, during, or after transplantation of autologous peripheral blood progenitor cells.

In another embodiment, a compound of formula | administered to patients with relapsed multiple myeloma after stem cell transplantation.

In another embodiment, the compound of formula I and prednisone are administered as maintenance treatment to patients with multiple myeloma after autologous stem cell transplantation.

In yet another embodiment, a compound of formula | and dexamethasone are given as emergency therapy to reduce the risk of post-transplant complications in patients with multiple myeloma.

In yet another embodiment, the compound of formula 1/ and dexamethasone are administered as maintenance therapy to patients with multiple myeloma after autologous bone marrow transplantation.

In yet another embodiment, the compound of formula I is administered after high dose administration

Of melphalan and autologous stem cell transplantation in patients with multiple myeloma in whom chemotherapy is effective.

In yet another embodiment, a compound of formula I and PEG INTRO-A are administered as maintenance therapy to patients with multiple myeloma after transplantation of autologous COZ34-expressing peripheral blood stem cells.

In yet another embodiment, a compound of formula I is administered with post-transplant consolidation chemotherapy to patients with newly diagnosed multiple myeloma to evaluate anti-angiogenesis.

In yet another embodiment, a compound of Formula 1/ and dexamethasone are administered as maintenance therapy after consolidation with OSER chemotherapy following treatment with high-dose melphalan and peripheral blood stem cell transplantation in multiple myeloma patients 65 years of age and older.

In one embodiment, a compound of formula I! administered to patients with MNI. (eg, rIVSI) before, during, or after transplantation of autologous peripheral blood progenitor cells.

In another embodiment, the compound of formula I! administered to patients with MNI. (example,

RI ALL) after stem cell transplantation. 5.6.3 Cyclic therapy

In certain embodiments, prophylactic or therapeutic agents of the present invention are cyclically administered to a patient. Cyclic therapy involves the administration of an active agent for some period of time, followed by a break for some period of time, and the repetition of this sequential administration. Cyclic therapy can reduce the development of resistance to one or more types of treatment, avoid or reduce the side effects of one type of treatment and/or increases the effectiveness of treatment.

Thus, in certain embodiments, a compound of formula I of the present invention is administered daily in single or fractional doses over a four- or six-week cycle with a break of approximately one week or two weeks. The method of cyclic treatment, in addition, provides the possibility of increasing the frequency, number and duration of administration cycles. Thus, in certain embodiments, the present invention includes administration of a compound of the present invention, e.g., a compound of formula !, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof,

for a greater number of cycles than usual when the compound is administered alone. In certain embodiments, a compound of the present invention, e.g., a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered for a greater number of cycles that would normally cause dose-limiting toxicity in a patient not also receiving a second active ingredient.

In one embodiment, the compound of formula I is administered daily and continuously for three or four weeks at a dose of from about 0.1 to about 150 mg/d, followed by a break of one or two weeks.

In another embodiment, the compound of formula I! and the second active ingredient are administered orally, and the introduction of the compound of formula I! occurs 30-60 minutes before the introduction of the second active ingredient, during a cycle of four to six weeks. In certain embodiments, the combination of the compound of formula 1/ and the second active ingredient is administered by intravenous infusion over approximately 90 minutes in each cycle. In certain embodiments, one cycle comprises administering from about 0.1 to about 150 mg/day of a compound of formula I and from about 50 to about 200 mg/m"/day of a second active ingredient daily for three to four weeks and then off for one or two weeks. In certain embodiments, the number of cycles during which the patient is treated with the combination is in the range of from about one to about 24 cycles, from about two to about 16 cycles, or from about four to about three cycles. 5.7 Pharmaceutical Compositions and dosage forms

In one embodiment, the present invention relates to pharmaceutical compositions and dosage forms that contain a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof. In another embodiment, the pharmaceutical compositions and dosage forms additionally contain one or more excipients.

In certain embodiments, the pharmaceutical compositions and dosage forms of the present invention also contain one or more additional active ingredients. Therefore, the pharmaceutical compositions and dosage forms according to the present invention contain the compound of formula I

Zo or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, and a second active agent. Examples of optional second, or additional, active ingredients are described in this application (see, for example, section 4.3).

Individual standard dosage forms of the present invention are suitable for oral, transmucosal (e.g., intranasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., in the form of eye drops or other ophthalmic preparations), transdermal or transdermal administration to the patient. Examples of dosage forms include, without limitation: tablets; capsule tablets; capsules, such as soft elastic gelatin capsules; starch capsules; pastilles; wafers; dispersions; suppositories; powders; aerosols (for example, nasal sprays or inhalers); gels; liquid dosage forms suitable for oral and transmucosal administration to the patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to the patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (eg, crystalline or amorphous solids) that can be rehydrated to produce liquid dosage forms suitable for parenteral administration to a patient.

The composition, form and type of dosage forms according to the present invention may vary depending on their application. For example, a dosage form used in the immediate treatment of a disease may contain larger amounts of one or more active ingredients than a dosage form used in the long-term treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more active ingredients than an oral dosage form used to treat the same disease. See, for example, Ketipdfopier's manual

Ripaptaseciisa! bsiepsez, 181st unit, Mask Rybiiznipu, Easiop RA (1990).

Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form of the present invention depends on a variety of factors, including but not limited to the route of administration. For example, oral dosage forms such as tablets may contain excipients unsuitable for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on certain active ingredients in the dosage form. For example, the degradation of some active ingredients can be accelerated by some excipients, such as lactose, or by exposure to water. Active ingredients that include primary or secondary amines are particularly susceptible to such accelerated degradation. Accordingly, the present invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to significantly increase the rate of degradation of the active ingredient.

Compositions according to the present invention, which do not contain lactose, may contain excipients that are listed, for example, in the Pharmacopoeia of the United States (O5P) 25-ME20 (2002). In certain embodiments, the lactose-free compositions contain active ingredients, a binding agent/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In certain embodiments, lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

In addition, the present invention includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients, since water can contribute to the destruction of some compounds. For example, the addition of water (eg, 595) is widely accepted in the pharmaceutical industry as a means of promoting long-term storage to determine characteristics such as shelf life or stability of formulations over time. See, for example, Uep5 T. Sagviepvep, Yua eabiyu: Rgipsiriez 8 Rgasiise, 2a. Ed., Mags! OekKeg, MU, MU, 1995, pp. 379-80. In fact, water and heat accelerate the breakdown of some compounds. Thus, the effect of water on the formulation can be of great importance, as moisture and/or humidity are commonly involved during the manufacture, handling, packaging, storage, transportation, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms according to the present invention can be obtained using anhydrous ingredients or ingredients with a low moisture content and under conditions of low moisture content or low humidity. Pharmaceutical compositions and dosage forms that contain lactose and at least one active ingredient containing primary or

A secondary amine is preferably anhydrous if significant contact with moisture and/or humidity is expected during production, packaging and/or storage.

An anhydrous pharmaceutical composition must be prepared and stored in such a way as to preserve its anhydrous nature. Accordingly, in certain embodiments, the present invention relates to anhydrous compositions packaged using materials that repel water so that they can be included in suitable regulatory kits. Examples of suitable packaging materials include, but are not limited to, hermetically sealed packages of foil, plastic, containers for standard dosage forms (eg, vials), blister packs, and tape packages.

The present invention includes pharmaceutical compositions and dosage forms that contain one or more compounds that reduce the rate at which the active ingredient will be destroyed. Such compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, hydrogen buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and certain types of active ingredients in a dosage form may vary depending on factors such as, but not limited to, the route by which it is to be administered to patients. In certain embodiments, dosage forms of the present invention contain a compound of formula I or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in an amount ranging from about 0.10 to about 1000 mg, from about 0.10 to about 500 mg,

BO from about 0.10 to about 200 mg, from about 0.10 to about 150 mg, from about 0.10 to about 100 mg, or from about 0.10 to about 50 mg. In certain embodiments, the dosage forms of the present invention contain a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in an amount of about 0.1, about 1, about 2, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, about 25, about 50, about 100, about 150 or about 200 mg. 5.7.1 Oral dosage forms

In certain embodiments, pharmaceutical compositions of the present invention that are suitable for oral administration are formulated as individual dosage forms, examples of which include, but are not limited to, tablets (eg, chewable tablets), capsule tablets,

capsules and liquids (for example, flavored syrups). Such dosage forms contain given amounts of active ingredients and can be obtained by some methods known in pharmacy.

