CN101647798A - Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases - Google Patents
Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases Download PDFInfo
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- CN101647798A CN101647798A CN200910167156A CN200910167156A CN101647798A CN 101647798 A CN101647798 A CN 101647798A CN 200910167156 A CN200910167156 A CN 200910167156A CN 200910167156 A CN200910167156 A CN 200910167156A CN 101647798 A CN101647798 A CN 101647798A
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Abstract
Methods of treating, preventing and/or managing cancer as well as and diseases and disorders associated with, or characterized by, undesired angiogenesis are disclosed. Specific methods encompass theadministration of an immunomodulatory compound alone or in combination with a second active ingredient. The invention further relates to methods of reducing or avoiding adverse side effects associatedwith chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy which comprise the administration of an immunomodulatory compound. Pharmaceutical compositions, single unitdosage forms, and kits suitable for use in methods of the invention are also disclosed.
Description
The present patent application is a divisional application of the invention patent application having international application number PCT/US2004/014004, international application date 5/2004, application number 200480020445.0 at the national stage of entry into china entitled "methods and compositions for treating and managing cancer and other diseases using immunomodulatory compounds".
1. Field of the invention
The present invention relates to methods of treating, preventing and/or managing cancer, as well as other diseases, including but not limited to diseases associated with or characterized by undesired angiogenesis, by administering one or more immunomodulatory compounds alone or in combination with other therapies. In particular, the invention encompasses the use of specific combinations or "cocktails" of drugs or other therapies (such as radiation therapy) to treat these specific cancers, including those cancers that are not effective for conventional therapies. The invention also relates to pharmaceutical compositions and regimens.
2. Background of the invention
2.1 Pathology of cancer and other diseases
Cancer is mainly characterized by an increase in the number of abnormal cells derived from a normal tissue, invasion of adjacent tissues by these abnormal cells, or spread of malignant cells to regional lymph nodes and distant sites through lymph fluid or blood (metastasis). Clinical data and molecular biological studies have demonstrated that cancer is a multistep process that begins with subtle preneoplastic changes that can in some cases progress to tumors. Neoplastic lesions can develop within the same species of cells and increase the ability to invade, grow, metastasize and become heterogeneous, especially if the neoplastic cells have escaped host immune surveillance. Roitt, i., Brostoff, J and Kale, d., Immunology 17.1-17.12 (third edition, Mosby, st. louis, mo., 1993).
A large number of cancers have been described in the medical literature. Examples thereof include lung cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, brain cancer and intestinal cancer. The incidence of cancer continues to rise as the population ages, new cancers emerge, and susceptible populations (e.g., people infected with AIDS or overly exposed to sunlight) increase. There is therefore an urgent need for new methods and compositions for the treatment of cancer.
Many cancer types are associated with a process of neovascularization known as angiogenesis. Several mechanisms have been elucidated that are involved in tumor-induced angiogenesis. The most critical guide for these mechanisms is the secretion of cytokines with angiogenic properties by tumor cells. Examples of such cytokines include acidic and basic fibroblast growth factors (a, b-FGF), angiogenin, Vascular Endothelial Growth Factor (VEGF), and TNF- α. Alternatively, tumor cells can release angiogenic peptides by producing proteases that in turn disrupt the extracellular matrix that stores certain cytokines (e.g., b-FGF). Angiogenesis can also be induced indirectly by the recruitment of inflammatory cells (specifically macrophages), which subsequently release angiogenic cytokines (e.g., TNF- α, bFGF).
Many other diseases and conditions are also associated with or characterized by undesired angiogenesis. For example, enhanced or unregulated angiogenesis has resulted in a number of diseases and clinical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, flushing (neovascularization of the canthus), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, post-crystalline fibroplasia and proliferative vitreoretinopathy.
Accordingly, compounds that control angiogenesis or inhibit the production of certain cytokines, including TNF- α, are useful in the treatment and prevention of various diseases and disorders.
2.2 methods of treating cancer
Current cancer treatment methods include surgery, chemotherapy, hormonal therapy and/or radiation therapy to eradicate neoplastic cells in a patient (see, e.g., Stockdale, 1998, Medicine, Vol.3, Rubenstein and Federman eds., Chapter 12, section IV). More recently, cancer treatment methods also include biological therapy or immunotherapy. All of these methods have significant drawbacks for the patient. For example, surgery may be contraindicated or unacceptable to the patient due to patient health issues. In addition, surgery cannot completely remove tumor tissue. Radiotherapy is only effective when the tumor tissue is more sensitive to radiation than normal tissue. Radiotherapy also often has serious side effects. Hormone therapy is rarely used alone. Although hormone therapy can be effective, it is often used to prevent or delay cancer recurrence after other treatments have removed a large proportion of the cancer cells. Biological and immunotherapy are limited in number and may cause side effects such as rashes or swelling, cold-like symptoms including fever, cold and fatigue, digestive tract problems or allergic reactions.
In the case of chemotherapy, there are many chemotherapeutic agents for the treatment of cancer. Cancer chemotherapy acts primarily by inhibiting DNA synthesis directly, or indirectly by inhibiting deoxynucleoside triphosphate precursor biosynthesis, to prevent DNA replication and concomitant cell division. Gilman et al, Goodman and Gilman's: the Pharmacological Basis of Therapeutics, eds (McGraw Hill, New York).
Various chemotherapeutic agents can be used via the tube, but chemotherapy has a number of drawbacks. Stockdale, Medicine, Vol.3, Rubenstein and Federman eds, Chapter 12, section 10, 1998. Almost all chemotherapeutic agents are toxic and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. Furthermore, even when chemotherapeutic agents are used in combination, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. Indeed, those cells that are resistant to a particular chemotherapeutic agent used in a treatment regimen often demonstrate resistance to other drugs, even though those agents act by a different mechanism than the drug used in the particular treatment. This phenomenon is known as multiple drug resistance or multidrug resistance. Due to this resistance, many cancer evidences are refractory to standard chemotherapy.
Other diseases or conditions associated with or characterized by undesired angiogenesis are also difficult to treat. However, compounds such as protamine, heparin and steroids have been proposed for the treatment of certain specific diseases. Taylor et al, Nature 297: 307 (1982); folkman et al, Science 221: 719 (1983); and U.S. patent nos. 5,001,116 and 4,994,443. Thalidomide (thalidomide) and some of its derivatives have also been proposed for the treatment of such diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 to D' Amato.
There remains an urgent need for safe and effective methods for treating, preventing and managing cancer as well as other diseases and conditions, particularly those that are ineffective to standard therapeutic approaches such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicity and/or side effects associated with conventional therapies.
2.3IMIDSTM
Many studies have been conducted with the aim of providing safe and effective compounds for treating diseases associated with abnormal production of TNF- α. See, e.g., Marriott, J.B., et al, Expert Opin. biol. ther.1(4): 1-8 (2001); G.W.Muller et al, Journal of Medicinal Chemistry39 (17): 3238-3240 (1996); and G.W.Muller et al, Bioorganic&Medicinal chemistry Letters 8: 2669-2674(1998). Several studies have focused on a group of compounds with the ability to effectively inhibit TNF-alpha production by LPS stimulation of PBMCs. L.g.corral et al, ann.rheum.dis.58: (supplement I)1107-1113 (1999). These compounds are referred to as IMiDsTM(Celgene company) or immunomodulating drugs, showed not only a strong TNF-. alpha.inhibitory effect but also significant inhibition of LPS-induced monocyte IL 1. beta. and IL12 production. LPS-induced IL6 was also inhibited, albeit only partially, by immunomodulatory compounds. These compounds are potent mimetics of LPS-induced IL10 (supra). ImiDTMSpecific examples of (D) include, but are not limited to, substituted 2- (2, 6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoles as described in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G.W. Muller et al.
3. Summary of the invention
The present invention includes methods of treating and preventing certain types of cancer, including primary and metastatic cancers, as well as cancers that are refractory or resistant to conventional chemotherapy. The methods comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof. The invention also includes methods of treating certain cancers (e.g., preventing or prolonging their recurrence, or prolonging the time to remission) comprising administering to a patient in need of such treatment a prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof.
In particular methods of the invention, the immunomodulatory compounds are administered in combination with therapies conventionally used to treat, prevent, or manage cancer. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy.
The invention also includes methods of treating, managing or preventing diseases and disorders other than cancer that are associated with or characterized by undesired angiogenesis, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof.
In other methods of the invention, the immunomodulatory compounds are administered in combination with therapies conventionally used to treat, prevent or manage diseases or conditions associated with or characterized by undesired angiogenesis. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy.
The invention includes pharmaceutical compositions, single unit dosage forms, dosage regimens and kits comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, and a second or additional active agent. The second active agent comprises a particular combination of drugs or a "cocktail".
4. Brief description of the drawings
FIG. 1 compares 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (REVLIMID)TM) And the effect of thalidomide (thalidomide) in inhibiting proliferation of Multiple Myeloma (MM) cell lines in vitro studies. Measurement of the uptake of [2 ], [ solution ] by different MM cell lines (MM 1S, Hs Sultan, U266 and RPMI-8226)3H]Thymidine acts as an indicator of cell proliferation.
5. Detailed description of the invention
A first embodiment of the present invention encompasses methods of treating, managing or preventing cancer, which comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof.
In particular methods of this embodiment, the immunomodulatory compound is administered in combination with another drug ("second active agent") or method of treating, managing or preventing cancer. Second active agents include small and large molecules (e.g., proteins and antibodies, examples of which are provided herein), as well as stem cells. Methods or therapies that may be employed in administering the immunomodulatory compounds include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-pharmaceutical methods currently used to treat, prevent, or manage cancer.
Another embodiment of the invention encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are associated with or characterized by undesired angiogenesis. These methods comprise administering a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof.
Examples of diseases and conditions associated with or characterized by undesired angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases, and rubeosis (neovascularization of the canthus). Specific examples of diseases and conditions associated with or characterized by undesired angiogenesis include, but are not limited to, endometriosis, crohn's disease, heart failure, progressive heart failure, kidney damage, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary conditions, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q syndrome.
In particular methods encompassed by this embodiment, the immunomodulatory compound is administered in combination with a second active agent or a method of treating, managing or preventing such a disease or condition. Second active agents include small and large molecules (e.g., proteins and antibodies, examples of which are provided herein), as well as stem cells. Methods or therapies that may be employed in administering immunomodulatory compounds include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-pharmaceutical methods currently used to treat, prevent or manage diseases and conditions associated with or characterized by undesired angiogenesis.
The invention also includes pharmaceutical compositions (e.g., single unit dosage forms) useful in the methods of the invention. Specific pharmaceutical compositions include an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, and a second active agent.
5.1 immunomodulatory Compounds
The compounds of the present invention may be commercially available or prepared according to the methods described in the patents or patent applications disclosed herein. In addition, optically pure compositions can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard organic chemical synthesis techniques. The compounds useful in the present invention may include immunomodulatory compounds that may be racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, stereoisomers, inclusions and prodrugs thereof.
The term "solvate" as used herein, unless otherwise indicated, includes hydrates of the compounds of the present invention.
Preferred compounds for use in the present invention are small organic molecules having a molecular weight of less than 1,000g/mol and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules.
Unless otherwise indicated, the terms "immunomodulatory compounds" and "IMiDsTM"(Celgene Corp.) here includes small organic molecules that significantly inhibit TNF- α, LPS-induced monocyte IL1 β and IL12 and partially inhibit IL6 production. Specific immunomodulatory compounds are described below.
TNF- α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF- α is responsible for a diverse range of signaling events within the cell. TNF-alpha may play a pathological role in cancer. Without being limited by theory, one biological effect of the immunomodulatory compounds of the invention is to decrease synthesis of TNF- α. Immunomodulatory compounds of the invention can enhance the degradation of TNF- α mRNA.
Furthermore, without being limited by theory, immunomodulatory compounds useful in the invention are also potent co-stimulators of T cells and can significantly increase cell proliferation in a dose-dependent manner. Immunomodulatory compounds of the invention have a higher co-stimulatory effect on a subset of CD8+ T cells than on CD4+ T cells. Furthermore, the compounds preferably have anti-inflammatory properties and are effective in co-stimulating T cells.
Specific examples of immunomodulatory compounds include, but are not limited to, cyano and carboxy derivatives of substituted styrenes, such as those described in U.S. Pat. No.5,929,117; 1-oxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline and 1, 3-dioxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, such as those described in U.S. Pat. Nos. 5,874,448 and 5,955,476; tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines as described in U.S. Pat. No.5,798,368; 1-oxo and 1, 3-dioxo-2- (2, 6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide), including but not limited to those described in U.S. Pat. Nos. 5,635,517, 6,476,052, 6,555,554, and 6,403,613; 1-oxo and 1, 3-dioxoisoindolines substituted at the 4-or 5-position of the indoline ring described in U.S. Pat. No.6,380,239 (e.g., 4- (4-amino-1, 3-dioxoisoindolin-2-yl) -4-carbamoylbutyric acid); isoindolin-1-one and isoindoline-1, 3-dione substituted at the 2-position with 2, 6-dioxo-3-hydroxypiperidin-5-yl (e.g., 2- (2, 6-dioxo-3-hydroxy-5-fluoropiperidin-5-yl) -4-aminoisoindolin-1-one), described in U.S. Pat. No.6,458,810; non-polypeptide cyclic amides of the type disclosed in U.S. Pat. Nos. 5,698,579 and 5,877,200; amino thalidomide, and analogs, hydrolysates, metabolites, derivatives and precursors of amino thalidomide, as well as substituted 2- (2, 6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoles, such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; and isoindole-imide compounds such as those described in U.S. patent application Ser. No.09/972,487, filed 5/10/5, 2001, U.S. patent application Ser. No.10/032,286, filed 21/12/2001, and International application No. PCT/US01/50401 (International application No. WO 02/059106). Each of the patents and patent applications referred to herein are incorporated by reference. Immunomodulatory compounds do not include thalidomide.
Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo-and 1, 3 dioxo-2- (2, 6 dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring, as described in U.S. Pat. No.5,635,517, which is incorporated herein by reference. These compounds have structure I:
wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH2,R2Is hydrogen or lower alkyl, especially methyl. Specific immunomodulatory compounds include, but are not limited to:
1-oxo-2- (2, 6-dioxopiperidin-3-yl) -4-aminoisoindoline;
1-oxo-2- (2, 6-dioxopiperidin-3-yl) -5-aminoisoindoline;
1-oxo-2- (2, 6-dioxopiperidin-3-yl) -6-aminoisoindoline;
1-oxo-2- (2, 6-dioxopiperidin-3-yl) -7-aminoisoindoline;
1, 3-dioxo-2- (2, 6-dioxopiperidin-3-yl) -4-aminoisoindoline; and
1, 3-dioxo-2- (2, 6-dioxopiperidin-3-yl) -5-aminoisoindoline.
Other specific immunomodulatory compounds of the invention belong to the substituted 2- (2, 6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoles, such as those described in U.S. Pat. Nos. 6,281,230, 6,316,471, 6,335,349, and 6,476,052, and International patent application PCT/US97/13375 (International application No. WO 98/03502), the disclosures of which are each incorporated herein by reference. Representative compounds have the formula:
wherein:
one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH2;
(i)R1、R2、R3And R4Each independently is halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or (ii) R1、R2、R3And R4One is-NHR5And R is1、R2、R3And R4The remainder of (A) is hydrogen;
R3is hydrogen or alkyl having 1 to 8 carbon atoms;
R6is hydrogen, alkyl containing 1 to 8 carbon atoms, benzyl or halogen;
provided that if X and Y are both C ═ O and (i) R1、R2、R3And R4Are both fluorine or (ii) R1、R2、R3Or R4One is amino, then R6Is not hydrogen.
Representative of this class of compounds have the formula:
wherein R is1Is hydrogen or methyl. In a separate embodiment, the invention encompasses the use of enantiomerically pure forms of these compounds (e.g., the optically pure (R) or (S) enantiomer).
Other specific immunomodulatory compounds of the invention belong to the isoindole-imide class, which are described in U.S. patent application publication Nos. US 2003/0096841 and US 2003/0045552, and International application No. PCT/US01/50401 (International application No. WO02/059106), each of which is incorporated herein by reference. Representative compounds have formula II:
and pharmaceutically acceptable salts, hydrates, solvates, inclusions, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
one of X and Y is C ═ O, and the other is CH2Or C ═ O;
R1is H, (C)1-C8) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl,(C0-C4) Alkyl radical- (C)1-C6) Heterocycloalkyl group, (C)0-C4) Alkyl radical- (C)2-C5) Heteroaryl, C (O) R3、C(S)R3、C(O)OR4、(C1-C8) alkyl-N (R)6)2、(C1-C8) alkyl-OR5、(C1-C8) alkyl-C (O) OR5、C(O)NHR3、C(S)NHR3、C(O)NR3R3′、C(S)NR3R3' or (C)1-C8) alkyl-O (CO) R5;
R2Is H, F, benzyl, (C)1-C8) Alkyl, (C)2-C8) Alkenyl or (C)2-C8) An alkynyl group;
R3and R3' independently is (C)1-C8) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl, (C)0-C4) Alkyl radical- (C)1-C6) Heterocycloalkyl group, (C)0-C4) Alkyl radical- (C)2-C8) Heteroaryl, (C)0-C8) alkyl-N (R)6)2、(C1-C8) alkyl-OR5、(C1-C8) alkyl-C (O) OR5、(C1-C8) alkyl-O (CO) R5OR C (O) OR5;
R4Is (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, (C)1-C4) alkyl-OR5Benzyl, aryl, (C)0-C4) Alkyl radical- (C)1-C6) Heterocycloalkyl or (C)0-C4) Alkyl radical- (C)2-C5) A heteroaryl group;
R5is (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl or (C)2-C8) A heteroaryl group;
R6independently at each occurrence, H, (C)1-C8) Alkyl, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl, (C)2-C5) Heteroaryl or (C)0-C8) alkyl-C (O) O-R5Or R is6Groups may be joined together to form a heterocycloalkyl group;
n is 0 or 1; and
denotes a chiral carbon center.
In specific compounds of formula II, R is when n is 01Is (C)3-C7) Cycloalkyl group, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl, (C)0-C4) Alkyl radical- (C)1-C6) Heterocycloalkyl group, (C)0-C4) Alkyl radical- (C)2-C5) Heteroaryl, C (O) R3、C(O)OR4、(C1-C8) alkyl-N (R)6)2、(C1-C8) alkyl-OR5、(C1-C8) alkyl-C (O) OR5、C(S)NHR3Or (C)1-C8) alkyl-O (CO) R5;
R2Is H or (C)1-C8) An alkyl group; and
R3is (C)1-C8) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl, (C)0-C4) Alkyl radical- (C)1-C6) Heterocycloalkyl group, (C)0-C4) Alkyl radical- (C)2-C5) Heteroaryl, (C)5-C8) alkyl-N (R)6)2;(C0-C8) alkyl-NH-C (O) O-R5;(C1-C8) alkyl-OR5、(C1-C8) alkyl-C (O) OR5、(C1-C8) alkyl-O (CO) R5OR C (O) OR5(ii) a And other variations having the same definition.
In other specific compounds of formula II, R2Is H or (C)1-C4) An alkyl group.
In other specific compounds of formula II, R1Is (C)1-C8) Alkyl or benzyl.
In other specific compounds of formula II, R1Is H, (C)1-C8) Alkyl, benzyl, CH2OCH3、CH2CH2OCH3Or is or
In other embodiments of the compounds of formula II, R1Is that
Wherein Q is O or S, R7Each occurrence is independently H, (C)1-C8) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C8) Alkenyl, (C)2-C8) Alkynyl, benzyl, aryl, halogen, (C)0-C4) Alkyl radical- (C)1-C6) Heterocycloalkyl group, (C)0-C4) Alkyl radical- (C)2-C5) Heteroaryl, (C)0-C8) alkyl-N (R)6)2、(C1-C8) alkyl-OR5、(C1-C8) alkyl-C (O) OR5、(C1-C8) alkyl-O (CO) R5OR C (O) OR5Or adjacent R7May together form an alkyl or aryl bicyclic ring.
In other specific compounds of formula II, R1Is C (O) R3。
In other specific compounds of formula II, R3Is (C)0-C4) Alkyl radical- (C)2-C5) Heteroaryl, (C)1-C8) Alkyl, aryl or (C)0-C4) alkyl-OR5。
In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.
In other specific compounds of formula II, R1Is C (O) OR4。
In other specific compounds of formula II, the H of C (O) NHC (O) may be replaced by (C)1-C4) Alkyl, aryl or benzyl.
Other examples of such compounds include, but are not limited to: [2- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-ylmethyl ] -amide; (2- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-ylmethyl) -carbamic acid tert-butyl ester; 4- (aminomethyl) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione; n- (2- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-ylmethyl) -acetamide; n- { (2- (2, 6-dioxo (3-piperidinyl) -1, 3-dioxoisoindolin-4-yl) methyl) cyclopropyl-carboxamide; 2-chloro-N- { (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl } acetamide; n- (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) -3-pyridylcarboxamide; 3- { 1-oxo-4- (benzylamino) isoindolin-2-yl } piperidine-2, 6-dione; 2- (2, 6-dioxo (3-piperidyl)) -4- (benzylamino) isoindoline-1, 3-dione; n- { (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl } propionamide; n { (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl } -3-pyridylcarboxamide; n- { (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl } heptanamide; n- { (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl } -2-furanyl carboxamide; methyl { N- (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) carbamoyl } acetate; n- (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) pentanamide; n- (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) -2-thienylcarboxamide; n- { [2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl ] methyl } (butylamino) carboxamide; n- { [2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl ] methyl } (octylamino) carboxamide; and N- { [2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl ] methyl } (benzylamino) carboxamide.
Other specific immunomodulatory compounds of the invention belong to the isoindole-imide class, which is described in U.S. patent application publication No. US 2002/0045643, International application WO98/54170, and U.S. patent application No.6,395,754, which are incorporated herein by reference. Representative compounds have formula III:
and pharmaceutically acceptable salts, hydrates, solvates, inclusions, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
one of X and Y is C ═ O, and the other is CH2Or C ═ O;
r is H or CH2OCOR′;
(i)R1、R2、R3Or R4Each independently of the other is halogen, alkyl having 1 to 4 carbon atoms or alkyl having 1 to 4 carbon atomsAlkoxy of (i), or (ii) R1、R2、R3Or R4One of which is nitro or-NHR5And R is1、R2、R3And R4The remainder of (A) is hydrogen;
R5is hydrogen or alkyl having 1 to 8 carbon atoms;
R6is hydrogen, alkyl having 1 to 8 carbon atoms, benzo, chloro or fluoro;
r' is R7-CHR10-N(R8R9);
R7Is m-or p-phenylene or- (C)nH2n) -, where n is 0 to 4;
R8and R9Independently of one another, hydrogen or alkyl having 1 to 8 carbon atoms, or R8And R9Together being tetramethylene, pentamethylene, hexamethylene or-CH2CH2X1CH2CH2-, wherein X1is-O-, -S-or-NH-;
R10is hydrogen, alkyl of 8 carbon atoms or phenyl; and
denotes a chiral carbon center.
Other representative compounds have the formula:
wherein:
one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH2;
(i)R1、R2、R3Or R4Each independently is halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or (ii) R1、R2、R3Or R4One is-NHR5And R is1、R2、R3And R4The remainder of (A) is hydrogen;
R5is hydrogen or alkyl having 1 to 8 carbon atoms;
R6is hydrogen, alkyl having 1 to 8 carbon atoms, benzo, chloro or fluoro;
R7is m-or p-phenylene or- (C)nH2n) -, where n is 0 to 4;
R8and R9Independently of one another, hydrogen or alkyl having 1 to 8 carbon atoms, or R8And R9Together being tetramethylene, pentamethylene, hexamethylene or-CH2CH2X1CH2CH2-, wherein X1is-O-, -S-or-NH-;
R10is hydrogen, alkyl of 8 carbon atoms or phenyl.
Other representative compounds have the formula:
wherein,
one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH2;
R1、R2、R3And R4Each independently is halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or (ii) R1、R2、R3And R4One is nitro or protected amino, and R1、R2、R3And R4The remainder of (A) is hydrogen; and
R6is hydrogen, containing 1-8 carbon atomsAlkyl, benzo, chloro or fluoro of a molecule;
other representative compounds have the formula:
wherein:
one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH2;
(i)R1、R2、R3Or R4Each independently is halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or (ii) R1、R2、R3Or R4One is-NHR5And R is1、R2、R3And R4The remainder of (A) is hydrogen;
R5is hydrogen, alkyl having 1 to 8 carbon atoms or CO-R7-CH(R10)NR8R9Wherein R is7、R8、R9And R10Each as defined above; and
R6is hydrogen, alkyl having 1 to 8 carbon atoms, benzo, chloro or fluoro;
specific examples of the compounds have the following formula:
wherein:
one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH2;
R6Is hydrogen, alkyl having 1 to 8 carbon atoms, benzyl, chlorine or fluorine;
R7is m-or p-phenylene or- (C)nH2n) -, where n is 0 to 4;
R8and R9Independently of one another, hydrogen or alkyl having 1 to 8 carbon atoms, or R8And R9Together being tetramethylene, pentamethylene, hexamethylene or-CH2CH2X1CH2CH2-, wherein X1is-O-, -S-or-NH-; and
R10is hydrogen, alkyl of 8 carbon atoms or phenyl.
The most preferred immunomodulatory compounds of the invention are 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione and 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. Such compounds can be obtained by standard synthetic methods (see, e.g., U.S. patent application No.5,635,517, herein incorporated by reference). This compound is available from Celgene corporation (warrenn, NJ). 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione has the following chemical structure:
the compound 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione has the following chemical structure:
in another embodiment, specific immunomodulatory compounds of the invention include polymorphic forms of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, such as forms A, B, C, D, E, F, G and H described in U.S. provisional application No.60/499,723, filed 9/4/2003, which is incorporated herein by reference. For example, form a of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is an unsolvated crystal, and is obtainable from a solvent system that does not contain water. Form a has an X-ray powder diffraction pattern with distinct peaks at about 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 270 ℃.
Form B of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a hemihydrate crystalline material, and can be prepared using a variety of solvent systems, including but not limited to hexane, toluene, and water. Form B has an X-ray powder diffraction pattern with distinct peaks at about 16, 18, 22, and 27 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 268 ℃.
Form C of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a semi-solvated crystalline material that can be prepared using a solvent such as, but not limited to, acetone. Form C has an X-ray powder diffraction pattern with distinct peaks at about 15.5 and 25 degrees 2 theta and a differential scanning calorimetry maximum melting temperature of about 269 ℃.
Form D of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a solvated crystalline polymorph prepared from a mixture of acetonitrile and water. Form D has an X-ray powder diffraction pattern with distinct peaks at about 27 and 28 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 270 ℃.
Form E of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a crystalline dihydrate obtainable by slurrying 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in water and then slowly evaporating 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in a solvent system having an acetone to water ratio of about 9: 1. Form E has an X-ray powder diffraction pattern with distinct peaks at about 20, 24.5, and 29 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 269 ℃.
