111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`us 20040029832Al
`
`(19) United States
`(12) Patent Application Publication
`Zeldis
`
`(10) Pub. No.: US 2004/0029832 Al
`Feb. 12,2004
`(43) Pub. Date:
`
`(54) METHODS AND COMPOSITIONS USING
`IMMUNOMODULATORY COMPOUNDS FOR
`TREATMENT AND MANAGEMENT OF
`CANCERS AND OTHER DISEASES
`
`(76)
`
`Inventor:
`
`Jerome B. Zeldis, Princeton, NJ (US)
`
`Correspondence Address:
`PENNIE AND EDMONDS
`1155 AVENUE OF THE AMERICAS
`NEW YORK, NY 100362711
`
`(21)
`
`Appl. No.:
`
`10/438,213
`
`(22)
`
`Filed:
`
`May 15,2003
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/380,842, filed on May
`17, 2002. Provisional application No. 60/424,600,
`filed on Nov. 6, 2002.
`
`Publication Classification
`
`Int. CI? .................................................. A61K 31/724
`(51)
`(52) U.S. CI. ................................................................ 514/58
`
`(57)
`
`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. Spe(cid:173)
`cific methods encompass the administration of an immuno(cid:173)
`modulatory compound alone or in combination with a
`second active ingredient. The invention further relates to
`methods of reducing or avoiding adverse side effects asso(cid:173)
`ciated with chemotherapy, radiation therapy, hormonal
`therapy, biological therapy or immunotherapy which com(cid:173)
`prise the administration of an immunomodulatory com(cid:173)
`pound. Pharmaceutical compositions, single unit dosage
`forms, and kits suitable for use in methods of the invention
`are also disclosed.
`
`Apotex Ex. 1004, p. 1
`
`

`

`Patent Application Publication Feb. 12, 2004
`
`US 2004/0029832 Al
`
`'''-.-,'
`
`-...-;'
`
`.::....'
`
`. "i'.
`
`'0 \.,;,.,....;...;...;..,l,-""'....-~_;";;,,..;. _ _ _ _ ....... -
`.0 "\l,C(X)1 ~ Q.01 ;,Q.1
`,19
`100
`,.;
`ThaI'IMIDs,(JJM)
`.. ~.:- , .
`
`- ~-
`
`'
`
`,0 , ,o:ci:lo1 (1.0010;0'1 '0.,
`,
`, rh::tJ 1I~0s wM) •..
`
`1
`
`10
`
`1Q)
`
`Apotex Ex. 1004, p. 2
`
`