See in general, the guide Vetipdiop5 Rpaptaseciysai! bsiepsev, 181st unit, Musk Rybiizpipo, Eaviop RA (1990).

In certain embodiments, the oral dosage forms of the present invention are prepared by combining the active ingredients in a thorough mixture with at least one excipient, according to conventional pharmaceutical mixing techniques. Excipients can take a wide variety of forms, depending on the form of the drug desired for administration.

For example, excipients suitable for use in oral liquid or aerosol dosage forms 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 dosage forms (eg, powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

Because of their ease of administration, tablets and capsules are the most preferred oral standard dosage forms, and in this case solid excipients are used.

If desired, tablets can be coated with standard aqueous or non-aqueous technologies. Such dosage forms can be obtained by some methods known in pharmacy. In certain embodiments, pharmaceutical compositions and dosage forms are obtained by homogeneously and thoroughly mixing the active ingredients with liquid carriers, finely divided solid carriers, or both of these ingredients and then, if necessary, profiling the product into the desired dosage form.

In certain embodiments, the tablet is obtained by compression or molding. In certain embodiments, compressed tablets are obtained by pressing in a suitable machine the active ingredients in a free-flowing form, for example, powder or granules, optionally mixed with an excipient. In certain embodiments, molded tablets may be obtained by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.

Examples of excipients that may be used in the oral dosage forms of the present invention include, but are not limited to, binding agents, fillers, disintegrants, and lubricants. Binding agents suitable for use in the pharmaceutical compositions and dosage forms of the present invention include, without limitation, corn starch, potato starch or other starches, gelatin, natural and synthetic resins such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, kieselguhr, cellulose and its derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (for example,

MoMo 2208, 2906, 2910), microcrystalline cellulose and its mixtures.

Acceptable forms of microcrystalline cellulose include without limitation AVICEL-RN-101,

AVICEL-RN-103, AVICEL KSOS-581, AVICEL-RN-105 (EMS Sogrogaiiyop, Ategisap Mizzose Oimiviop,

Amis! Zaie5, Magsy5 NookK, RA) and their mixtures. A certain binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose (for example, AVICEL KS-581).

Suitable anhydrous or low moisture excipients or additives include AVICEL-RN-103 M and Starch 15001 M.

Examples of excipients suitable for use in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, salicylic acid, sorbitol, starch, pregelatinized starch and their mixtures. In certain embodiments, the binder or filler in the pharmaceutical compositions of the present invention is present in an amount of from about 50 to about 99 95 wt. pharmaceutical composition or dosage form.

Disintegrants are used in the compositions according to the present invention to obtain tablets capable of destruction under the influence of an aqueous medium. Tablets that contain too much disintegrant may disintegrate on storage, while those that contain too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant, which is neither too much nor too little to adversely alter the release of the active ingredients, should be used to form the solid oral dosage forms of the present invention. The amount of baking powder used varies based on the type of formulation. In certain embodiments, the pharmaceutical compositions of the present invention contain from about 0.5 to about 15 wt. 95 from about 1 to about 5 wt. 95 baking powder.

Disintegrants suitable for use in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, others starches, pregelatinized starches, other starches, clays, other algins, other celluloses, resins and their mixtures.

Lubricants suitable for use in the pharmaceutical compositions and dosage forms of the present invention 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 oil (eg, 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.

Additional lubricants include, without limitation, siloid silica gel (AEROSIL2O0,

MMK Sgase So., Waiitoge, MO), coagulated aerosol of synthetic silicon dioxide (Redizza So. oi Riapo, TX), SAV-O-51Y. (pyrogenic silicon dioxide, Saboi So. oi Voviop, MA) and their mixtures. In certain embodiments, lubricants, if used at all, are contained in an amount of less than about 1 wt. 95 pharmaceutical compositions or dosage forms in which they are included.

In certain embodiments, the present invention relates to a solid oral dosage form containing a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide, and gelatin.

In certain embodiments, the present invention relates to a solid oral dosage form containing a compound of formula I! or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

In certain embodiments, the present invention relates to a solid oral dosage form comprising the hydrochloride of a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide and gelatin.

In certain embodiments, the present invention relates to a solid oral dosage form comprising the hydrochloride of a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, and anhydrous lactose, microcrystalline cellulose , polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide and gelatin. 5.7.2 Dosage forms with delayed release

In certain embodiments, the active ingredients of the present invention are administered via controlled release or delivery devices. Examples include, without limitation, those described in US Patent No. 3,845,770; 3916899; 3536809; 3598123; 4008719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639476, 5354556 and 5733566, each of which is fully incorporated herein by reference. In certain embodiments, such dosage forms are used to provide slow or controlled release of one or more active ingredients using, for example, hydropropyl methylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof. to provide the desired release profile in varying proportions. The present invention includes individual standard dosage forms suitable for oral administration, including without limitation tablets, capsules, gelatin capsules, and capsule-shaped tablets, which are adapted for controlled release.

All controlled-release pharmaceutical products share the common goal of improving drug therapy relative to that achieved by their non-controlled-release counterparts. Ideally, the use of an optimally designed drug of controlled release in medical treatment is characterized by the minimum amount of the medicinal substance used to treat or stop the progression of the patient's pathological condition in the minimum amount of time. Advantages of 60 controlled-release formulations include prolonged drug activity, reduced frequency of administration, and increased patient compliance with the proposed administration schedule. In addition, controlled-release formulations may be used to influence the time of onset of action or other characteristics, such as drug levels in the blood, and thus may influence the occurrence of adverse (eg, adverse) effects.

Most controlled-release formulations are designed to initially release some amount of the drug (active ingredient) that quickly produces the desired therapeutic effect, and to gradually and continuously release other amounts of the drug to maintain that level of therapeutic or prophylactic effect over a long period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by various conditions, including without limitation pH, temperature, enzymes, water, or other physiological conditions or compounds. 5.7.3 Parenteral dosage forms

Parenteral dosage forms can be administered to patients by various routes, including but not limited to subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial administration. Due to the fact that when administered parenterally, dosage forms usually bypass the natural defense mechanisms of the patient's body against infectious and contaminating agents, parenteral dosage forms are preferably sterile or suitable for sterilization before administration to the patient. Examples of parenteral dosage forms include, without limitation, solutions ready for injection, dry products ready for dissolution or suspension in a pharmaceutically acceptable base for injection, suspensions ready for injection, and emulsions.

Some suitable bases that can be used to prepare the parenteral dosage forms of the present invention include, without limitation: water for injection

Pharmacopoeia of the United States; aqueous bases such as, but not limited to, sodium chloride solution for injection, Ringer's solution for injection, dextrose solution for injection, dextrose sodium chloride solution for injection, and Ringer's lactate solution for injection; water-miscible bases such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; non-aqueous bases such as without

Corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate are limited.

Compounds that increase the solubility of one or more active ingredients described in this application may also be included in the parenteral dosage forms of the present invention.

For example, cyclodextrin and its derivatives can be used to increase the solubility of a compound of the present invention, for example, a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof. See, for example, US Patent No. 5,134,127, the disclosure of which is fully incorporated herein by reference. 5.7.4 Topical and transmucosal dosage forms

Topical and transmucosal dosage forms of the present invention include, without limitation, sprays, aerosols, solutions, emulsions, suspensions, eye drops, or other ophthalmic preparations, or forms thereof known to those skilled in the art. See, for example, the manual of Ketipdiopye Rnaptaseshis! Zsiepsev, 16 apa 187 unit 5. Mask Rybiizpipo, Eabsiop RA (1980 5 1990); ии Ипигодисиюп ию Рнаптасешисаи! rosade Bopt5, 4 ed., ea 5 Rebideg, RPIiade!rnia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity may be formulated as oral rinses or oral gels.