Form F of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is an unsolvated crystal, and can be obtained by dehydrating form E. Form F has an X-ray powder diffraction pattern with distinct peaks at about 19, 19.5, and 25 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 269 ℃.
Form G of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is an unsolvated crystal that can be obtained from B and E in slurry form in a solvent such as, but not limited to, Tetrahydrofuran (THF). The X-ray powder diffraction pattern of form G has significant peaks at about 21, 23, and 24.5 degrees 2 Θ, and a differential scanning calorimetry maximum melting temperature of about 267 ℃.
Form H of 3- (4-amino-1-oxo-1, 3 dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a partially hydrated crystalline material, obtainable by exposing form E to 0% relative humidity. The X-ray powder diffraction pattern of form H has distinct peaks at about 15, 26, and 31 degrees 2-theta and a differential scanning calorimetry maximum melting temperature of about 269 ℃.
Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline and 1, 3-dioxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, such as those described in U.S. Pat. Nos. 5,874,448 and 5,955,476, both of which are incorporated herein by reference. Representative compounds have the formula:
wherein Y is oxygen or H2And are and
R1、R2、R3and R4Each hydrogen, halogen, containing 1-4Alkyl of carbon atoms, alkoxy of 1 to 4 carbon atoms, or amino.
Other specific immunomodulatory compounds of the invention include, but are not limited to, tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines disclosed in U.S. Pat. No.5,798,368, which is incorporated herein by reference. Representative compounds have the formula:
wherein R is1、R2、R3And R4Each independently a halogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms.
Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo and 1, 3 dioxo-2- (2, 6 dioxopiperidin-3-yl) isoindolines disclosed in U.S. Pat. No.6,403,613, which is incorporated herein by reference. Representative compounds have the formula:
wherein
Y is oxygen or H2,
R1And R2One of which is halogen, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, R1And R2Wherein the other is independently hydrogen, halogen, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, and
R3is hydrogen, alkyl or benzyl.
Specific examples of such compounds have the formula:
wherein R is1And R2One of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, dialkylamino (wherein each alkyl has 1 to 4 carbon atoms), cyano or carbamoyl,
R1and R2One is independently hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylamino wherein the alkyl has 1 to 4 carbon atoms, dialkylamino wherein each alkyl has 1 to 4 carbon atoms, cyano or carbamoyl, and
R3is hydrogen, alkyl having 1 to 4 carbon atoms or benzyl. Other representative compounds have the formula:
wherein R is1And R2One of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, dialkylamino (wherein each alkyl has 1 to 4 carbon atoms), cyano or carbamoyl,
R1and R2One is independently hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylamino wherein the alkyl has 1 to 4 carbon atoms, dialkylamino wherein each alkyl has 1 to 4 carbon atoms, cyano or carbamoyl, and
R3is hydrogen, alkyl having 1 to 4 carbon atoms or benzyl.
Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo and 1, 3-dioxoisoindolines substituted at the 4-or 5-position of the indoline ring described in U.S. Pat. No.6,380,239, which is incorporated herein by reference. Representative compounds have the formula:
wherein the carbon atom denoted C constitutes the chiral centre (when n is other than 0 and R1And R2When not identical); x1And X2One of which is amino, nitro, alkyl having 1 to 6 carbon atoms or NH-Z, and X1Or X2The other is hydrogen; r1And R2Each independently is hydroxy or NH-Z; r3Is hydrogen, alkyl containing 1 to 6 carbon atoms, halogen or haloalkyl; z is hydrogen, aryl, alkyl containing 1 to 6 carbon atoms, formyl or acyl containing 1 to 6 carbon atoms; and n has a value of 0, 1 or 2; provided that if X is1Is amino and n is 1 or 2, then R1And R2Are not hydroxyl; and salts thereof. Other representative compounds have the formula:
wherein when n is not 0 and R1And R2When not identical, the carbon atom denoted by C constitutes a chiral center; x1And X2One of which is amino, nitro, alkyl having 1 to 6 carbon atoms or NH-Z, and X1Or X2The other is hydrogen; r1And R2Each independently is hydroxy or NH-Z; r3Is alkyl containing 1-6 carbon atoms, halogen or hydrogen; z is hydrogen, aryl or alkyl or acyl containing 1 to 6 carbon atoms; and n has a value of 0, 1 or 2.
Other representative compounds have the formula:
wherein when n is not 0 and R1And R2When not identical, the carbon atom denoted by C constitutes a chiral center; x1And X2One of which is amino, nitro, alkyl having 1 to 6 carbon atoms or NH-Z, and X1Or X2The other is hydrogen; r1And R2Each independently is hydroxy or NH-Z; r3Is alkyl containing 1-6 carbon atoms, halogen or hydrogen; z is hydrogen, aryl or alkyl or acyl containing 1 to 6 carbon atoms; and n has a value of 0, 1 or 2; and salts thereof. Specific examples of such compounds have the formula:
wherein, X1And X2One is nitro or NH-Z, and X1Or X2The other of (a) is hydrogen;
R1and R2Each independently is hydroxy or NH-Z;
R3is alkyl containing 1-6 carbon atoms, halogen or hydrogen;
z is hydrogen, phenyl, acyl containing 1 to 6 carbon atoms or alkyl containing 1 to 6 carbon atoms; and
n has a value of 0, 1 or 2;
provided that if X is1And X2One is nitro and n is 1 or 2, then R1And R2Is not a hydroxyl group; and
if-COR1And- (CH)2)nCOR2Not the same, the carbon atom denoted C constitutes the chiral center. Other representative compounds have the formula:
wherein, X1And X2One is an alkyl group containing 1 to 6 carbon atoms;
R1and R2Each independently is hydroxy or NH-Z;
R3is alkyl containing 1-6 carbon atoms, halogen or hydrogen;
z is hydrogen, phenyl, acyl containing 1 to 6 carbon atoms or alkyl containing 1 to 6 carbon atoms; and
n has a value of 0, 1 or 2; and
if-COR1And- (CH)2)nCOR2Not the same, the carbon atom denoted C constitutes the chiral center.
Other specific immunomodulatory compounds of the invention include, but are not limited to, isoindolin-1-one and isoindoline-1, 3-dione substituted at the 2-position with 2, 6-dioxo-3-hydroxypiperidin-5-yl as described in U.S. Pat. No.6,458,810, which is incorporated herein by reference. Representative compounds have the formula:
wherein:
the carbon atoms represented by x constitute a chiral center;
x is-C (O) -or-CH2-;
R1Is alkyl having 1 to 8 carbon atoms or-NHR3;
R2Is hydrogen, alkyl having 1 to 8 carbon atoms or halogen; and
R3is hydrogen;
alkyl having 1 to 8 carbon atoms, unsubstituted or substituted with alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms;
cycloalkyl groups containing 3 to 18 carbon atoms;
phenyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms;
benzyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms, or-COR4Wherein
R4Is hydrogen;
alkyl having 1 to 8 carbon atoms, unsubstituted or substituted with alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms;
cycloalkyl groups containing 3 to 18 carbon atoms;
phenyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms; or
Benzyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms.
The compounds of the present invention may be commercially available or prepared according to the methods described in the patents or patent applications disclosed herein. In addition, optically pure compositions can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard organic chemical synthesis techniques.
The term "pharmaceutically acceptable salts" as used herein includes, unless otherwise indicated, non-toxic acid and base addition salts of the compounds to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, tartaric, lactic, succinic, citric, malic, maleic, sorbic, aconitic, salicylic, phthalic, apolyolic, heptanoic, and the like.
Naturally occurring acidic compounds are capable of forming salts with various pharmaceutically acceptable bases. Bases which can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts (i.e., salts containing a pharmaceutically acceptable cation such as, but not limited to, salts of an alkali metal or alkaline earth metal, especially calcium, magnesium, sodium or potassium salts). Suitable organic bases include, but are not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.
Unless otherwise indicated, the term "prodrug" as used herein refers to a derivative of a compound that hydrolyzes, oxidizes, or reacts under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of the immunomodulatory compounds of the invention that contain biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those containing-NO, -NO2-ONO or-ONO2Derivatives of some of the immunomodulatory compounds of the invention. Prodrugs can generally be prepared by well-known methods, such as Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (edited by Manfrede E.Wolff, fifth edition, 1995)) And Design of Prodrugs (H.Bundgaard eds., Elselvier, New York 1985).
Unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" herein refer to an amide, ester, carbamate, carbonate, ureide, or phosphate ester, respectively, of a compound that: 1) does not affect the biological activity of the compound but may confer beneficial in vivo properties to the compound, such as uptake, duration of action or allowing it to act; or 2) is biologically inactive, but converts the biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, 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, alpha-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 polyether amines.
Various immunomodulatory compounds of the invention contain one or more chiral centers and may exist as racemic mixtures of enantiomers or mixtures of diastereomers. The invention includes the use of stereochemically pure forms of this compound, as well as the use of mixtures of those forms. For example, mixtures containing equal or unequal amounts of enantiomers of a particular immunomodulatory compound of the invention can be used in the methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using known resolving agents or chiral columns, as well as other standard organic chemical synthesis techniques. See, e.g., Jacques, j, et al, eneriomers, Racemates and solutions (Wiley-Interscience, new york, 1981); wilen, s.h. et al, Tetrahedron 33: 2725 (1977); eliel, E.L., Stereochemistry of carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, s.h., Tables of resolvyzg Agents and Optical solutions p.268 (ed. e.l.eliel, Univ.of NotreDame Press, Notre Dame, IN, 1972).
The term "stereochemically pure" as used herein, unless otherwise indicated, refers to a composition which comprises one stereoisomer of a compound and which is substantially free of other stereoisomers of the compound. For example, a stereochemically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereochemically pure composition of a compound having two chiral centers will be substantially free of the other diastereomers of the compound. A typical stereochemically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The term "stereoisomerically enriched" as used herein means, unless otherwise indicated, a composition containing greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound. Unless otherwise indicated, the term "enantiomerically pure" as used herein refers to a stereochemically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to compositions of compounds having one chiral center that are enriched in a particular stereoisomer.
It should be noted that if there is a difference between the structure shown and the name of the structure, the structure shown should be the subject of the difference. Further, if the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, it is intended that the structure or portion thereof will include all stereoisomers thereof.
5.2 second active agent
In the methods and compositions of the present invention, the immunomodulatory compound may be combined with another pharmacologically active compound ("second active agent"). It is believed that certain combinations will exert a synergistic effect in the treatment of specific cancer types, as well as certain diseases and conditions associated with or characterized by undesired angiogenesis. Immunomodulatory compounds can also mitigate adverse effects associated with certain second active agents, which can be used to mitigate adverse effects associated with immunomodulatory compounds.
One or more second active ingredients or agents may be used in the methods and compositions of the present invention with an immunomodulatory compound. The second active agent may be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).
Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents are anti-CD 40 monoclonal antibodies (e.g., SGN-40); histone deacetylase (deaclyase) inhibitors (e.g., SAHA and LAQ 824); heat shock protein-90 inhibitors (e.g., 17-AAG); insulin-like growth factor-1 receptor kinase inhibitors; vascular endothelial growth factor receptor kinase inhibitors (e.g., PTK 787); an insulin growth factor receptor inhibitor; a lysophosphatidic acid acyltransferase inhibitor; an IkB kinase inhibitor; a p38MAPK inhibitor; EGFR inhibitors (e.g., gefitinib (gefitinib) and erlotinib hydrochloride (erlotinib HCL)); HER-2 antibodies (e.g. trastuzumab)And pertuzumab (Omnitarg)TM) ); VEGFR antibodies (e.g., bevacizumab (Avastin)TM) ); VEGFR inhibitors (e.g., flk-1 specific kinase inhibitors, SU5416 and ptk787/zk 222584); P13K inhibitors (e.g., wortmannin); C-Met inhibitors (e.g., PHA-665752); monoclonal antibodies (e.g., rituximab)TositumomabMonoclonal antibody of EpigosamideAnd G250); and anti-TNF-alpha antibodies.
Typical macromolecular active agents are biomolecules such as naturally occurring proteins or artificial proteins. Proteins particularly useful in the present invention include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunocompetent cells (pathogenic cells) in vitro or in vivo. Other proteins stimulate committed erythroid progenitor cells to divide and differentiate in vitro or in vivo. Specific proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL 2") and canarypox IL-2), IL-10, IL-12 and IL-18; interferons such as interferon alpha-2 a, interferon alpha-2 b, interferon alpha-n 1, interferon alpha-n 3, interferon beta-Ia and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.
Specific proteins that may be used in the methods and compositions of the invention include, but are not limited to: filgrastim, tradename in the united statesSold (Amgen, Thousand Oaks, CA); samoustin, tradename in the United statesSold (Immunex, Seattle, WA); and a recombinant EPO (erythropoietin),which is sold under the trade name of U.S.ASold (Amgen, Thousand Oaks, Calif.).
Recombinant and mutant forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485, 5,393,870, and 5,229,496, all of which are incorporated herein by reference. Recombinant and mutant forms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643, 4,999,291, 5,528,823 and 5,580,755. All of these patents are incorporated herein by reference.
The present invention encompasses the use of natural proteins, naturally occurring proteins and recombinant proteins. The invention also includes mutants and derivatives (e.g., modified forms) of naturally occurring proteins that have at least a portion of the pharmacological activity of the protein on which they are based in vivo. Examples of mutants include, but are not limited to, proteins that contain one or more amino acid residues that differ from the corresponding residues in the naturally occurring form of the protein. The term "mutant" also includes proteins that lack the sugar moieties normally present in their naturally occurring form (e.g., non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to a protein or an active portion of a protein of interest. See, e.g., penechet, m.l. and Morrison, s.l., j.immunol.methods 248: 91-101(2001).