Acceptable excipients (eg, carriers or diluents) and other materials that can be used to prepare the topical and transmucosal dosage forms included in the present invention depend on the particular tissue to which the pharmaceutical composition or dosage form will be applied. Given this, in certain embodiments, excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions, or gels that are non-toxic. and pharmaceutically acceptable. If desired, wetting agents or humectants may also be added to pharmaceutical compositions and dosage forms. Additional examples of such ingredients can be found, for example, in the manual

Vetipdiopye Rpaptaseshisa! bsiepsev5, 167 apa 18 edv5., Mask Rybiiepipu, Eavsiop RA (1980 8 1990). The pH of the pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of the carrier solvent, its ionic strength or tonicity can be adjusted to improve delivery. Compounds such as stearates may also be added to pharmaceutical compositions or dosage forms to favorably alter the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearates can serve as a lipid base for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.

Various salts, hydrates or solvates of active ingredients can be used to further prove the properties of the resulting composition. 5.7.5 Kits

In certain embodiments, the active ingredients of the present invention are not administered to the patient at the same time or by the same route of administration. Therefore, the present invention relates to kits that, when used by a medical professional, can simplify the administration of appropriate amounts of active ingredients to a patient.

In certain embodiments, a kit of the present invention includes a dosage form of a compound of the present invention, for example, a compound of formula I/, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, the kit of the present invention further includes additional active ingredients such as oblimersen (GENACENS-U), melphalan, C-C5E, CM-C5E,

EPO, topotecan, dacarbazine, irinotecan, taxotere, IEM, COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone, II 2, II 8, II 18, Aga-C, vinorelbine, isotretinoin, 13 cis-retinoic acid or their pharmacologically active mutant or a derivative, or a combination thereof. Examples of additional active ingredients include, without limitation, those described in this application (see, for example, section 4.3).

In certain embodiments, the kit of the present invention further includes equipment used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, droppers, transdermal systems, and inhalers.

In certain embodiments, the kit of the present invention additionally includes cells or blood for transplantation, as well as pharmaceutically acceptable bases that can be used to administer one or more active ingredients. For example, if the active ingredient is presented in a solid form, the moisture content of which must be restored for parenteral use

For administration, the kit may include a hermetically sealed container with a suitable base in which the active ingredient may be dissolved to form a particulate-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable bases include, but are not limited to: water for injection according to the Pharmacopoeia

USA; aqueous bases such as, but not limited to, sodium chloride solution for injection, Ringer's solution for injection, dextrose solution for injection, dextrose sodium chloride solution for injection, and Ringer's lactate solution for injection; water-miscible bases such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous bases such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. 6. Examples

Certain embodiments of the invention are illustrated by the following non-limiting examples. 6.1 Preparation of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione o... o

MN at b

SO re

M"

Stage 1: To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 ml) was added in portions

Z-nitrophthalimide (25.0 g, 130 mmol) at 02С. The suspension was stirred at 02C for 3 hours and then heated to 302C for 3 hours. NSI (100 ml, 6H) was added to the solution. The resulting suspension was cooled to 09C for 1 hour. The suspension was filtered and washed with cold water (2 x 10 ml) to obtain 3-nitrophthalic acid as a white solid

BO substance (24.6 g, yield 90 95): "H NMR (0М50-ав) b 7.69 (width s, 1Н, МНН), 7.74 (t, 9-8 Hz, 1Н,

Ag), 7.92 (dd, 9-1, 8 Hz, 1H, Ag), 8.13 (dd, 9-1, 8 Gu, 1H, Ag), 8.15 (width c, 1H, INN ), 13.59 (s, 1H,

ON); ZS NMR (0М50-ав) 6 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.

Step 2: To a mixture of 3-nitrophthalic acid (24.6 g, 117 mmol) and potassium hydroxide (6.56 g, 117 mmol) in water (118 mL) was added a mixture of bromine (6 mL), potassium hydroxide (13.2 g, 234 mmol) in water (240 ml) at 02С, followed by the addition of a solution of potassium hydroxide (1.8 g, 351 mmol) in water (350 ml). After 5 minutes at 0"C, the mixture was heated in an oil bath at 1002C for 1 hour. The reaction solution was cooled to room temperature and then in an ice water bath for 30 minutes. A solution of NOSI (240 mL, 2N) was added dropwise to the mixture at O2C, and the resulting mixture was allowed to stand for 1 hour. 3.9 x 150 mm, 1 ml/min, 240 nm, CHzSM/O,1 95 NzRoOah, from 5 95 gradually to 95 95 during 5 min, 5.83 min (85 95); "H NMR (0M50-av ) b 6.90 (dd, 9-1, 8 Hz, 1H, Ag), 7.01 (dd, 9-1, 9 Hz, 1H, Ag), 7.31 (t, U-8 Hz, 1H , Ag), 8.5-9.5 (width c, ZN, ОН, МНг); ZS NMR (0M50-dv) b 105.58, 110.14, 120.07, 131.74, 149.80, 151.36, 166.30; РХ-MS: МН-183.

Step 3: A mixture of b-nitrobenzoic acid (1.5 g, 8.2 mmol) in acetic anhydride (15 mL) was heated at 2002C for 30 minutes in a microwave oven. The mixture was filtered and washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo. The solid was stirred in ether (20 mL) for 2 hours. The suspension was filtered and washed with ether (20 mL) to give 2-methyl-o-nitro-benzo|94|11,3|oxazin-4-one as a light brown solid (1.4 g, yield 85 90) : TOP: Umaieg5 Zutteigu St, 5 µm, 3.9 x 150 mm, 1 ml/min, 240 nm. SNizSM/0.1 95 NzRoh, from 5 95 gradually to 95 95 in 5 min, 5.36 min (92 95); "H NMR (0M50О-dv) 6 2.42 (s, ЗН, СН), 7.79 (dd, 9-1, 8 Hz, 1Н, Ag), 7.93 (dd, 9-1, 8 Hz , 1H, Ag), 8.06 (t, U-8 Hz, 1H,

Ag); C NMR (OM50-4c) b 20.87, 107.79, 121.54, 128.87, 137.19, 147.12, 148.46, 155.18, 161.78;

РХ-MS: МН-А207.

Step 4: Two vials each containing a suspension of 5-nitro-2-methyl-benzo|94|(/1,3|oxazin-4-one (0.60 g, 2.91 mmol) and 3-amino-piperidine-2,b-dione hydrochloride (0.48 g, 2.91 mmol) in pyridine (15 mL) was heated at 1702 for 10 minutes in a microwave oven.

The suspension was filtered and washed with pyridine (5 mL). The filtrate was concentrated in vacuo.

The resulting mixture was stirred in HCl (30 ml, 1H), ethyl acetate (15 ml) and ether (15 ml) for 2 hours. The suspension was filtered and washed with water (30 mL) and ethyl acetate (30 mL) to give a dark brown solid, which was stirred with methanol (50 mL) at room temperature overnight. The suspension was filtered and washed with methanol to give 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione as a black solid (490 mg, yield 27 95) . The solid was used in the next stage

Ko) without additional cleaning.

Step 5: A mixture of 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)/piperidine-2,6-dione (250 mu”) and

PaA(OH)»: on carbon (110 mg) in OME (dimethylformamide) (40 mL) was shaken under hydrogen (50 psi: (22586 mm Hg)) for 12 hours. The suspension was filtered through a celite pad and washed with OME (10 mL). The filtrate was concentrated in vacuo, and the resulting oil was purified by flash column chromatography (silica gel, methanol/methylene chloride) to give 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2,6 -dione as a white solid (156 mg, yield 69 95): HPLC: UMaiet5 butteigu Stiv, 5 µm, 3.9 x 150 mm, 1 mL/min, 240 nm. 10/90

CHZiSM/O, 1 95 NzRoOx, 3.52 min (99.9 95); melting point: 293-2959C; "H NMR (0M50-av) b 2.10-2.17 (m, 1H, SNN), 2.53 (s, ЗН, СНЗз), 2.59-2.69 (m, 2Н, SnNag), 2.76-2.89 (m, 1H, SNN), 5.14 (dd, 9-6, 11 Hu, 1H, MON), 6.56 (d, 9U-8 Hz, 1H, Ag), 6 .59 (d, U-8 Hz, 1H, Ag), 7.02 (s, 2H, MH"), 7.36 (t, 9-8 Hz, 1H, Ag), 10.98 (s, 1H , MH); C NMR (0M50-dv) b 20.98, 23.14, 30.52, 55.92, 104.15, 110.48, 111.37, 134.92, 148.17, 150 55, 153.62, 162.59, 169.65, 172.57; LC-MS: MH-287; Analytical calculated for C1i4H14MaOz--0.3 NgO: C, 57.65; H, 5.05: M , 19.21. Found: C, 57.50; H, 4.73; M, 19.00. 6.2 Analyzes 6.2.1 Analysis of TMEa inhibition in PMVS

Peripheral blood mononuclear cells (PBMCs) from healthy donors are obtained by centrifugation in a Risoyi Nuradne (Riagtasia, Rizsaijau, MU, OA) density gradient. Cells are cultured in KRMI 1640 medium (I ie Tesppoiodiev5, sgapa Isiapa, MM OSOBA) with the addition of 10 95 AB of human serum (Setipi Viorgodisiv, Uuodiapa, SA, OA), 2 mM I-glutamine, 100

units/ml of penicillin and 100 μg/ml of streptomycin (Se Tesppopiodiev5)).

PBMCs (2 x 105 cells) were seeded in 96-well flat-bottom plates for tissue culture

Soviag (Sogpipd, MU, OBA) in three repetitions. Cells were stimulated with I RBZ (from ZaitopePa aropiv edii, zidta catalog Mo I -1887. 51. I otsi5, MO, O5A) at a final concentration of 1 ng/ml in the absence or presence of the compounds to be tested. The compounds were dissolved in OM5BO (Zidta) and additional dilutions were made in the culture medium immediately before use. The final concentration of OM5O in all analyzes was approximately 0.25 95. Compounds were added to the cells 1 hour before stimulation of I P5. Then the cells were incubated for 18-20 hours at 379C in 595 CO", and then the supernatants were collected, diluted with culture medium and analyzed to determine the levels of TMEsF EGISA (Epdodep, Vob5iop, MA, O5A). because the values of ISvo were calculated using non-linear regression, a sigmoidal curve

"response-dose" limiting the upper limit to 100 95 and the lower limit to 0 95, providing the possibility of variable slope of the curve (sgarpraa Rgizt version 3.02). 6.2.2 Inhibition of proliferation of the MM cell line

The ability of the compounds to influence the proliferation of MM (multiple myeloma) cell lines was studied in the IP migo study. Uptake of NO-thymidine by MM cells of the HO29 line and uptake of 7-AAO by several MM cell lines (Не29, 026681, ApriI-6, KM5-34, ORM-2, ЮБ-15, ОЕ15/8, САС,

MMI.5 and I P-1) were measured as an indicator of cell proliferation. Cells were incubated in the presence of compounds for 72 hours (INI-thymidine was included during the last 6 hours of the incubation period) or 5 days, followed by 7-AAO capture to measure and count viable cells. 6.2.3 Production of cytokines by T cells

T cells were isolated from the leukocyte film by negative selection, using a mixture of T cell enrichment Kozeyeser?zh T Se! Ephisptepi SosKiaiY. Accordingly, the procedures recommended by the manufacturer were followed. All 96-well plates were pre-coated with 3 μg/ml of anti-human HCV antibodies in 100 μl of 1X PB5 (phosphate-buffered saline) for 4 hours at 37°C. The plates were washed three times with complete nutrient KRMI-1640 medium before T cell analysis. Then, T cells were seeded into plates pre-coated with POPs at a density of 2.5 x 105 cells/well in 180 μl of complete nutrient medium ERMI-1640. Cells were treated with 20 μl of compounds titrated in 10X at a concentration of 10, 1, 0.1, 0 .01, 0.001, 0.0001, and 0.00001 μM. The final concentrations of OM5O were 0.25 95. The plates were incubated for 48 hours at 37C, 595 CO2. After 48 hours, the supernatants were collected and tested by multiplex flow cytometric analysis (MCA) for detection of the following cytokines/chemokines: I -2, 1-3, /-5, 11-10, 11-13, 11-15, 1 -17a, CM-C5E, 2-5CE, IREM-u, TME-a and

CAMTEZ5 (regulated after activation of normal expressed and secreted T cells).

SVA tablets were analyzed on the I Shtipeh IZ100 device.

Cytokine levels were normalized to the amount produced in the presence of an amount of the test compound, and ESvo values were calculated using non-linear regression, a sigmoid dose-response curve7 limiting the upper limit to 10095 and the lower limit to 0 95, allowing for variable slope of the curve (sgarprai Rgiht version 3.02) .

Analysis of T cells stimulated by antibodies to POPs

All 96-well plates were precoated with 3 μg/ml of anti-human POP antibody in 100 μl of 1X PB5 for 4 hours at 37°C. The plates were washed 3 times with complete KRMI-1640 nutrient medium before T cell analysis. T cells were then seeded into the plates, pre-coated with an antibody to POPs at a density of 2.5 x 105 cells/well in 180 μl of complete nutrient medium KRMI-1640. Cells were treated with 20 μl of titrated 10X CeYdepe compounds at a concentration of 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0.00001 µM in duplicate Final concentrations

PM5O was 0.25 95. Tablets were incubated for 48 hours at 372С, 5 95 СО". After 48 hours, the supernatants were collected and tested by multiplex flow cytometric analysis (MCA) to detect the following cytokines/chemokines: 1I--2, II-3, 1-5, 1-10. 11-13, 1-15, 1 -17A, SM-

SB, -5SE, IEM-u, TME-sa and VAMTE5. SVA tablets were analyzed on the device I itipeh I5100. 6.2.4 Analysis of cytotoxicity

Ragade, POONNE, and Ves-1 cell lines were obtained from the American Type Culture Collection (Mapazzaz, MA, O5A). Cytotoxicity assays were quantified in 3-day product analyses

ATP in the following way:

Cells were seeded in 9b-well TC plates with a black/transparent bottom (VO Raisop, Sai zh 353948) at a density of 3000 cells/75 μl (for JuoNN-2 and Ragade cells) or 6000 cells/75 μl (Kes-1 cells) of the medium on the hole The basic solutions (40X) of the compounds were prepared in OM5O and the 4X solutions were obtained by diluting the basic solutions 40 x 1:10 with 195 OM5O in the culture medium. To each well of the analytical plate, 25 μl of the compound of formula I in 1 75 OM5O was added to the cells in triplicate so that the final volume was 100 μl and the final concentration

IOM5OY was 0.25 95. Then the tablets were hermetically sealed with air-permeable sealing films (IZS Vioechrhe55, Sai Zh T-2421-50) and placed in a humidified incubator at 372С, 595 СО» for 72 hours. In addition, the cells were seeded in a separate plate in the same way as mentioned above, 25 μl of medium in 1 95 ЮМ50О was added to each well.

This tablet was immediately tested in a luminescence assay for the viability of SeijiPiet-c1o cells

Gitipezsepi Sei! Miariyu Azzau (Rgoteda, Sai Zh 57572) as the zero time point, and these results were used to calculate SiISvo in experiments with Ragade and ONN-2 cells.