The macromolecular active agent may be administered in the form of an anti-cancer vaccine. For example, vaccines that secrete or secrete cytokines (e.g., IL-2, G-CSF, and GM-CSF) can be used in the methods, pharmaceutical compositions, and kits of the invention. See, e.g., emers, l.a., et al, curr. opinion mol. ther.3 (1): 77-84(2001).
In one embodiment of the invention, the macromolecular active agent reduces, eliminates or prevents adverse effects associated with administration of immunomodulatory compounds. Depending on the particular immunomodulatory compound and the disease or condition being treated, adverse effects can include, but are not limited to, drowsiness and lethargy, dizziness, as well as orthostatic hypotension, neutropenia, infection by neutropenia, increased viral load of HIV, bradycardia, schwann-john syndrome, and toxic epidermal necrolysis and seizures (e.g., grand mal spasm). A particular adverse effect is neutropenia.
Small molecule second active agents can be used to alleviate the adverse effects associated with administration of immunomodulatory compounds. However, as with certain macromolecules, it is believed that many small molecules are capable of providing a synergistic effect when administered with (e.g., before, after, or simultaneously with) an immunomodulatory compound. Examples of small molecule second active agents include, but are not limited to, anticancer drugs, antibiotics, immunosuppressants, and steroids.
Examples of anti-cancer drugs include, but are not limited to: semaxanib; (ii) a cyclosporin; etanercept; doxycycline; bordeaux (bortezomib); acivicin; aclarubicin; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; hexamethylmelamine; an apramycin; acetic acid dihydroamine anthraquinone; ansacholine; anastrozole; an atramycin; an asparaginase enzyme; a triptyline; azacytidine; a thiotepa; azomycin; batimastat; benztepa; bicalutamide; bishan mountain forest hydrochloride; bisnefaede iodonate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib; chlorambucil; a sirolimus; cisplatin; cladribine; cllinaltol mesylate; cyclophosphamide; cytarabine; (ii) a dacarbazine; dactinomycin; myeloid leukemia hydrochloride; decitabine; (ii) dexomaplatin; 2, dizagutanin; 1, dizagutinine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotandrosterone propionate; azomycin; edatrexae; (ii) nilisil hydrochloride; elsamitrucin; enloplatin; phenyl propinyl ester; a bis-epoxy piperidine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine phosphate; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; fadrozole hydrochloride; fazarabine; fenretinide; a fluorouracil deoxynucleoside; fludarabine phosphate; fluorouracil; fluorocyclocytidine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; an ifosfamide; emofosfam; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium; a cyclohexylnitrosourea; losoxantrone hydrochloride; -Marpropico; maytansine; mechlorethamine hydrochloride; megestrol acetate; (ii) estrene acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; meltupipide; mitodomide; micacacine; mitorubin; mitogen; mitosin; mitomycin; mitosporin; mitotane; mitoxantrone hydrochloride; mycophenolic acid; thiaurethane pyridazinol; a noggin; ormaplatin; a sulfinylpyridine; paclitaxel; adding a parzyme; a calicheamicin; neostigmine bromide; pirlimycin sulfate; hyperphosphamide; bromopropylpiperazine; 1, azinpyram; piroxantrone hydrochloride; mithramycin; pramipexole; porfimer sodium; a podomycin; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; isopentene adenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium sperphosphate; sparsomycin; helical germanium hydrochloride; spiromustine; cis-spiroplatinum; streptonigrin; streptomyces lanceolatus; a sulfochlorophenylurea; talimox; sodium tegafur; d, D-Tylox; tegafur; tiloxanthraquinone hydrochloride; temoporfin; teniposide; a tiroxiron; a testosterone ester; (ii) a thiopurine; thioguanine; thiotepa; thiazolfurin; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; trimetrexate; triptorelin; tobramzole hydrochloride; uracil mustard; a urethane imine; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vincristine sulfate; vinorelbine tartrate; isovincamine sulfate; vinzolidine sulfate; (ii) vorozole; zenitheline; a neocarzinostatin; and zorubicin hydrochloride.
Other anti-cancer agents include, but are not limited to: 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecyenol; (ii) Alexanox; aldesleukin; an ALL-TK antagonist; altretamine; amifostine; sulphaisoxazole (amidox); amifostine; (ii) aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; an angiogenesis inhibitor; antagonist D; an antagonist G; anrlex; anti-dorsal formation of protein-1; anti-androgens, prostate cancer agents; an estrogen antagonist; anti-cancer peptides; an antisense oligonucleotide; aphidicolin; modifying apoptosis genes; a modulator of apoptosis; depurination nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; (ii) atrazine; axinatatin 1; axinatatin 2; axinatatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives; balanol; batimastat; a BCR/ABL antagonist; benzochlor; benzoyl staurosporine; beta lactam derivatives; betaalethine; betacylmycinB; betulinic acid; a bFGF inhibitor; bicalutamide; a bisantrene group; bisaziridinylsphermine; (ii) bisnefarde; bistetralene A; bizelesin; brefflate; briprimine; butootitanium; buthionine esulfoximine; calcipotriol; inhibin C; a camptothecin derivative; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole (carboxyyamidotriazole); CaRest M3; CARN 700; a cartilage derived inhibitor; folding to get new; casein kinase Inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; (ii) chlorolins; chloroquinoxaline sulfonamide; (ii) cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin a 4; combretastatin analogs; a concanagen; crambescidin 816; clinatot; cryptophycin 8; cryptophycin a derivatives; curve A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfae; a cytolytic factor; hexestrol phosphate; daclizumab; decitabine; dehydrogenine B; deslorelin; groundDexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; diazaquinone; dynastine B; didox; diethylnorstanol; dihydro-5-azacytidine; dihydrotaxol, 9-; a dioxamycin; diphenylspiromustine; docetaxel; behenyl alcohol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; etokomustine; edifulin; epirubicin; (ii) nilotinib; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine phosphate analogue; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flutemastine; a flashterone; fludarabine; fluoroaurorunornicin hydrochloride; fowler; 2, fulvestrant; fostrexed; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; (ii) a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; norethoxyquin; ioxifene; iloperidone; emofosfam; ilomastat; imatinib (e.g. of) Imiquimod; an immune promoting peptide; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; iomycin; sweet potato picrol, 4-; iprop; isoxagliadine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; a lamellar element triacetate; lancet; leinamycin; lenolatiri; mushroom polysaccharide sulfate; leptin statin; letrozole; a leukocyte inhibitory factor; leukocyte interferon-alpha; leuprorelin + estrogen + progesterone; leuprorelin; levamisole; liazole; a linear polyamine analog; a lipophilic glycopeptide; a lipophilic platinum compound; lissoclinamide 7; lobaplatin; earthworm phosphatide; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; a cytolytic peptide; maytansine; m isannostatin A; marimastat; (ii) maxolone; maspin; a matrix dissolution factor inhibitor; a matrix metalloproteinase inhibitor; (ii) a melanoril; mebarone (merbarone); 1, meperiline; methioninase; metoclopramide; an inhibitor of MIF; mifepristone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofagotine; moraxest; abittus (Erbitux), human chorionic gonadotropin; monophosphoryl lipid a + mycobacteria (mycobactium) cell wall sk; mopidanol; mustard anticancer drugs; indian marine sponge (mycaperoxide) B; a mycobacterial cell wall extract; myriaporone; n-acetyldinaline; n-substituted benzamides; nafarelin; spraying naretide; naloxone + pentazocine; napavin; naphterpin; a nartostim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; quenching and tempering nitrous oxide; nitrous oxide antioxidant; nitrulyn; olimoesen cellO6-benzylguanine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; an oral cytokine inducer; ormaplatin; an oxateclone; oxaliplatin; oxanonomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; palauamine; soft esteroylcholic acid; pamidronic acid; panaxytriol; panomifen; parabacterin (paramactin); pazeliptin; a pemetrexed; pedunculing; a wood polysulphide sodium; pentostatin; (ii) pentazole; perfluorobromoalkane; hyperphosphamide; perilla alcohol; phenazinomomycin; phenyl acetate; a phosphatase inhibitor; carrying out streptolysin; pilocarpine hydrochloride; pirarubicin; pirtroxine; placetin A; placetin B; a plasminogen activator inhibitor; a platinum complex; a platinum compound; a platinum-triamine complex; porfimer sodium; a podomycin; prednisone; propyldi-acridone; prostaglandin J2; a proteasome inhibitor; protein a-based immunomodulation; inhibitors of protein kinase C; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorusAn inhibitor of an acidifying enzyme; purpurin; pyrazoline acridine; a glycohydroxyethylated hemoglobin polyoxyethylene conjugate; (ii) a raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated reteplatin; rhenium (Re) 186 etidronate (rhenium 186 ethidronate); rhizomycin; a ribozyme; RII viaminate; rohitukine; romurtide; loquimex; rubiginone B1; ruboxyl; safrog; saintopin; SarCNU; sarcophylol A; sargrastim; a Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium boron carbonate; sodium phenylacetate; solverol; a growth regulator binding protein; sonaming; phosphono-winteric acid; spicamycin D; spiromustine; spleenetin; spongistatin 1; squalamine; stiiamide; a matriptase inhibitor; sulfinosine; a vasoactive intestinal peptide potent antagonist; (ii) surfasta; suramin; aloperine; tamustine; tamoxifen methyl iodide; bovine iodomustine; tazarotene; sodium tegafur; tegafur; telluropyrylium; a telomerase inhibitor; temoporfin; teniposide; tetrachlorodecaoxide (tetrachlorodecaoxide); tetrazomine; (ii) a thioablistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thyntotrinan; thyroid stimulating hormone; rubia purpurea (tin ethyl purpurin); tirapazamine; cyclopentadienyl titanium dichloride; topstein; toremifene; a translation inhibitor; tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; a tyrosine phosphorylation inhibitor; an UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; a urokinase receptor antagonist; vapreotide; variolin B; vilareol; veratramin; verdins; verteporfin; vinorelbine; vinxaline; vitaxin; (ii) vorozole; zanoteron; zeniplatin; benzal vitamin C; and neat stastatin ester.
Specific second active agents include, but are not limited to, 2-methoxyestradiol, telomeric acid (telomestatin), multiple myeloma cellsApoptosis inducers (e.g. TRAIL), statins, semaxanib, cyclosporine, etanercept, doxycycline, pertuzumab, OlimersonRiximab (remicade), docetaxel, celecoxib, melphalan and dexamethasoneSteroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, Temodar, carboplatin, procarbazine, carmustine wafer capsule (gliadel), tamoxifen, topotecan, methotrexate,Taxol, taxotere, fluorouracil, leucovorin, irinotecan, receptacle, CPT-11, interferon alphA, pegylated interferon alphA (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepA, fludarabine, carboplatin, Doxorubicin liposomes, cytarabine, docetaxel (doxetaxol), paclitaxel (paclitaxel), vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, clarithromycin formulations, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, irinotecan, and so forthPaclitaxel, ganciclovir, doxorubicin, estramustine sodium phosphateSulindac and etoposide.
5.3 methods of treatment and prevention
The methods of the invention include methods of treating, preventing and/or managing various types of cancers and diseases and conditions associated with or characterized by undesired angiogenesis. The term "treating" as used herein, unless otherwise indicated, refers to the administration of a compound of the invention or other active agent after the onset of symptoms of a particular disease or condition. Unless otherwise indicated, the term "prevention" as used herein refers to administration prior to the onset of symptoms, particularly administration to patients suffering from cancer and other diseases and conditions associated with or characterized by undesired angiogenesis. The term "preventing" includes inhibiting the symptoms of a particular disease or disorder. Patients with cancer and a family history of diseases and disorders associated with or characterized by undesired angiogenesis are preferred candidates for prophylactic treatment. Unless otherwise indicated, the term "treating" as used herein includes preventing the recurrence of a particular disease or disorder in a patient who has been afflicted with the disease or disorder, and/or prolonging the period of time that symptoms are reduced in a patient who has been afflicted with the disease or disorder.
The term "cancer" as used herein includes, but is not limited to, solid tumors and blood borne tumors. The term "cancer" refers to diseases of skin tissue, blood and blood vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, breast, colon, endometrium, esophagus, eye, head, kidney, liver, lymph node, lung, oral cavity, neck, ovary, pancreas, prostate, rectum, stomach, testis, pharynx and uterus. Specific cancers include, but are not limited to, progressive malignancy, amyloidosis, neuroblastoma, meningioma, atypical meningioma, vascular involucral tumor, multiple brain metastases, glioblastoma multiforme, brain stem glioma, pre-refractory malignant cerebroma, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, degenerative oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, duchenne-and delta-colorectal carcinoma, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-lymphoma, cutaneous B-lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma (localized melanoma), Including but not limited to ocular melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma (scelroderma), cutaneous vasculitis, langerhans 'cell tissue cytopoiesis, leiomyosarcoma, progressive osteogenic fibrodysplasia, hormone-resistant prostate cancer, post-resection high-risk soft tissue sarcoma, unresectable (unresectable) hepatocellular carcinoma, waldenstrom's macroglobulinemia, stasis myeloma, indolent myeloma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and leiomyoma. In a specific embodiment, the cancer is metastatic. In another embodiment, the cancer is refractory to or resistant to chemotherapy or radiation therapy; especially thalidomide, is difficult to treat.
When referring to diseases and conditions other than cancer, the terms "diseases and conditions associated with or characterized by undesired angiogenesis", "diseases and conditions associated with undesired angiogenesis" and "diseases and conditions characterized by undesired angiogenesis" herein refer to diseases, conditions and conditions caused, mediated or implicated in undesired, unwanted or uncontrolled angiogenesis, including, but not limited to, inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases and retinal neovascular diseases.