After 72 hours of incubation, 100 μl of SeTieg-Sio reagent was added to each well and incubated at room temperature with gentle shaking for 30 minutes. The tablets were then analyzed for luminescence in a TorSoipi MHT Keadeg bo reader (RasKkaga). Each well was counted for one second. Values from two wells were averaged and then compared to a zero time point control with OM5O (inhibition 0 95) to calculate percent inhibition of cell growth. The average values of SiSvo for OPONN-2 and Ragade cells were calculated from these three experiments. The values of ISzo Nes-1 were calculated according to two experiments. 6.2.5 Cell cycle analysis

Cells were treated with OM5O or some compound of the present invention for 48 hours. Propidium iodide staining was performed using SusieTE5T RI 05 (Vesyup

OisKkipzop), according to the manufacturer's protocol. After staining, the cells were analyzed by flow cytometer EASsSzZsSaiiirig using Moangia t software (Vesup biskKip5op). 6.2.6 Analysis of apoptosis

Cells were treated with OM5O or some amount of the compound according to the present invention at different time points, then washed with annexin-m washing buffer (VO Wiozsieepse5). Cells were incubated with annexin-M binding protein and propidium iodide (VO Wiozsiepse5) for 10 minutes. Samples were analyzed using flow cytometry. 6.2.7 Analysis of MK cells 96-well flat-bottomed plates were coated with 100 µg/ml human to (5idta) overnight at 49C. The next day, the unbound dO was washed away with cold 1X RV5. Then MK-cells (natural killers) were seeded into I(ds) coated 96-well plates in the amount of 2 x 109 cells per well in 180 μl of KRMI-1640 medium and 10 ng/ml of gpII/-2 (recombinant human interleukin-2) was added (K 8. OO Buziet5, MM). The test compounds were added in a volume of 20 μL of OM5O. The final concentrations of the test compounds were 0.0001, 0.001, 0.01, 0.1, 1, or 10 μM. The final concentrations of OM5O were 0 ,25 95. After 48 hours, the supernatants were collected and analyzed

EGIZA to determine the products of IEM. 6.2.8 Results

Values of biological activity of the compound of the formula | summarized in Tables 1 to 5. In the above-described analysis of human T cells stimulated with an antibody to POPs, the compound of formula I enhanced the production of 1-2, 11/-3, 11/-5, 1-10, I/-15, aM- C5E, IME-y, KAMTEZ and TME-y in concentrations from 0.01 to 10 µM. Strengthening of products I/-2, 11/-3, I/-13, YAM-S5E, TME-a and

With EAMTEZ, the compound was concentration-dependent. At a concentration of 0.1 µM of the compound of the formula, the production of II-2 and 1-13 was enhanced to levels, respectively, 14 and 7 times higher than the levels in control cells. At a concentration of 1 μM of the compound of formula I, the production of 1-2 and 1-13 was enhanced to levels, respectively, 17 and 8 times higher than the levels in control cells. At low concentrations (x0.01 μM), the compound increased the production of 1I--10 by 2 times, but inhibited the production of 1II/-10 at a concentration of 1 and 10 μM. The compound increased production 1-5-fold and 4-fold at concentrations of 0.01 and 0.1 μM, respectively, showing less enhancement at both lower and higher concentrations.

In addition, it was observed that in the analysis on the human umbilical artery, the compound of formula I was an active antiangiogenic agent with an IC of 9.4 NM; and the compound of the formula ! did not inhibit the proliferation of NOMES (human umbilical endothelial cells).

When analyzing the use of Matrigel in mice, it was observed that the compound of the formula significantly inhibited the growth of blood vessels at a dose of 30 mg/kg and showed a dose-dependent inhibition of angiogenesis.

It was observed that the compound of formula I caused an arrest at the division stage 51 in the cell lines UNNI and MUZBIO-0I SI 2. It was also observed that in the proliferation assays, the compound of formula I acted synergistically with rituxan, according to the data calculated using the Chow-Talalai method.

In a xenograft model of OOoNN, it was observed that a compound of formula I inhibited tumor growth, and that the combination of a compound of formula I with rituxan caused a significant delay in the time to end point of tumor onset (63 95) at a dose of 30 mg/kg. Inhibition of tumor growth was observed at a dose of 30 mg/kg of the compound of formula I in combination with rituxan (1 mg/kg), respectively, at 45 95 and 55 95 on the 122nd day. It was also observed that the compound of formula I! significantly inhibited the number of blood vessels formed in the tumor.

In the MUZY-0I SI 2 xenograft model, the combination of the compound of formula I with rituxan (2 mg/kg intravenously once a week) resulted in complete regression by 60 95 and 90 95 (tumor volume "25 mm) respectively at a dose of 3 and 30 mg .

In the MCI-HO29 MM xenograft model, the compound of formula I inhibited tumor growth

Neg29 in a dose-dependent manner. At day 199, the compound showed 93 95 tumor growth inhibition at 30 mg/kg, 73 95 tumor growth inhibition at 3 mg/kg, and 59 95 tumor growth inhibition at 0.3 mg/kg. because a dose-dependent inhibition of tumor volume was observed in the 087 SV xenograft model. The compound of formula I significantly inhibited the growth of the Sh87 tumor at a dose of 3 and 30 mg/kg once daily.

Table 1

Types of ip migo activity

ISvo or ESvo (µM)

RVMS TMEa 0.063a

UMIV TMEa 0.164a

Induced ARZ TMEa 0.017a2

T-cell 1-2 0.012-0.0142

ALL (MS. ronna (gi

Gagade (SV-OI-VSI. 0.00942

IRMu MK-cells 0.00152

B-cell proliferation 0.0152 0.0612

Colonies of immature MK a-ISvo, 6-SISvo, S-ESvo

Table 2

Types of IP migo activity (5-day analysis of UN-thymidine incorporation) nn ISvo (μM)

OSI-Guto 0.0085. 2932 0.11-0.12

ABC subtype tm

VIMA

RMVI. Kagraz-1106P 0.58-0.71

M 5Y-0I SI 2 0.79-2.1

Orni's SVS subtype

OsI-tsute

Table C

Activity of the compound of the formula I against cells resistant to lenalidomide now: 1051 1052 1053 1054 compound of the formula! oivza | 03092 2974. 4238 2,099 6,593

Table 4

The effect of the compound of formula I on the expression of NIBE-1sa protein in solid tumor cells 96 Inhibition at (1 µm)

MSE-7 74.82 9

NST116 74.60 95

Colorectal cancer ntg9 78.54 95 nHStT15 69.26 95

Ovarian cancer 100.00 ze 63.39 95

Continuation of Table 4 96 Inhibition at (1 µm)

Prostate cancer rit45 66.01 95 33.72 96 786-0 41.70 9e 73.81 96

Table 5

Antiproliferative activity of the compound of formula I on SI ALL cell lines.

The compound of the formula Correlation with antiproliferative activity (100

Scores of ABC 2.

Scores of MEKV 2.

Output activity 2.

Output activity 2.

Initial gene expression is not correlated P»0.05 | 172-021 of cyclin 01

Initial gene expression 2.

Initial gene expression 2. 6.3 Pharmacokinetics

It was observed that the compound of formula I had a half-life of i/2 230 min in human plasma. Pharmacokinetic parameters after oral administration to mice, rats and monkeys are summarized in Tables 5 to 7.

The effect of the compound of formula I increased in a dose-proportional manner up to 30 mg/kg in mice

SIU (with severe combined immunodeficiency), CO-IO5 rats and male monkeys. The compound of the formula at a concentration of 10 µM did not inhibit any progenitor cells.

Table 6

Pharmacokinetics after oral administration of NN Rats ZO

Dose (mg/kg) 30 orally 2900 4800 300 se" (nia (ic) 7100 25000 12000

Tiftodd//111111111111111111111111111111111127 11111580

C.r. (ml/min/kg) 1

PAST NI MON NO UNN NO U ZON

Table 7

Pharmacokinetic profiles in male monkeys

Dose (mg/kg) Stach (ng/ml) AIsSoch- (ng"h/ml) 100 (0.36 μM) 1300 (4.5 μM-h) 1100 (3.8 μM) 14000 (49 μM -h) 3100 (11 μm) 38000 (130 μM-h) 7700 (27 μM) 99000 (350 μM-h)

Table 8

Pharmacokinetics in monkeys on the 1st day

Stakh (ng/ml) AOSo-za (ng"hr./ml) 015 From 2 to 4 (ta) Zb(t) AZO(t) ' 2 (6 bZ(i) OR 15 From 2 to 4 (t) B10 (t) 4600(t) ' 2( 680 each

From 2 to 4 (th) 4200(th zvo a. t: Male; B. 7: Female.

Table 9

Pharmacokinetics in monkeys on the 27th day

Dose (mg/kg) Stakh (ng/ml) AShsSo-ha (ng"h/ml) " From 2 to 4 (2 57 4501 15 2 (t) 56bO(t) 5700(t) " From 0.5 to 2 () 590 4200 15 From 2 to 4 (t) 5800(t) t2000(t) 4( tod 750001 a. t: Male; B. 7: Female.