Examples of such diseases and conditions associated with undesired angiogenesis include, but are not limited to, endometriosis, crohn's disease, heart failure, progressive heart failure, kidney damage, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic fossa, epidemic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium keratitis, sjogren's disease, rosacea, vesicular disease (phylectenulosis), syphilis, lipoidosis, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoal infections, kaposi's sarcoma, predatory corneal ulcers, freon's limbic degeneration, limbic keratolysis, rheumatoid arthritis, systemic lupus erythematosus, Polyarteritis, trauma, wegener's sarcoidosis, scleritis, stevensis disease, periphigoid radiation keratoastigmatism, sickle cell anemia, sarcoidosis, elastoseudoma, paget's disease, vascular occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, lyme disease, ilus disease, hodgkin's disease, retinitis, choroiditis, ocular pseudohistoplasmosis syndrome, bestosis, stargardt disease, pars plana's ciliitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, flushing, sarcoidosis, sclerosis, soriatis, psoriasis, primary sclerosing cholangitis, proctitis, primary biliary srosis, idiopathic pulmonary fibrosis, alcoholic hepatitis, endotoxemia, toxic shock syndrome, retrovirus replication, wasting, marasmus, and nephrosis, Meningitis, silica-induced fibrosis, asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, 5q syndrome, and veterinary conditions caused by feline immunodeficiency virus, equine infectious anemia virus, caprine arthritis virus, visna virus, sydisovirus, or lentivirus.
In particular embodiments of the invention, the diseases and conditions associated with undesired angiogenesis do not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, HIV, hepatitis, adult respiratory distress syndrome, bone resorption diseases, chronic obstructive pulmonary disease, chronic inflammatory pulmonary disease, dermatitis, cystic fibrosis, septic shock, septicemia, endotoxic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, fibrotic disease, cachexia, transplant rejection, rheumatoid spondylitis, osteoporosis, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus (systemic lupus erythematosus), erythema nodosum leprosum occurring in leprosy, radiation injury, Asthma, hyperoxic alveolar injury (hyperoxic alveolar injury), malaria, mycobacterial infection, and opportunistic infection by HIV.
The invention includes methods of treating patients who have been treated for cancer or diseases and conditions associated with or characterized by undesired angiogenesis but who have not responded to standard therapy, as well as those who have not previously been treated. The invention also includes methods of treating patients of any age, but some diseases or conditions are more common in certain age groups. The invention also includes methods of treating patients who have undergone surgery at the tissue level to treat a disease or condition, as well as those who have not undergone surgery. Because patients with cancer and diseases and conditions characterized by undesired angiogenesis have different clinical manifestations and multiple clinical outcomes, the treatment given to a patient may vary depending on his/her prognosis. The specific second agent, type of surgery, and type of non-drug based standard therapy that is effective for treating an individual with cancer and other diseases or conditions can be readily determined by the skilled clinician without undue experimentation.
The methods encompassed by the present invention comprise administering to a patient (e.g., a human) having or at risk of having cancer or a disease or condition mediated by undesired angiogenesis one or more immunomodulatory compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof.
In one embodiment of the invention, the immunomodulatory compounds of the invention may be administered orally in a single dose or in divided daily doses in an amount of about 0.10 to about 150 mg/day. In a specific embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione can be administered in an amount of about 0.1-1mg per day or about 0.1-5mg every other day. In a preferred embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl-piperidine-2, 6-dione) is administered in an amount of about 1-25mg per day or about 10-50mg every other day.
In a specific embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione can be administered to a patient with multiple myeloma recurrence in an amount of about 1,2, or 5mg per day. In a specific embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione can be administered initially in an amount of 1 mg/day, followed by weekly escalation of the dose to 10, 20, 25, 30, and 50 mg/day. In a specific embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione can be administered to a patient having a solid tumor in an amount of up to about 30 mg/day. In a specific embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione can be administered to a patient having a glioma in an amount of up to about 40 mg/day.
In a specific embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione can be administered to a patient suffering from a disease or condition associated with or characterized by undesired angiogenesis in an amount of about 0.1 to 1mg per day or about 0.1 to 5mg every other day, including, but not limited to, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary conditions, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, recalcitrant anemia, and 5q syndrome.
In another embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl-piperidine-2, 6-dione can be administered to a patient having a disease or condition associated with or characterized by undesired angiogenesis, including but not limited to endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary conditions, malignancy-related hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and syndrome 5q, in an amount of about 1-25mg per day or about 10-50mg every other day.
5.3.1 combination therapy with a second active agent
Particular methods of the invention comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, in combination with one or more second active agents, and/or in combination with radiation therapy, blood transfusion or surgery. Examples of immunomodulatory compounds of the invention are disclosed herein (see, e.g., section 5.1). Examples of second active agents are also disclosed herein (see, e.g., section 5.2).
Administration of the selective cytokine inhibitory drug and the second active agent to the patient can be carried out simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down prior to entering the blood vessel) and the disease being treated. A preferred route of administration of the immunomodulatory compounds of the invention is oral. Preferred routes of administration of the second active agent or component of the invention are known to those of ordinary skill in the art. See, for example, Playsitians' Desk Reference, 1755-1760 (56 th edition, 2002).
In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously in an amount of about 1-1000mg, about 5-500mg, about 10-350mg, or about 50-200mg once a day or twice a day. The specific dosage of the second active agent will depend upon the specific agent used, the type of disease being treated or managed, the severity and stage of the disease, and the amounts of the immunomodulatory compound of the invention and any optional additional active agents concurrently administered to the patient. In one embodiment, the second active agent is oblimersenGM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazineTrans retinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitors, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or combinations thereof.
In one embodiment, GM-CSF, G-CSF or EPO is administered subcutaneously for about 5 days in a4 or 6 week cycle at a dose of about 1 to 750mg/m2A preferred dosage is about 25-500 mg/m/day2More preferably, the dosage is from about 50 to about 250mg/m2The most preferred dosage is about 50-200mg/m2The day is. In certain embodiments, GM-CSF may be about 60-500mcg/m2Is administered intravenously over at least 2 hours, or at about 5-12mcg/m2The amount per day was administered subcutaneously. In one embodiment, G-CSF can be administered subcutaneously in an initial amount of about 1 mcg/kg/day, and the dose can be adjusted based on an increase in total granulocyte count. Maintenance amounts of G-CSF can be administered subcutaneously in amounts of about 300 (for smaller patients) or 480 mcg. In certain embodiments, EPO may be administered subcutaneously in an amount of 10,000 units three times a week.
In another embodiment, the selective cytokine inhibitory drug may be administered alone or in combination with a second active agent to a patient with metastatic melanoma (localized melanoma, including but not limited to ocular melanoma) in an amount of about 0.1mg to 150mg per day. In one embodiment, the dosage is from about 1 to about 25 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione and from about 200 to about 1,000mg/m2Daily dacarbazine is administered to patients with metastatic or localized melanoma. In another embodiment, a dose of about 1 to about 25 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione and temozolomide is administered to a patient with metastatic or localized melanoma. In another embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered to a metastatic or localized melanoma patient whose disease has progressed on treatment with dacarbazine, IL-2, and/or IFN in an amount of about 1-25 mg/day. In one embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is present in an amount of about 1An amount of 5 mg/day twice a day or about 30 mg/day four times a day is administered in combination with dexamethasone to patients with relapsed or refractory multiple myeloma.
In another embodiment, the immunomodulatory compound is administered in combination with melphalan and dexamethasone to a patient suffering from amyloidosis. In a specific embodiment, the immunomodulatory compounds of the invention may be administered with a steroid to a patient suffering from amyloidosis.
In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine and cisplatin to a patient with locally progressive or metastatic cell bladder cancer.
In another embodiment, the selective cytokine inhibitory drug is administered in combination with a second active ingredient which is: temozolomide administered to a patient having a recurrent or progressive brain tumor or a recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide, to a patient with recurrent or progressive CNS cancer; temodar administered to a patient with recurrent or progressive meningioma, malignant meningioma, vascular involuntary tumor, multiple brain metastases, recurrent brain tumor, or newly diagnosed glioblastoma multiforme; irinotecan for administration to patients with relapsed glioblastoma; carboplatin, administered to a brain stem glioma patient; procarbazine, administered to a patient with progressive glioblastoma; cyclophosphamide, given to patients with poor prognosis malignant brain tumors, newly diagnosed or relapsed glioblastoma multiforme;administering to a highly recurrent glioblastoma patient; temozolomide and tamoxifen administered to a patient with anaplastic astrocytoma; or topotecan, to a patient having glioma, glioblastoma, anaplastic astrocytoma, or degenerative oligodendroglioma.
In another embodiment, the immunomodulatory compound is administered in combination with methotrexate and cyclophosphamide to a patient with metastatic breast cancer.
In another embodiment, the immunomodulatory compound is administered in combination with temozolomide to a patient with a neuroendocrine tumor.
In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine to a patient with recurrent or metastatic head or neck cancer. In another embodiment, the immunomodulatory compound is administered in combination with gemcitabine to a pancreatic cancer patient.
In another embodiment, the immunomodulatory compound is a peptide of formula ITaxol and/or taxotere are administered in combination to a patient with colon cancer.
In another embodiment, the immunomodulatory compound is administered in combination with capecitabine to a refractory colorectal cancer patient or a patient who has failed the first treatment or who is poorly behaved in the treatment of colon cancer or colorectal cancer.
In another embodiment, the immunomodulatory compound is administered to patients with Duoxirane-and delta-colorectal cancer or to patients who have been treated for metastatic colorectal cancer in combination with fluorouracil, leucovorin and irinotecan.
In another embodiment, the immunomodulatory compound is administered in combination with capecitabine, hiloda, and/or CPT-11 to a refractory colorectal cancer patient.
In another embodiment, the immunomodulatory compounds of the invention are administered to refractory colorectal cancer patients or to unresectable or metastatic colorectal cancer patients in combination with capecitabine and irinotecan.
In another embodiment, an immunomodulatory compound is administered alone or in combination with interferon alpha or capecitabine to a patient with unresectable or metastatic hepatocellular carcinoma; or in combination with cisplatin and thiotepa, to patients with primary or metastatic liver cancer.
In another embodiment, the immunomodulatory compound is administered in combination with pegylated interferon alfa to a patient with kaposi's sarcoma.
In another embodiment, the immunomodulatory compound is administered in combination with fludarabine, carboplatin and/or topotecan to a patient with refractory or relapsed or high-risk acute myeloid leukemia.
In another embodiment, the immunomodulatory compound is administered to a patient with worsening karotype acute myeloblastic leukemia in combination with daunorubicin liposomes, topotecan, and/or cytarabine.
In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine and irinotecan to a non-small cell lung cancer patient. In one embodiment, the selective cytokine inhibitory drug is administered in combination with carboplatin and irinotecan to a non-small cell lung cancer patient. In one embodiment, the immunomodulatory compound is administered with docetaxel in a non-small cell lung cancer patient treated with carbon/VP 16 and radiation therapy.
In another embodiment, the immunomodulatory compound is administered in combination with carboplatin and/or taxotere or in combination with carboplatin, paclitaxel, and/or chest radiation therapy to a patient with non-small cell lung cancer. In one embodiment, the selective cytokine inhibitory drug is administered in combination with taxotere to a stage IIIB or stage IV non-small cell lung cancer patient.
In another embodiment, the immunomodulatory compounds of the invention are related to OrimersonIn combination with small cell lung cancer.
In another embodiment, the immunomodulatory compound is administered to patients with various types of lymphomas, 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-grade follicular lymphoma, either alone or in combination with a second active ingredient (e.g., vinblastine or fludarabine).
In another embodiment, the immunomodulatory compounds are administered to melanoma patients of various types and stages in combination with taxotere, IL-2, IFN, GM-CSF and/or dacarbazine.
In another embodiment, the immunomodulatory compound is administered alone or in combination with vinorelbine to a patient with malignant mesothelioma or a patient with stage IIIB non-small cell lung cancer with peritoneal implant or a patient with malignant pleural effusion mesothelioma syndrome.
In another embodiment, the immunomodulatory compound is administered to multiple myelomA patients of various types or stages in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, clarithromycin formulations, vinblastine, melphalan, busulfan, cyclophosphamide, IFN, palmidronate, prednisone, A dicarbonate compound, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or combinations thereof.
In another embodiment, the immunomodulatory compound is a compound that is conjugated to doxorubicinVincristine and/or dexamethasoneIn combination with patients with relapsed or refractory multiple myeloma.
In another embodiment, the immunomodulatory compound is administered in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, hiloda, taxol, dexamethasone, or combinations thereof, to patients with various types or stages of ovarian cancer (e.g., peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer, or recurrent ovarian cancer).
In another embodiment, the immunomodulatory compound is administered to a subject with prostate cancer of various types or stages in combination with hiloda, 5FU/LV, gemcitabine, irinotecan + gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, taxol, doxorubicin, docetaxel, estramustine, Emcyt, or combinations thereof.
In another embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered to a prostate cancer patient with taxotere.
In another embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione is administered with GM-CSF to a prostate cancer patient.
In another embodiment, the immunomodulatory compound is administered with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, or,Or combinations thereof, to patients with renal cell carcinoma of various types or stages.
In another embodiment, the immunomodulatory compound is administered in combination with an IFN, COX-2 inhibitor (e.g., IFN, COX-2 inhibitor, etc.)) And/or sulindac in combination with patients with various types or stages of gynecological cancer, uterine cancer or soft tissue sarcoma.
In another embodiment, the immunomodulatory compound is administered to a patient having a solid tumor of various types or stages in combination with celebrex, etoposide, cyclophosphamide, docetaxel, qpecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
In another embodiment, the immunomodulatory compound is administered to a patient with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apectibine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
The present invention also includes methods of increasing the dose of an anti-cancer agent or an anti-cancer agent that can be safely and effectively administered to a patient, comprising administering to the patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable derivative, salt, solvate, inclusion, hydrate or prodrug thereof. Patients that may benefit from this method are patients suffering from adverse effects associated with anticancer drugs or combinations thereof for the treatment of specific cancers of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal gland, kidney, prostate, breast, colorectal. Administration of the immunomodulatory compounds of the invention will alleviate or reduce the adverse effects of the amount of anticancer drug that is so severe that it is limited.
In one embodiment, the immunomodulatory compounds of the invention may be administered orally daily at a dose of about 0.1-150mg, preferably about 1-50mg, more preferably about 2-25mg, before, during or after the occurrence of the adverse effects associated with administration of an anti-cancer agent to a patient. In a specific embodiment, the immunomodulatory compounds of the invention are administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects associated with the anti-cancer drug, including but not limited to neutropenia or cytopenia.
In one embodiment, the immunomodulatory compounds of the invention may be administered to patients suffering from diseases and conditions associated with or characterized by undesirable angiogenesis in combination with other active ingredients including, but not limited to, anticancer agents, anti-inflammatory agents, antihistamines, antibiotics, and steroids.
In another embodiment, the invention encompasses methods of treating, preventing and/or managing cancer, which comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, in combination with (e.g., before, during or after) conventional therapy, including but not limited to surgery, immunotherapy, biologic therapy, radiation therapy or other non-pharmaceutical methods based on therapies currently used to treat, prevent or manage cancer. The combined use of the immunomodulatory compounds of the invention and conventional therapies may provide a unique treatment regimen that is exceptionally effective in certain patients. Without being bound by theory, it is believed that the immunomodulatory compounds of the invention may provide additive or synergistic effects when administered concurrently with conventional therapies.
In another embodiment, the invention encompasses methods of treating, preventing and/or managing diseases and disorders associated with or characterized by undesired angiogenesis, which comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, in combination with (e.g., before, during or after) conventional therapy, including but not limited to surgery, immunotherapy, biological therapy, radiation therapy, or other non-pharmaceutical methods based on therapies currently used to treat, prevent or manage diseases and disorders associated with or characterized by undesired angiogenesis. The combined use of the immunomodulatory compounds of the invention and conventional therapies may provide a unique treatment regimen that is exceptionally effective in certain patients. Without being bound by theory, it is believed that the immunomodulatory compounds of the invention may provide additive or synergistic effects when administered concurrently with conventional therapies.
As discussed elsewhere herein, the present invention includes a method of alleviating, treating and/or preventing adverse or undesirable effects associated with conventional therapies including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. One or more immunomodulatory compounds of the invention and other active ingredients may be administered to a patient before, during, or after adverse effects associated with conventional therapy occur.
In one embodiment, an immunomodulatory compound of the invention can be administered orally, either alone or in combination with a second active agent disclosed herein (see, e.g., section 5.2), before, during or after conventional therapy, in an amount of about 0.1-150mg, preferably about 1-25mg, more preferably about 2-10mg per day.
In a specific embodiment of this method, an immunomodulatory compound of the invention and docetaxel are administered to a non-small cell lung cancer patient that has been treated with carbon/VP 16 and radiation therapy.
5.3.2 combination with transplantation therapy
The compounds of the invention may be used to reduce the risk of Graft Versus Host Disease (GVHD). Accordingly, the present invention includes methods of treating, preventing and/or managing cancer, comprising administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, in combination with transplantation therapy.
As is well known to those of ordinary skill in the art, the treatment of cancer is often based on the stage and mechanism of the disease. For example, with the inevitable transformation of leukemia occurring at some stages of cancer, peripheral blood stem cells, hematopoietic stem cell preparations or bone marrow transplantation may be necessary. The use of the immunomodulatory compounds of the invention in combination with transplantation therapy provides a unique and unexpected synergistic effect. In particular, the immunomodulatory compounds of the invention exhibit immunomodulatory activity when used with transplantation therapy in cancer patients, which activity may provide additive or synergistic effects.
The immunomodulatory compounds of the invention can be used in combination with transplantation therapy to alleviate complications associated with invasive transplantation procedures and the risk of GVHD. The present invention includes methods of treating, preventing and/or managing cancer, comprising administering to a patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, before, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow. Examples of stem cells suitable for use in the methods of the present invention are disclosed in U.S. patent application Ser. No. 10/411,655, filed by R.Hariri et al, 4/11/2003, which is incorporated herein by reference in its entirety.
In another embodiment, the invention includes methods of treating, preventing and/or managing diseases and disorders associated with or characterized by undesired angiogenesis, comprising administering to a patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof, before, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow.
In one embodiment of the method, the immunomodulatory compounds of the invention are administered to multiple myeloma patients before, during, or after transplantation of autologous peripheral blood progenitor cells.
In another embodiment, the immunomodulatory compound is administered to a relapsed multiple myeloma patient after stem cell transplantation.
In another embodiment, the immunomodulatory compound and prednisone are administered as a maintenance therapy to multiple myeloma patients following autologous stem cell transplantation.
In another embodiment, an immunomodulatory compound and dexamethasone are administered to multiple myeloma patients as a remedial therapy to reduce the risk post-transplant.
In another embodiment, the immunomodulatory compound and dexamethasone are administered as a maintenance therapy to multiple myeloma patients following autologous bone marrow transplantation.
In another embodiment, the immunomodulatory compound is administered to a patient with chemotherapy-sensitive multiple myeloma after administration of a high dose of melphalan and autologous stem cell transplantation.
In another embodiment, the immunomodulatory compound and PEG INTRO-A are administered as A maintenance therapy to multiple myelomA patients following transplantation of autologous peripheral stem cells selected for CD 34.
In another embodiment, the immunomodulatory compound is administered with a post-transplant booster chemotherapy to newly diagnosed multiple myeloma patients to evaluate anti-angiogenesis.
In another embodiment, an immunomodulatory compound and dexamethasone are administered as maintenance therapy following high dose melphalan and peripheral blood stem cell transplantation therapy to multiple myeloma patients 65 years or older following DCEP potentiation.
5.3.3 cycling therapy
In certain embodiments, the prophylactic or therapeutic agents of the invention are cyclically administered to a patient. Cycling therapy involves the administration of the active agent for a period of time, followed by a cessation of the period of time, and repetition of this sequential administration. Cycling therapy may reduce resistance to one or more of the therapies, avoid or reduce side effects of one of the therapies, and/or improve treatment efficacy.
Thus, in a particular embodiment of the invention, the immunomodulatory compounds of the invention are administered daily in a single or separate dose over a 4-6 week cycle, with discontinuation for about 1 or 2 weeks during the cycle. The invention also allows for increasing the frequency, number and length of administration cycles. Thus, another particular embodiment of the invention comprises administering more rounds of an immunomodulatory compound of the invention, the number of rounds being higher than the typical number of rounds administered alone. In yet another specific embodiment of the invention, the immunomodulatory compounds of the invention are administered in higher rounds that would normally cause dose-limiting toxicity in patients not administered the second active ingredient.
In one embodiment, the selective cytokine inhibitory drugs of this invention are administered at a dose of about 0.1-150 mg/day for 3 or 4 consecutive weeks daily, followed by 1 or 2 weeks off. The 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione is preferably administered continuously daily and in a primary dose of 0.1-5 mg/day, with increasing doses (weekly) of 1-10 mg/day up to a maximum dose of 50 mg/day, as long as the therapy is tolerated. In a specific embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered in an amount of about 1, 5, 10, or 25 mg/day, preferably about 10 mg/day, for 3-4 weeks in a4 or 6 week cycle, followed by 1 or 2 weeks off.
In one embodiment of the invention, the selective cytokine inhibitory drug of the invention and the second active ingredient are administered orally and the selective cytokine inhibitory drug of the invention is administered 30-60 minutes before the second active ingredient in a 4-6 week cycle. In another embodiment of the invention, the combination of an immunomodulatory compound of the invention and a second active ingredient is administered by intravenous infusion over about 90 minutes per cycle. In a specific embodiment, a cycle comprises about 1-25 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione and about 50-200mg/m2The second active ingredient/day, is administered for 3-4 weeks, then discontinued for 1 or 2 weeks. In another embodiment, each cycle comprises about 5-10 mg/day of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione and about 50-200mg/m2The second active ingredient/day, is administered for 3-4 weeks, then discontinued for 1 or 2 weeks. The number of cycles of combination therapy administered to a patient is typically about 1-24 cycles, more typically about 2-16 cycles, and more typically about 4-3 cycles.
5.4 pharmaceutical compositions and dosage forms
The pharmaceutical compositions may be presented in discrete single unit dosage forms. Pharmaceutical compositions and dosage forms of the invention comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof. Pharmaceutical compositions and dosage forms of the invention may also comprise one or more excipients.
The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise the active ingredients (e.g., immunomodulatory compounds and second active agents) described herein. Examples of optional second or additional active ingredients are disclosed herein (see, e.g., section 5.2).
The single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or transmucosal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic formulations), transdermal, or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules, such as elastic soft gelatin capsules; a cachet; keeping in mouth; a lozenge; a dispersant; suppositories; a powder agent; aerosols (e.g., nasal sprays or inhalants); gelling agent; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic formulations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
The composition, shape and type of dosage form of the present invention will vary depending on its use. For example, a dosage form for the rapid treatment of a disease may contain an amount of one or more active ingredients that is greater than the amount contained in a dosage form for the slow treatment of the same disease. Similarly, a parenteral dosage form will contain less of the active ingredient or ingredients than an oral dosage form used to treat the same disease. The manner in which these particular dosage forms are contained in the present invention, as well as other manners, will be different from one another and will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th edition, MackPublishing, Easton PA (1990).
Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those of ordinary skill in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the manner in which the dosage form is administered to a patient. For example, oral dosage forms (e.g., tablets) may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may depend on the particular active ingredient in the dosage form. For example, some excipients (e.g., lactose), or when exposed to water, may accelerate the decomposition of some active ingredients. Active ingredients containing primary or secondary amines are particularly sensitive to this accelerated decomposition. Thus, the invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono-or disaccharides. The term "lactose-free" as used herein means that the amount of lactose, if any, is insufficient to substantially accelerate the rate of degradation of the active ingredient.
The lactose-free compositions of the invention may contain excipients well known in the art, listed, for example, in U.S. pharmacopeia (USP)25-NF20 (2002). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredient, binder/filler and lubricant. Preferably, the lactose-free dosage form contains the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.
The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, as water promotes the degradation of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage to determine temporal characteristics of the formulation, such as shelf life or stability. See, e.g., Jens t. carstensen, Drug Stability: principles & Practice, second edition, Marcel Dekker, NY, NY, 1995, pages 379-80. In fact, water and heat will accelerate the decomposition of some compounds. Thus, the effect of water on the formulation will be significant, as moisture and/or humidity is typically encountered during manufacture, handling, packaging, storage, shipment and use of the formulation.
The anhydrous pharmaceutical compositions and dosage forms of the present invention can be manufactured with anhydrous or low moisture content ingredients and under low humidity conditions. Pharmaceutical compositions and dosage forms containing sucrose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantially exposed to moisture and/or humidity during manufacture, packaging, and/or storage.
Anhydrous pharmaceutical compositions should be prepared and stored in a manner that maintains their anhydrous nature. Accordingly, anhydrous compositions are preferably packaged with materials known to prevent exposure to water, so that they can be packaged in suitable formulation boxes. Examples of suitable packaging include, but are not limited to, sealed films, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
The invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.
Like the amount and type of excipient, the amount of a particular active ingredient type in a dosage form may vary depending upon a variety of factors including, but not limited to, the route of administration. However, a typical dosage form of the invention contains an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in an amount of about 0.10 to about 150 mg. Typical dosage forms contain an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in an amount of about 0.1, 1,2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, or 200 mg. In one embodiment, preferred dosage forms contain 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione in an amount of about 1,2, 5, 10, 25 or 50 mg. In one embodiment, preferred dosage forms contain 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in an amount of about 5, 10, 25, or 50 mg. Typical dosage forms contain the second active ingredient in an amount of 1-1000mg, about 5-500mg, about 10-350mg, or about 50-200 mg. The particular amount of anti-cancer agent will, of course, depend upon the particular agent used, the type of cancer being treated or managed, as well as the amount of immunomodulatory compound of the invention and any optional additional active agents concurrently administered to the patient.
5.4.1 oral dosage forms
Pharmaceutical compositions of the present invention suitable for oral administration may be formulated in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and may be manufactured by pharmaceutical methods well known to those of ordinary skill in the art. See generally Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).
Typical oral dosage forms of the invention are manufactured by intimately mixing the active ingredient with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients may take a wide variety of forms depending on the form of preparation 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, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
Tablets and capsules are the most preferred oral unit dosage form for ease of dispersion, in which case solid excipients may be used. If desired, the tablets may be coated using standard aqueous or non-aqueous techniques. Such dosage forms may be manufactured by any pharmaceutical method. Generally, pharmaceutical compositions and dosage forms are prepared by intimately mixing the active ingredient with liquid carriers, finely divided solid carriers or both, and then shaping the product into the desired presentation, if necessary.