Oral administration of a compound of formula I at a dose of 100, 300, and 10,000 mg/kg/day for 7 consecutive days in male CO-IZ5 rats generally resulted in an almost dose-proportional increase in exposure. The NOAEI (no observed adverse effect level) was determined to be 1000 mg/kg/day. 6.4 Analysis of thymidine incorporation by cells of OI ALL. ip migo

A panel of OSI BC cell lines with different cytogenetic characteristics was tested to determine their sensitivity to the antiproliferative activity of the compound of formula I (Fig. 2). Cells were treated with the compound of formula I for 5 days at 372C; cell proliferation was determined using the ZH-thymidine incorporation method. Results from independent experiments are shown (mean x 50 (standard deviation)) in Fig. 2. The compound, starting from 0.1 to 1 µM, significantly (p-0.05) inhibited the proliferation of several cell lines of OSI ALL, in particular, cells of the ABC subtype, such as cells of Kim, 02932, TMO8, OSI-GuZz and OSI-Gu10 . ABC subtype cells are more sensitive to the antiproliferative effect than cells of other subtypes, including cells

SSV-OI VSI and RMVI. 6.5 Inhibitory effect on the activity of MEKV in the cells of OSI ALL.

Cells of OI ALL were treated with a compound of the formula! or a double inhibitor of IKK 1/2 (used as a positive control for inhibitors) for 2 days. MEKV activity was investigated by analysis of the active motif of the transcription factor using nuclear extracts from cells after treatment. The results are shown in fig. 1 (the average value is 50).

The compound of formula I significantly inhibits the activity of рб5 and р5О0 MEKV at concentrations of 0.1 μM, 1 μM and 10

MKM. It was found that the compound of formula I! inhibits MEkV activity in some cell lines

RI VS. ABC subtype, such as cells 02932 and OSI-Gu10. These results suggest that effects on MEKV signaling may be involved in the antiproliferative activity of the compound of formula I against ALL ABC-JUOI cells, and that baseline MEKV activity may represent a prognostic biomarker for the efficacy of the compound's antitumor treatment of lymphoma. 6.6 Xenograft model in ip mimo mice for OSI-Guio cell subtype

The effectiveness of the compound of formula I against the subtype of OSI-Yu10 cells is investigated in the xenograft model in mice i.p. mimo. Female SV.17 5SIUO mice aged from b to 12 weeks are injected subcutaneously in the side with approximately 0.2 ml/mouse of 1x107 OSI-Gu10 tumor cells in 100 95 matrigel. Treatment with the compound of formula I! begins as soon as the tumor reaches an average size of 100 to 150 mg. Body weight is measured on 5/2 and then twice a week until the end of the study. Measurements of the tumor with a compass are performed twice a week. The end point of the study is tumor growth delay (TO). Maintenance is calculated as a percentage. Animals are monitored individually. The end point of the study is a tumor volume of 1000 mm or 60 days, whichever comes first. Animals in which treatment is effective may be observed longer.

Tumor resection: cut out tumors in an RNase-free environment (divide into three parts). The first part is stored by quick freezing in the form of a powder for further protein analysis, the transportation condition is -802С. The second part is stored later in

RNA, quickly frozen, transport condition -809С. The third part is stored in formalin for 24 hours, then in 70 95 ethanol, transferred at room temperature to RAI (plasminogen activator inhibitor) for embedding in paraffin. The processing plan is shown below. 717 | 70 |Carrier! | - |Orally / |Once for 28 days! 6.7 Models of multiple myeloma

The ability of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2,b-dione to inhibit the growth of cancer cells was evaluated on a number of multiple myeloma (MM) cell lines using the methods of ipo and ip o mimo (fig. 5A and 58). It was shown that 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidin-2,6b-dione inhibited the proliferation of MM cells in a number of cell lines (Figs. 5A, 58 and 6 ).

For example, the antiproliferative effect of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)/piperidin-

Zo 2,6-dione was demonstrated in the M929 xenograft model (Fig. 6). 6.8 Models of the effect of cereblon on cells of ABC-OI ALL, multiple myeloma and colorectal cancer

The effect of cereblon protein (SABM) on the effectiveness of inhibiting proliferation, the course of the cell cycle and/or cell invasion of various cancer cell lines by the compound of formula I was studied.

It was found that the compound of formula I interacts with the endogenous myeloma CAVM in a dose-dependent manner. The compound of formula I also interacts in a dose-dependent manner with SAVM Ners2g HO. In addition, it was found that the compound of formula I inhibits the ubiquitination of SAVM at an IC of 208.7 μM.

Model of ABC-OI VS cells.

Cereblon expression was found to modulate the efficacy of the compound of formula I! against the proliferation of AVOS-OI ALL cell lines (Fig. 7A-7C). Cereblon was required to inhibit each of the indicators of IBE4 expression, ME-KkV activity, and cell proliferation.

Myeloma cell models

The effect of cereblon was also evaluated on HO29 myeloma cells. NUO29 cells were subjected to incorrect transfection, transfection of 5iRNA (small interfering RNA) as a negative control, and SEVM-5zivMA-7 for 24, 48, 72, and 96 hours. Cells were treated with OM5O (0.19) 24 hours after transfection or with a compound of formula I for 1, 2, 3 days, and the effects on the cell cycle and proliferation were examined. The compound of the formula | caused a delay in the course of the cell cycle, measured as a decrease in the number of cells in phase 5, in the control of incorrect transfection and in the negative control of transfection of 5iRNA cells after 72 hours of treatment (Fig. 8).

Knockout of SCM significantly eliminated the drug-induced cell cycle delay in HO29 cells from 65 to 22 95 for the compound of formula I.

BT-RSK and Western blot analysis were used to measure the levels of key regulators of the cell cycle and apoptosis to further investigate the effects of SEVM on cell cycle arrest induced by the compound of formula I. In HO29 cells, cell cycle arrest in phase 51 by the compound of formula | coincides with a decrease in the level of the tumor suppressor, rik, the phosphorylation of both the oncogene and IKE4, a survival factor for myeloma cells. Western blot analysis showed that the compound of the formula | decreased the phosphorylation of rkKb (Fig. 9A and 9B) and the total level of the IKE4 protein (Fig. 9C and 90). This effect was reduced by SCM knockdown, indicating that inhibition of the cell cycle by drugs requires the presence of the protein

SAVM

It was found that the compound of formula I inhibits the proliferation of SEVM-sensitive cell lines

MM 266, 100-1 and 1K-2 (fig. 10).

Colorectal cancer cell model

Cereblon expression also modulates the anti-invasive activity of the compound of formula II in HST-15 colorectal cancer cells (Fig. 11). The ability of the compound of formula I to inhibit the invasion of HST-15 cells was reduced by 5sSnVvm (small interfering SKVM). 6.9 Models of solid tumors

The compound of the formula !/ was evaluated for its effect on cell lines of solid tumors of various histological nature (for example, breast, ovarian, colon and rectal, HSC (hereditary colorectal cancer)). The compound of formula I inhibits the hypoxia-induced expression of NIET1-4 in many cell lines of solid tumors (Fig. 12A-12I). In addition, the compound of formula I inhibits the invasion of solid tumor cells (table 10) and the formation of cell colonies (table 11) to varying degrees. Inhibition of the formation of colonies of cells of solid tumors was studied by a single treatment with a compound of formula I at a high concentration (10 μM) on the 1st day, followed by monitoring the formation of a cell colony for 10-20 days (table 11, fig. 13A and 138).

The compound of formula 1 inhibits the growth of tumor cells of glioblastoma 87 at a dose of 3 and 30 mg/kg once a day in a xenograft model (Fig. 14).