For example, tablets may be made by compression or molding. Compressed tablets may be manufactured by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients. Molded tablets may be made by molding in a suitable machine a mixture of the 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, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, those sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. One particular binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TMAnd Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler material in the pharmaceutical composition or dosage form of the present invention is generally present in an amount of about 50 to about 99 weight percent.
Disintegrants are used in the compositions of the invention to cause the tablets to disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate at a desired rate or under desired conditions. Thus, a sufficient amount of disintegrant should be neither too much nor too little, either of which would detrimentally alter the release of the active ingredient used in the solid oral dosage form of the invention. The amount of disintegrant used will vary depending on the type of formulation and can be readily determined by one of ordinary skill in the art. Typical pharmaceutical compositions contain about 0.5-15 weight percent, preferably about 1-5 weight percent, of disintegrant.
Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium carboxymethyl starch, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants useful 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, glycerol, sorbitol, mannitol, polyethylene glycol, other alcohols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, and mixtures thereof. Other lubricants include, for example, syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co., Ballmor, Maryland), a solidified aerosol of synthetic silica (sold by Degussa Co., of Prino, Tex.), CAB-O-SIL (a fumed silica product sold by Cabot Co., of Boston, Mass.), and mixtures thereof. Lubricants, if used, are generally used in amounts less than 1% by weight of the pharmaceutical composition or dosage form in which they are incorporated.
The solid oral dosage forms of the invention preferably contain an immunomodulatory compound of the invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide, and gelatin.
5.4.2 delayed Release dosage forms
The active ingredients of the present invention may be administered by controlled release devices or by delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in the following U.S. patents: no.3,845,770, 3,916,899, 3,536,809, 3,598,123, and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms may be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymers, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide a desired release profile in varying proportions. Suitable control formulations known to those of ordinary skill in the art include those described herein and may be conveniently selected for use with the active ingredients of the present invention. Thus, the present invention encompasses single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets suitable for controlled release.
A common goal of all controlled release drug products is to have their drug efficacy superior to their uncontrollable counterparts. Ideally, the use of optimally designed controlled release articles in drug therapy would allow for the cure or control of symptoms in a minimum amount of time with a minimum of drug. Advantages of controlled release formulations include increased pharmaceutical activity, decreased frequency of administration, and increased patient compliance. In addition, controlled release formulations can be used to affect the onset of action or other characteristics, such as the level of drug in the blood, and thus can affect the occurrence of side effects (e.g., adverse effects).
Most controlled release formulations are designed to initially release an amount of the drug (active ingredient) that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of the drug to maintain such therapeutic or prophylactic levels over an extended period of time. To maintain such constant drug levels in vivo, the drug must be released from the dosage form at a rate that replaces the amount of drug that is metabolized and expelled from the body. Controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.
5.4.3 parenteral dosage forms
Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since the administration of such dosage forms typically bypasses the natural defenses of the patient against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to use in the patient. Examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry products to be dissolved or suspended in a pharmaceutically acceptable carrier for injection, suspensions for injection, and emulsions.
Suitable carriers for use in the parenteral dosage forms of the invention are well known to those of ordinary skill in the art. Examples include, but are not limited to: water for injection as specified by USP; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
The compounds disclosed herein that enhance the solubility of one or more active ingredients may also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of the immunomodulatory compounds and derivatives thereof of the invention. See, for example, U.S. Pat. No.5,134,127, which is incorporated herein by reference.
5.4.4 topical and mucosal dosage forms
Topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic formulations or other forms known to those of ordinary skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th editions, MackPublishing, Easton PA (1980 and 1990); and Introduction to pharmaceutical dose Forms, 4 th edition, Lea & Febiger, Philadelphia (1985). The dosage form suitable for treating oral mucosal tissue can be made into mouthwash or oral gel.
Suitable excipients (e.g., carriers and vehicles and diluents) and other materials that can be used in the topical and mucosal dosage forms of the invention are well known to those of ordinary skill in the pharmaceutical arts and depend on the particular tissue to which the pharmaceutical composition or dosage form is to be administered. Based on this fact, typical excipients include, but are not limited to, water, propanol, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form non-toxic and pharmaceutically acceptable solutions, emulsions or gels. Wetting agents or humectants may also be added to the pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's pharmaceutical sciences, 16 th and 18 th editions, Mack Publishing, Easton PA (1980 and 1990).
The pH of the pharmaceutical composition or dosage form may be adjusted to facilitate delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength, or tonicity can be adjusted to facilitate transport. Compounds such as stearates can be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to facilitate delivery. In this regard, stearates can serve as lipid carriers for the formulation, as emulsifiers or surface active agents, and as delivery or permeation enhancers. Different salts, hydrates or solvates of the active ingredients may also be used to adjust the properties of the resulting composition.
5.4.5 kits
In general, the active ingredients of the present invention are preferably not administered to a patient at the same time or by the same route of administration. Thus, the invention includes kits, which a practitioner can simply administer to a patient appropriate amounts of the active ingredients when using such a kit.
A typical kit of the invention comprises a dosage form of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or inclusion thereof. The kits of the invention may also contain other active ingredients, such as orlimersonMelphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, tylicarbThe composition comprises Sudi, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or pharmacologically active mutant or derivative thereof or combination thereof. Examples of other active ingredients include, but are not limited to, those described herein (see, e.g., section 5.2).
The kit of the invention may also comprise a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
The kit of the invention may also comprise cells or blood for transplantation and a pharmaceutically acceptable carrier for administering one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may comprise a sealed container containing a suitable carrier in which the active ingredient is soluble to form a sterile, particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: water for injection as specified by USP; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
6. Examples of the embodiments
The following non-limiting examples illustrate some embodiments of the invention.
6.1 modulation of cytokine production
A series of non-clinical pharmacological and toxicological studies have been conducted to support clinical evaluation of immunomodulatory compounds of the invention in human subjects. Unless otherwise indicated, these studies were conducted in accordance with internationally recognized research design guidelines and were in compliance with the requirements of the drug safety testing Practice (GLP).
The inhibitory effect of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione and thalidomide on TNF-. alpha.production after LPS stimulation of human PBMC and human whole blood was investigated in vitro (Muller et al, Bioorg Med. Clzem. Lett.9: 1625-1630, 1999). IC of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione for inhibiting TNF-alpha production after LPS stimulation of PBMC and human whole blood50Values were about 24nM (6.55ng/mL) and about 25nM (6.83ng/mL), respectively. In vitro studies have shown that the pharmacological activity profile of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is similar to that of thalidomide, but at least 200-fold stronger. In vitro studies also demonstrated that 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione inhibits MM.IS and Hs Sultan cell proliferation by 50% at a concentration of 2.73-27.3ng/mL (0.01-0.1. mu.M).
IC of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for inhibiting TNF-alpha production following LPS stimulation of PBMC and human whole blood50Values were about 100nM (25.9ng/mL) and about 480nM (103.6ng/mL), respectively. In contrast, thalidomide inhibits IC production of TNF- α following LPS stimulation of PBMC50The value was about 194. mu.M (50.2. mu.g/mL). In vitro studies have shown that the pharmacological activity profile of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is similar to that of thalidomide, but is 50-2000 times stronger. It has also been shown that the compound stimulates T cell proliferation about 50-100 fold more strongly than thalidomide after initial induction by T Cell Receptor (TCR) activation. 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is also about 50-100 fold more potent than thalidomide in increasing IL-2 and IFN- γ production following TCR activation of PBMC (IL-2) or T cells (IFN- γ). Furthermore, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione showed a dose-dependent inhibition of LPS-stimulated pro-inflammatory cytokines TNF-. alpha., IL-1. beta., and IL-6 production by PBMC, but it increased the anti-inflammatory cytokine IL-10 is generated.
6.2 inhibition of MM cell proliferation
The effect of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione and thalidomide on the proliferation of MM cell lines was compared in an in vitro study. Measuring the uptake of [2 ], [ MM ] of different MM cell lines (MM.1S, Hs Sultan, U266 and RPMI-8226)3H]Thymidine acts as an indicator of cell proliferation. Cells were incubated for 48 hours in the presence of the compound; term of culture period3H]Thymidine is present for at least 8 hours. The concentrations of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione added to MM.1S and Hs Sultan cells to cause 50% inhibition of cell proliferation were 0.4 μm and 1 μm, respectively. In contrast, addition of thalidomide up to 100 μm to mm.1s and Hs Sultan cells resulted in only 15% and 20% inhibition of cell proliferation, respectively. The results are summarized in fig. 1.
6.3 toxicology Studies
The effect of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione on cardiovascular and respiratory function was studied in anesthetized dogs. Two groups of beagle dogs (2/gender/group) were used. One group received only three doses of vehicle, while the other group received three ascending doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (2, 10 and 20 mg/kg). In all cases, the doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, or vehicle, are administered continuously by jugular infusion at intervals of at least 30 minutes.
All doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione resulted in minimal cardiovascular and respiratory changes compared to the vehicle group. Statistically significant differences between the vehicle and treatment groups were only slight increases in arterial blood pressure (from 94 to 101mmHg) following administration of low doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. This effect lasted about 15 minutes and was not observed at higher doses. Deviations in thigh blood flow, respiratory parameters, and corrected Qtc intervals are common in both the control and treatment groups and are considered treatment-independent.
6.4 circulation therapy in patients
In a specific embodiment, the immunomodulatory compounds of the invention are cyclically administered to a cancer patient. Cycling therapy involves administering a first agent for a period of time, then discontinuing the administration for a period of time, and repeating this sequence of administrations. Cycling therapy may reduce resistance to one or more of the therapies, avoid or reduce side effects of one of the therapies, and/or improve treatment efficacy.
In a specific embodiment, the prophylactic or therapeutic agent is administered about once or twice daily for a cycle of about 4 to 6 weeks. A cycle may include administration of a therapeutic or prophylactic agent for 3-4 weeks, and discontinuation of the agent for at least 1 week or 2 weeks. The number of cycles employed is typically about 1 to about 24 cycles, more typically about 2 to about 16 cycles, and still more typically about 4 to about 8 cycles.
For example, in a 4-week cycle, 25 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered beginning on day 1. Compound administration was stopped on day 22 for 1 week. On day 29, 25 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione was started.
6.5 clinical study in patients
6.5.1 treatment of relapsed multiple myeloma
Administration of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione (Actimid) to patients with relapsed/refractory multiple myelomaTM). The study was performed according to the clinical trial protocol. Patients are at least 18 years old and have been diagnosed with multiple myeloma (with pathological proteins in serum and/or urine) and are considered refractory after at least two cycles of treatment, or relapse after two cycles of treatment.
Progressive disease patients were considered refractory in previous protocols according to the criteria of Southwest Oncology Group (SWOG). Recurrence after remission was defined as an increase in M component from baseline levels of more than 25%; the M lesion protein that has disappeared reappears; or an increase in the size and number of lytic bone lesions identified on the radiographs. Patients may have been previously treated with thalidomide, but they cannot tolerate this treatment. Zubrod physical status was 0-2 for all patients.
Administering to the patient 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione at a dose of 1,2, 5 or 10 mg/day for up to 4 weeks; there were 3 patients at the beginning for each dose level. Administration is performed almost simultaneously every morning; all doses were administered in the fasted state (no food or no food for at least 2 hours before and after administration). The 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione dose is administered in an ascending manner such that patients in the first group receive the lowest dose of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione (1 mg/day), ascending to the next higher dose level only when the current dose has proven safe and tolerable. If one of the three patients had dose-limiting toxicity (DLT) at any dose level, three new patients were supplemented at that dose. (ii) increasing to the next dose level if no additional three patients had developed DLT; the dose is similarly increased until the MTD is determined or the maximum daily dose (10 mg/day) is reached. However, if one of the additional three patients had a DLT, the MTD was reached. The MTD was considered to have been exceeded if two or more of the additional three patients developed DLTs, while three new patients were supplemented at this dose level to confirm the MTD. Once the MTD was confirmed, four new patients were supplemented at this dose level, so that a total of 10 patients were treated at MTD.
Blood samples were collected on days 1 and 28 for pharmacokinetic parameter analysis according to the following sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6,8, 10, 12, 18 and 24 hours post-dose. Additional blood samples were collected weekly to determine the level of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione. Whole urine was collected according to the following time periods: 0-4, 4-8, 8-12 and 12-24 hours after administration. Safety was assessed by monitoring adverse events, vital signs, ECG, clinical laboratory assessments (hematology, lymphocyte phenotype, and urinalysis), and physical examination at specific times during the study.
The results of the intermediate pharmacokinetic analysis obtained after single and multiple doses of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione are given to multiple myeloma patients in tables 1 and 2 below. These data show that 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione is stably absorbed in patients with relapsed multiple myeloma at all dose levels. The maximum plasma concentration occurs at a median number T between 2.5 and 2.8 hours after day 1 administration and 3 to 4 hours after week 4 administrationmax. At all doses, plasma concentrations reached C unimodalmaxAnd then decreases. The start of the exclusion phase occurred 3-10 hours after the administration on day 1 and week 4, respectively.
These data also show that 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione accumulates to a lesser extent (meaning C) after 4 weeks of administrationmaxAnd AUC(0-r)Are about 1.02 to 1.52 and about 0.94 to 1.62), respectively). AUC(0-r)And CmaxThe increase in value is almost proportional to the increase in dose. 5-fold higher dose of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione for CmaxIncrease was 3.2-fold and 2.2-fold on day 1 and week 4, respectively. Similarly, a 5-fold increase in dose resulted in AUC(0-r)Increase was 3.6-fold and 2.3-fold on day 1 and week 4, respectively.
TABLE 1
Actimid in relapsed multiple myeloma patientsTMPharmacokinetic parameters of
t is 24 hours, N/A is not available
TABLE 2
After multiple oral administrations (1, 2 and 5 mg/day)
Actimid in relapsed multiple myeloma patientsTMPharmacokinetic parameters
t 24 hours, N/a unusable, N3 patients
6.5.2 treatment of relapsed multiple myeloma
A biphasic 1 clinical study was conducted on 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione to determine the maximum tolerated dose in patients with refractory or relapsed multiple myeloma. These studies also determined the safety profile of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione when administered orally at elevated doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for up to 4 weeks. Patients were started with 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione treatment at 5 mg/day, then elevated to 10, 25, and 50 mg/day. Recruited patients were treated for 28 days at their prescribed dose, and prolonged treatment was selected for those patients who did not show disease progression or presented dose dependent toxicity (DLT). Patients were evaluated for adverse events at each visit and the severity of these events was graded according to the National Cancer Institute (NCI) universal toxicity criteria. Treatment is terminated if the patient develops DLT (grade 3 or higher non-hematological toxicity or grade 4 hematological toxicity).
27 patients were recruited for this study. All patients had relapsed multiple myeloma and 18 (72%) were refractory to remedial therapy. Of these patients, 15 had previously undergone autologous stem cell transplantation and 16 patients had previously received thalidomide therapy. The median number of previous treatments was 3 (range 2-6).
Blood and urine samples were collected on days 1 and 28 for analysis of pharmacokinetic parameters. Blood samples were collected according to the following sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6,8, 10, 12, 18 and 24 hours post-dose. In addition, additional blood samples were collected weekly to determine the level of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. Whole urine was collected according to the following time periods: 0-4, 4-8, 8-12 and 12-24 hours after administration. Treatment efficacy was assessed by quantifying M-protein (by immunoelectrophoresis), creatinine clearance, and 24 hour protein calculation in collected plasma and 24 hour urine, as well as screening, baseline, week 2 and 4, and monthly (or early termination). According to the optimal response criteria, if the patient's serum concentration of pathological proteins or 24-hour urinary protein secretion drops to the next lower level, bone marrow aspiration and/or tissue biopsy is also performed at months 3,6 and 12. Preliminary results for the 28-day treatment are summarized below.
Preliminary pharmacokinetic analysis based on these two studies demonstrated AUC and CmaxValues were appropriately increased with dose after single and multiple dose administration to multiple myeloma patients (as seen in healthy volunteers). In addition, a single dose AUC was compared after administration of the same dose of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione(0-∞)And multi-dose AUC(0-r)There was no evidence of accumulation of multiple doses. In analogy to the study performed in healthy volunteers, a double peak was observed. Multiple myeloma patients compared to healthy male volunteersmaxAnd AUC values were slightly higher, while the clearance of multiple myeloma patients was lower than that of healthy volunteers, consistent with their weaker renal function (both as a result of their increased age and disease). Finally, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione has a shorter half-life in patients than healthy volunteers (8 hours on average, up to 17 hours).
In this study, 3 patients in the first group were treated at 5 mg/day for 28 days for any Dose Limiting Toxicity (DLT). The second group of 3 patients then continued to be treated at 10 mg/day. Patients in the second group given 10 mg/day 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione were also well tolerated.
6.5.3 treatment of solid tumors
Studies with 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione were performed in patients with various types of solid tumors, including metastatic melanoma (13), pancreatic cancer (2), unknown primary carcinoids (1), renal cancer (1), breast cancer (1), and NSCLC (2). The patient received 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for several days at 5 mg/day, followed by increasing the dose to 10 mg/day, 25 mg/day, and 50 mg/day every 7 days for a total of 4 weeks of treatment. Patients presenting with clinical benefit are treated as indicated patients to allow continued treatment.
The study initially had 20 patients, followed by 16 additional patients at higher doses (adrenal cancer, NSCLC, malignant mesothelioma, breast cancer, metastatic melanoma (8), renal cell carcinoma (4)). These 16 additional patients were given weekly elevated doses of 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day and 150 mg/day over 6 weeks and treated for an additional 6 weeks.
The first phase of the study was designed to determine the Maximum Tolerated Dose (MTD) of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in refractory solid tumor and/or lymphoma patients, and to determine the pharmacokinetic and side-effect profile of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in these patient populations. This study design requires that there must be at least 3 patients per dose level and that the patients must complete 28 days of treatment before proceeding to the next higher dose level. Patients in the first group were dosed with 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione starting at 5 mg/day. Patients will raise doses to 10, 20, 25 and 30 mg/day, provided they are not toxic.
In this study, the MTD was defined as the highest dose of less than 2 of the 6 patients treated that did not exhibit grade 3 or higher non-hematologic toxicity or grade 4 or higher hematologic toxicity. At any given dose level in the study, if 1 of 3 patients develops toxicity, 3 additional patients must be treated with that particular dose. However, if 2 of 6 patients had a DLT, the MTD was considered to have been exceeded. No further dose escalation is required at the aforementioned dose levels and no additional patient supplementation is required. The amount of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione administered will increase until the MTD appears or the maximum daily dose is reached.
No DLT was reported in the first 20 patients participating in the study. 13 of the first 20 patients tested and 2 non-patients tested were treated as indicated patients continuing with doses up to 150 mg/day.
6.5.4 treatment of gliomas
This study was conducted to find toxicity in patients with recurrent high-grade glioma. The study was designed to administer higher doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione to patients until the Maximum Tolerated Dose (MTD) was determined. This study also attempted to obtain preliminary toxicity information and pharmacokinetic data for 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, as well as data relating to surrogate endpoints of in vivo vascular activity using functional neuroimaging studies and in vitro serum angiogenic peptide assays.
Patients in the first group received 2.5mg/m in a 4-week cycle2Dosage per day. 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered once daily for 3 weeks, followed by 1 week discontinuation, during each 4 week treatment cycle. Patients who complete one treatment cycle may receive another 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione treatment cycle if both criteria are met. First, the patient's disease must be stable or have developed partial efficacy or full efficacy, or the patient is selected from 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2,6-dione treatment is benefited by a reduction in tumor-related symptoms such as neurological deficits. Second, patients must recover from the toxicity associated with 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione that occurred in the previous 42 days of circulation or earlier (28 days of circulation + minimum 2 weeks of recovery), as a function of the level of toxicity returning to grade 1 or below. The dose should be changed in patients who had developed DLT in the previous cycle. DLT is defined as a non-hematologic toxicity event grade or a hematologic toxicity event grade 4 associated with investigational therapy of greater than or equal to 3. Patients who presented DLT in the first cycle and who failed to respond to treatment were excluded from the study.
The 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione dose was then increased to 5,8, 11, 15, and 20mg/m2Daily, up to a maximum daily dose of 40 mg. Patients continued to receive 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in 4-week cycles per dose level until one termination study criteria was reached.
Each group had three patients. If at least one person develops DLT, 3 additional patients were added to the group at that particular dose level. If 2 people develop DLT, then the MTD is considered to be exceeded (defined as the dose at which each patient at a dose level of less than 1/3 developed DLT) and 4 additional patients are treated with the previous dose.
Patients who develop DLT in the first 4-week cycle will be excluded from the study unless they respond to treatment. Patients who have completed their first 4-week cycle without DLT, but who subsequently develop grade 3 or 4 blood and/or non-hematologic toxicity, will cease treatment for at least 1 week. If toxicity returns to below grade 2 within 3 weeks, the patient is treated with a second dose level that is lower than the dose that caused the toxicity (or a 50% reduction if the patient is treated with the first or second dose level). Patients with grade 3 or 4 toxicities that did not return below grade 1 within 3 weeks or that experienced other grade 3 toxicities at the reduced dose were excluded from the study.
Pharmacokinetic sampling was performed prior to the first administration of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (day 1) and at 0.5, 1,2, 4, 6,8, 24, and 48 hours post-administration. Samples were taken both on days 7 and 21 at 0.5, 1,2, 4, 6,8, 24 and 48 hours before and after dosing to assess the steady state of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione levels.
6.5.5 treatment of metastatic melanoma
Metastatic melanoma patients were started with 5 mg/day 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for 7 days. The dose was then raised every 7 days for a total of 4 weeks of treatment to 10 mg/day, 25 mg/day and 50 mg/day, respectively. Of the 13 melanoma patients treated with this course of treatment 5 showed stable disease or partial effects within the first 4 weeks of treatment. Tumor responses were observed in skin and subcutaneous lesions (5 patients), lymph nodes (2 patients) and liver (1 patient). The reaction period is about 6 months. This indicates that the compound is promising as a new anti-cancer drug with both anti-angiogenic and immunomodulatory properties.
6.5.6 treatment of relapsed or refractory multiple myeloma
Relapsed and refractory dure-Salmon stage III multiple myeloma patients who either have failed at least three previous therapies, or who are in poor physical condition, neutropenia or cytopenia are treated with a combination of melphalan (50mg, intravenous), an immunomodulatory compound of the invention (about 1-150mg, oral daily), and dexamethasone (40 mg/day, oral 1-4 days). Maintenance therapy, including daily administration of the immunomodulatory compounds of the invention and monthly administration of dexamethasone continues until the disease progresses. Combination therapy with the immunomodulatory compounds of the invention and melphalan and dexamethasone is highly effective and generally tolerated in multiple myeloma patients with high dose pretreatment and poor prognosis.
The embodiments of the invention described above are intended to be merely exemplary, and those skilled in the art will know or be able to ascertain using no more than routine experimentation, many equivalents to the specific compounds, materials and procedures. All such equivalent variations are considered to be within the scope of the invention and are encompassed by the appended claims.
Claims (28)
- Use of unsolvated crystals of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for the preparation of a medicament for the treatment of cancer, wherein the unsolvated crystals have an X-ray powder diffraction pattern that peaks at about 8, 14.5, and 16 degrees 2 Θ.
- 2. The use of claim 1, wherein the X-ray powder diffraction pattern of the unsolvated crystalline form of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione further has peaks at about 17.5, 20.5, 24, and 26 degrees 2-theta.
- 3. The use of claim 1, wherein the differential scanning calorimetry maximum melting temperature of the unsolvated crystalline form of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is about 270 ℃.
- Use of unsolvated crystals of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for the preparation of a medicament for the treatment of cancer, wherein the unsolvated crystals have an X-ray powder diffraction pattern that peaks at about 19, 19.5, and 25 degrees 2 Θ.
- 5. The use according to claim 4, wherein the differential scanning calorimetry maximum melting temperature of the unsolvated crystalline form of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is 269 ℃.
- Use of unsolvated crystals of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for the preparation of a medicament for the treatment of cancer, wherein the unsolvated crystals have an X-ray powder diffraction pattern that peaks at about 21, 23, and 24.5 degrees 2 Θ.
- 7. The use of claims 1-6, wherein the cancer is multiple myeloma.
- 8. The use according to any one of claims 1 to 6, wherein the cancer is metastatic melanoma.
- 9. The use according to any one of claims 1 to 6, wherein the cancer is localized melanoma.
- 10. The use according to any one of claims 1 to 6, wherein the cancer is prostate cancer.
- 11. The use according to any one of claims 1 to 6, wherein the cancer is ovarian cancer.
- 12. The use according to any one of claims 1 to 6, wherein the cancer is a blood cancer.
- 13. The use according to any one of claims 1 to 6, wherein the cancer is karotype acute myeloblastic leukemia.
- 14. The use according to any one of claims 1 to 6, wherein the cancer is myeloid leukemia.
- 15. The use according to any one of claims 1 to 6, wherein the cancer is non-Hodgkin's lymphoma.
- 16. The use according to any one of claims 1 to 6, wherein the cancer is pancreatic cancer.
- 17. The use according to any one of claims 1 to 6, wherein the cancer is renal cancer.
- 18. The use according to any one of claims 1 to 6, wherein the cancer is lung cancer.
- 19. The use of any one of claims 18, wherein the lung cancer is non-small cell lung cancer.
- 20. The use according to any one of claims 1 to 6, wherein the cancer is a head cancer.
- 21. The use according to any one of claims 1 to 6, wherein the cancer is a cancer of the neck.
- 22. The use according to any one of claims 1 to 6, wherein the cancer is bladder cancer.
- 23. The use according to any one of claims 1 to 6, wherein the crystalline 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered in an amount of 0.1 to 150 mg/day.
- 24. The use according to claim 23, wherein the crystalline 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered in an amount of 1-50 mg/day.
- 25. The use according to claim 24, wherein the crystalline 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered in an amount of 1, 10, 20, 25, 30, or 50 mg/day.
- 26. The use according to claim 24, wherein the crystalline 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered in an amount of 25 mg/day.
- 27. The use according to any one of claims 1 to 6, wherein the crystalline 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered orally.
- 28. The use according to any one of claims 1 to 6, wherein the crystalline 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered in the form of a capsule or tablet.
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US10/438,213 | 2003-05-15 | ||
US10/438,213 US7968569B2 (en) | 2002-05-17 | 2003-05-15 | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US10/704,237 | 2003-11-06 |
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CN101696205B (en) | 2009-11-02 | 2011-10-19 | 南京卡文迪许生物工程技术有限公司 | 3-(substituted xylylenimine-2-yl)-2,6-dioxopiperidine polymorph and pharmaceutical composition |
CN102949722A (en) * | 2011-08-26 | 2013-03-06 | 中国医学科学院放射医学研究所 | Novel pharmaceutical composition based on p38 inhibitor and cell growth factor |
EP2841564B1 (en) * | 2012-04-24 | 2018-03-07 | Stemlab, S.A. | Composition and method of stem cells for preservervation of cardiac tissue |
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