Table 10

Effects of the compound of formula I on the invasion of cells of solid tumors

Compound of formula I glioblastoma

Table 11

The effects of the compound of formula I on the formation of cell colonies of solid tumors, hepatocellular cancer, hereditary colorectal cancer, HUK" sv: ------------- a

НЕДО ///777777771117Ї17111171717171717168777с21 5268 7 Ї77717171717171717171061сСсС1С kpyoblastoma at 11111116 breast cancer a; 10 µM of the compound of formula I. x1p«0.5; and re0.001 (compared to OM5O). 6.10 Determination of the cytokine profile of PBMC

The compound of formula I was chosen to determine the activity profile of eleven (11) cytokines and chemokines, i.e., interleukin (13-18, 11/-6, 1/-8, granulocyte-macrophage colony-stimulating factor (5M-C5E), a chemokine of macrophage origin ( MOSS), macrophage inflammatory protein-1 alpha (MIR-14), macrophage inflammatory protein-1 beta (MIR-1B), tumor necrosis factor-alpha (TME-α), 1-10, monocyte chemotactic protein-1 (MOP- 1) and KAMTEZ (regulated after activation of normal expressed and secreted T cells), using lipopolysaccharide-stimulated human peripheral blood mononuclear cells (PRVMSZ5) obtained from 2-6 donors.

The compound of formula I inhibited the production (in order of potency) of TME-a (ISvo-0.034 μM), » 1-18 (ISvo-0.054 μM) » 1-6 (ISvo-0.060 μm) » MOS (ISvo-0.062 μM) » MIR-1 (ISvo-0.30 μM) » OM-

C5E (ISvo-0.95 μM) » 1I-8 (ISvo»10 μM) » MIR-18B (ISvo»10 μM) (table 12). Compound formula

It also enhanced the production of 1-10, MCP-1, and KAMTEZ with an average percentage increase relative to control values of 480 95, 236 95, and 131 95, respectively, at a concentration of 0.1 µM.

Table 12

Summary of the cytokine inhibition profile of the compound of formula I 0-6 П-- |й-й8 som-o5E YMOS (MiR-ta |MIR-B |ТМБа 6.11 NOMES tube formation, migration and invasion caused by MESE, VESBE and NOE

The compound of formula I demonstrated high inhibitory activity in an IP myo invasion assay of human umbilical cord vascular endothelial cells (HOMES). The compound of the formula strongly inhibited invasion induced by vascular endothelial growth factor (VEF), basic fibroblast growth factor (BEF), and hepatocyte growth factor (HOR), weakly inhibited MESE and BEOE-induced NOMES tube formation and migration, and either enhanced or did not inhibit NOMES proliferation , caused by a growth factor. The IC value for inhibition of MESE-induced NOMES invasion was 0.29 nM. The value of ISzo for inhibition of VES-induced NOMES invasion was 5.5 nM. The ISvho value for inhibition of NOE-induced NOMES invasion was 110 nM. The compound of formula I inhibited the induced MESE and BESE migration, respectively, at

C8 9b and 28 95 at a concentration of 1 µM. 6.12 Clinical protocol

Described below is a prospective phase 1a/165 clinical study to determine the safety, tolerability, pharmacokinetics and efficacy of a compound of formula I when administered orally to individuals with advanced solid tumors, non-Hodgkin's lymphoma, or multiple myeloma. In the study, it will be necessary to determine the intolerable dose (TOD), the maximum tolerated dose (TOD) and the recommended dose for phase 2-0 (CR2O). The effect of the compound on biomarkers of angiogenesis in tumor biopsies before and after treatment will be evaluated.

Research structure

The study is structured as a phase 1a/10 study, which consists of two parts: an increase in the dose (Part A) and the application of the indicated dose in a larger number of subjects included in the trial (Part B). In Part A, subjects will receive single and multiple escalating doses of a compound of formula I to determine pharmacokinetics (PC) and identify the maximum tolerated dose (MT) and recommended dose for a phase 2 study (MR2O). A standard dose-escalation scheme (3-3) (Bitop et al., 1997) will be used to identify baseline toxicity. Primary cohorts of three will receive a compound of formula I (0.5 mg once daily) in 100 95 dose increments until the first event of grade C or higher toxicity suspected to be drug-related in the first cycle, at which point the specific the cohort will be expanded to a total of six individuals. This standard dose escalation schedule will be initiated to establish the intolerable dose (TOD) and MTO. Safety evaluation can also be performed with smaller dose increments and in additional subjects within a given dose cohort. In Part A, approximately 20-40 individuals will be treated and assessed; however, the total number of subjects in Part A depends on the number of dose cohorts required to establish the MTO. A dose will be considered MTO if 2 or more of the 6 evaluable subjects in the cohort develop a drug-related dose-limiting toxicity (DTO) during cycle 1. Once the MTO is established, the dose increase will be stopped. The MTO is defined as the last dose level below the MTO in 0 or 1 of 6 evaluable subjects who developed OI T during the 1st cycle. An intermediate dose (ie, the dose between the MTO and the last dose level before the MTO) or additional individuals within any dose cohort may be needed to more precisely determine the MTO and CR2O.

In Part B, individuals may start at the MTO level and/or a lower dose level based on safety, part A LC and/or RO (phased dose) data. Treatment and assessment of safety and antitumor activity will be performed in approximately 100 individuals (up to 20 per cohort), stratified by tumor type after every two cycles of treatment. The appropriate dose, doses or regimen will also be determined. During Phase B, safety data will be regularly reviewed as appropriate for continuation of the study.

Study population

The study will enroll men and women aged 18 years or older with advanced solid tumors (5T), non-Hodgkin's lymphoma (NM), multiple myeloma (MM), or advanced unresectable solid tumors, including individuals who have experienced disease progression on standard therapy (or the inability to tolerate it), or for which there is no standard treatment. Selected tumor types include metastatic breast cancer (MTBC), glioblastoma multiforme (BM), hepatocellular carcinoma (HCC), diffuse large B-cell lymphoma (BCL), and multiple myeloma (MM).

Introduction and duration of the study

During the first cycle, in Part A only, each individual will be administered a single daily dose of a compound of formula I on Day 1, followed by a 48-hour observation and LC measurement period, followed by a 28-day dosing break (Cycle 1 - 30 days). In subsequent cycles of part A, individuals are treated in 28-day cycles at

With continuous administration from the 1st day to the 28th day. A compound of formula I will be administered once or twice daily at a dose of 0.1, 0.5, 1, 2, 4, 5, 7.5, 10, 20, 25 or 50 mg in the initial dose. The dose can be 0.1, 0.5, 1, 2, 4, 5, 7.5, 10 mg, administered once a day. The dose can be 50, 25 or 10 mg administered twice a day. During treatment, the dose can be selected with an increase or decrease relative to the initial dose. As described above, if necessary, the drug can be administered cyclically.

In Part B, individuals are continuously injected with the drug for 28 days from the start of administration - there is no 48-hour period of LC data collection after the initial single dose.

Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity, or individual/physician decision to discontinue. Individuals may continue to take the compound without interruption for as long as the researcher believes it has a beneficial effect on them.

Enrollment of individuals into the study is expected to occur over approximately 24 months. It is expected that the completion of active treatment and observation of individuals will take another 3-6 months.

Schemes of treatment within the framework of the study

The SeIdepe Sogrogayop company will supply the compound of formula I (NS) in the form of capsules of 0.1 mg, 0.5 mg, 1 mg and 3 mg for oral administration. The compound will be packaged in vials inside boxes containing the drug for 28 days.

In Part A (escalation phase), the starting dose level will be 0.5 mg once daily after a single LC dose. After administration of the first dose to the last individual in any cohort, individuals are observed for at least 30 days before the cohort can begin administration of the next, higher protocol-specified dose. An increase in the dose in one individual is not allowed until it is authorized by the Safety Review Committee (SRC), which will consist of the principal investigator and the medical controller from CeIdepe.

In Part B, subjects may receive a compound of Formula I in MTO and/or at a lower dose level based on safety, PK and RO assessments in Part A. Safety and antitumor effects will be evaluated in approximately 100 subjects (preselected tumor types in groups that include up to 20 individuals). because Review of performance evaluations

The evaluation of the effectiveness of the treatment will be evaluated after every 2 cycles. The primary indicator of effectiveness is the response of the tumor to treatment. The response of the tumor to treatment will be based on the Criteria for evaluating the effectiveness of treatment in solid tumors (KESI5T 1.1),

International Working Group Criteria (IWG) for MNI, International Standard Treatment Efficacy Criteria for Multiple Myeloma (MME) (Appendix A, Section 18.1) or Neuro-oncology Working Group Evaluation of Treatment Efficacy (NAWG) for SVM.

Secondary study endpoints include blood and tumor biomarker measurements, pathohistological indicators of treatment efficacy, and correlation with pharmacogenomic data.

Additional performance indicators will also be investigated (for example, functional status according to the criteria of ESOS (Eastern Cooperative Oncology Group), results according to PET data); in addition, changes in hypovascularity will be measured by volume transfer constant (Kigap5b) and initial AUC (IA) (area under the curve as the dose increases) using OSE-MVI (dynamic contrast-enhanced magnetic resonance imaging).

Overview of security assessments

Safety indicators for this study include adverse events, clinical laboratory parameters, 12-lead ECG (centrally analyzed), LVEF (left ventricular ejection fraction), physical examinations, and vital signs.

Overview of pharmacokinetic evaluations

The PK profiles of the compound of formula I and its metabolites will be determined in serial blood and blood samples during the first cycle of treatment. If possible, they will be correlated with the pharmacodynamic (PO) ladder.

The above examples are presented to provide those skilled in the art with a complete description of how to use the claimed embodiments and are not intended to limit the scope of the invention described herein. It is assumed that modifications that are obvious to specialists in this field are within the scope of the following claims. All publications, patents, and patent applications cited in the specification are hereby incorporated by reference as if each publication, patent, or patent application were specifically and individually indicated to be incorporated herein by reference.

Coo)

Claims (35)

FORMULA OF THE INVENTION 1. Use of a therapeutically effective amount of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,6-dione, which has the following structure: M vn " OM o H ; or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof for the manufacture of a medicament for the treatment or management of a patient suffering from cancer, wherein the medicament is suitable for administration to a patient in need of such treatment or management. 2. Application according to claim 1, where the cancer is an advanced malignant disease, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumor with an unfavorable prognosis, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, adenocarcinoma of the rectum, colorectal cancer of the Siu stage according to Dukes, inoperable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotypic acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma , diffuse large B-cell lymphoma, poorly differentiated follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant mesothelioma syndrome with pleural effusion, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, gi steatocytosis from Langerhans cells, leiomyosarcoma, progressive ossifying fibrodysplasia, prostate cancer, refractory to hormones, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenström's macroglobulinemia, indolent myeloma, slow-growing myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent non-metastatic stage MI prostate cancer, hormone-refractory prostate cancer , chemotherapy-resistant prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. 3. Application according to claim 1, where the cancer is a hematological tumor. 4. Use according to claim 1, where the cancer is myeloma or lymphoma. 5. Application according to claim 1, where the cancer is a solid tumor. 6. Use according to claim 1, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer or kidney cancer. 7. Use according to claim 1, where the cancer is hepatocellular carcinoma, prostate cancer, ovarian cancer or glioblastoma. 8. The use of claim 1, wherein the cancer is non-Hodgkin's lymphoma. 9. Application according to claim 8, where the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma. 10. Application according to claim 9, where the diffuse large B-cell lymphoma belongs to the activated B-cell phenotype. 11. Application according to claim 10, where the diffuse large B-cell lymphoma is characterized by the expression of one or more biomarkers overexpressed in the cell lines KIMA, 002932, TMO8 or OSI-Ig uto. 12. Use according to any one of claims 1-11, wherein the cancer is recurrent or refractory. 13. Use according to any one of claims 1-12, wherein the cancer is resistant to drug therapy. 14. Use of a therapeutically effective amount of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-ylpiperidine-2,6-dione or its pharmaceutically acceptable salt, solvate or hydrate to obtain a medicinal product for the treatment or management of a patient with non-Hodgkin's lymphoma, wherein the medicament is suitable for administration to the patient, and wherein the patient is identified as suffering from non-Hodgkin's lymphoma responsive to 3-(5-amino-2-methyl-4-oxo-4|H-quinazoline-3- il)/piperidine-2,b-dione. 15. Application according to claim 14, where the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma. 16. Use according to claim 14, wherein the non-Hodgkin's lymphoma belongs to the activated B-cell phenotype. 17. Use according to claim 15, where the diffuse large B-cell lymphoma belongs to the activated B-cell phenotype. 18. Application according to claim 17, where the diffuse large B-cell lymphoma is characterized by the expression of one or more biomarkers overexpressed in the cell lines KIMA, 002932, TMO8 or OSI-Ig uto. 19. Use according to claim 14, wherein the identification of a patient having non-Hodgkin's lymphoma sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,b-dione or its salt, solvate, or hydrate, includes characterization of the patient's non-Hodgkin lymphoma phenotype as an activated B-cell subtype. 20. Application according to claim 19, wherein the phenotype of non-Hodgkin's lymphoma is characterized as an activated B-cell subtype of diffuse large B-cell lymphoma. 21. Application according to claim 19, where the non-Hodgkin lymphoma phenotype is characterized by the expression of one or more biomarkers overexpressed in KIMA, 02932, TMO8 or OSI-Guto cell lines. 22. The use of claim 14, wherein identifying the non-Hodgkin lymphoma phenotype comprises obtaining a biological sample from a patient having lymphoma. 23. Application according to claim 22, where the biological sample is a lymph node biopsy, a bone marrow biopsy or a sample of peripheral blood tumor cells. 24. Use according to claim 14, wherein the identification of a patient having non-Hodgkin's lymphoma sensitive to treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,b-dione or its salt, solvate or hydrate, includes the identification of a gene associated with an activated B-cell phenotype. 25. Application according to claim 24, where the gene associated with the activated B-cell phenotype is selected from the group consisting of IKE4/MYOMI, ROCHRI, 5P1TV, SAKOT11 and VGIMR/ROCMI. 26. Use according to claim 14, wherein the identification of a patient having non-Hodgkin's lymphoma sensitive to 60 treatment with 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)upiperidine-2,b-dione or its salt, solvate or hydrate, includes measuring the level of ME-kV activity in a biological sample obtained from a patient. 27. Application according to claim 26, where the biological sample is a lymph node biopsy, a bone marrow biopsy or a sample of peripheral blood tumor cells. 28. Application according to claim 19, wherein the characterization of the phenotype of the patient's non-Hodgkin lymphoma as an activated B-cell subtype includes measuring one or more of the following indicators: () overexpression of 5RIV, a hematopoiesis-specific family of Ebb5 transcription factors required for the survival of cells of the activated B-cell subtype ; (i) higher constitutive expression of IKE4/MOMI than in cells of the SWR subtype; (iii) higher constitutive expression of EOHRI1 stimulated by trisomy 3; (im) higher constitutive expression of Vitr!1, i.e. RKOMI1; (m) higher constitutive expression of the SAKO11 gene; and (m) increased level of activity of ME-KV relative to the cells of the ALL axis. non-activated B-cell subtype. 29. Use according to any of claims 1-28, where the compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidin-2,6b-dione hydrochloride or its salt, solvate or hydrate. 30. Use according to any one of claims 1-29, which additionally includes the administration of a therapeutically effective amount of one or more additional active agents. 31. Application according to claim 30, where the additional active agent is selected from the group consisting of an alkylating agent, adenosine analogue, glucocorticoid, kinase inhibitor, ZUK inhibitor, ROEZ inhibitor, ROE7 inhibitor, doxorubicin, chlorambucil, vincristine, bendamustine, forskolin and rituximab. 32. Use according to any of claims 1-31, where 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-ylpiperidine-2,6-dione or its pharmaceutically acceptable salt, solvate or hydrate are intended to be administered in an amount of from about 0.5 to about 50 mg per day, or from about 0.5 to about 5 mg per day, or from about 0.5, 1, 2, 4, 5, 10, 15, 20, 25 or 50 mg per day. 33. Use according to claim 32, where the compound is intended for oral administration in a capsule or tablet. Zo 34. Use according to any one of claims 1-33, wherein the diffuse large B-cell lymphoma is relapsed, refractory or resistant to conventional treatment. 35. Use according to any one of claims 1-34, wherein the compound is administered for 21 days followed by a seven-day break in a 28-day cycle. at. Kekrakrninchusti poi MGKV U weight KO re ke хх х шшнш шишш ши EE 0 У BE Х х и Fk A