`

`US 2004/0029832 A1
`
`Feb. 12,2004
`
`1
`
`METHODS AND COMPOSITIONS USING
`IMMUNOMODULATORY COMPOUNDS FOR
`TREATMENT AND MANAGEMENT OF CANCERS
`AND OTHER DISEASES
`
`[0001] This application claims the benefit of U.S. provi(cid:173)
`sional application No. 60/380,842, filed May 17, 2002, and
`No. 60/424,600, filed Nov. 6, 2002, the entireties of which
`are incorporated herein by reference.
`
`1. Field of the Invention
`
`[0002] This invention relates to methods of treating, pre(cid:173)
`venting and/or managing specific cancers, and other diseases
`including, but not limited to, those associated with, or
`characterized by, undesired angiogenesis, by the adminis(cid:173)
`tration of one or more immunomodulatory compounds alone
`or in combination with other therapeutics. In particular, the
`invention encompasses the use of specific combinations, or
`"cocktails," of drugs and other therapy, e.g., radiation to
`treat these specific cancers, including those refractory to
`conventional therapy. The invention also relates to pharma(cid:173)
`ceutical compositions and dosing regimens.
`
`2. BACKGROUND OF THE INVENTION
`
`[0003] 2.1 Pathobiology of Cancer and Other Diseases
`
`[0004] Cancer is characterized primarily by an increase in
`the number of abnormal cells derived from a given normal
`tissue, invasion of adjacent tissues by these abnormal cells,
`or lymphatic or blood-borne spread of malignant cells to
`regional lymph nodes and to distant sites (metastasis).
`Clinical data and molecular biologic studies indicate that
`cancer is a multistep process that begins with minor pre(cid:173)
`neoplastic changes, which may under certain conditions
`progress to neoplasia. The neoplastic lesion may evolve
`clonally and develop an increasing capacity for invasion,
`growth, metastasis, and heterogeneity, especially under con(cid:173)
`ditions in which the neoplastic cells escape the host's
`immune surveillance. Roitt, I., Brostoff, J and Kale, D.,
`Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo.,
`1993).
`
`[0005] There is an enormous variety of cancers which are
`described in detail in the medical literature. Examples
`includes cancer of the lung, colon, rectum, prostate, breast,
`brain, and intestine. The incidence of cancer continues to
`climb as the general population ages, as new cancers
`develop, and as susceptible populations (e.g., people
`infected with AIDS or excessively exposed to sunlight)
`grow. A tremendous demand therefore exists for new meth(cid:173)
`ods and compositions that can be used to treat patients with
`cancer.
`
`[0006] Many types of cancers are associated with new
`blood vessel formation, a process known as angiogenesis.
`Several of the mechanisms involved in tumor-induced
`angiogenesis have been elucidated. The most direct of these
`mechanisms is the secretion by the tumor cells of cytokines
`with angiogenic properties. Examples of these cytokines
`include acidic and basic fibroblastic growth factor (a,b(cid:173)
`FGF), angiogenin, vascular endothelial growth factor
`(VEGF), and TNF-a. Alternatively, tumor cells can release
`angiogenic pep tides through the production of proteases and
`the subsequent breakdown of the extracellular matrix where
`some cytokines are stored (e.g., b-FGF). Angiogenesis can
`
`also be induced indirectly through the recruitment of inflam(cid:173)
`matory cells (particularly macrophages) and their subse(cid:173)
`quent release of angiogenic cytokines (e.g., TNF-a, bFGF).
`
`[0007] A variety of other diseases and disorders are also
`associated with, or characterized by, undesired angiogenesis.
`For example, enhanced or unregulated angiogenesis has
`been implicated in a number of diseases and medical con(cid:173)
`ditions including, but not limited to, ocular neovascular
`diseases, choroidal neovascular diseases, retina neovascular
`diseases, rubeosis (neovascularization of the angle), viral
`diseases, genetic diseases, inflammatory diseases, allergic
`diseases, and autoimmune diseases. Examples of such dis(cid:173)
`eases and conditions include, but are not limited to: diabetic
`retinopathy; retinopathy of prematurity; corneal graft rejec(cid:173)
`tion; neovascular glaucoma; retrolental fibroplasia; and pro(cid:173)
`liferative vitreoretinopathy.
`
`[0008] Accordingly, compounds that can control angio(cid:173)
`genesis or inhibit the production of certain cytokines,
`including TNF-a, may be useful in the treatment and pre(cid:173)
`vention of various diseases and conditions.
`
`[0009] 2.2 Methods of Treating Cancer
`
`[0010] Current cancer therapy may involve surgery, che(cid:173)
`motherapy, hormonal therapy and/or radiation treatment to
`eradicate neoplastic cells in a patient (see, for example,
`Stockdale, 1998, Medicine, vol. 3, Rubenstein and Feder(cid:173)
`man, eds., Chapter 12, Section IV). Recently, cancer therapy
`could also involve biological therapy or immunotherapy. All
`of these approaches pose significant drawbacks for the
`patient. Surgery, for example, may be contraindicated due to
`the health of a patient or may be unacceptable to the patient.
`Additionally, surgery may not completely remove neoplastic
`tissue. Radiation therapy is only effective when the neoplas(cid:173)
`tic tissue exhibits a higher sensitivity to radiation than
`normal tissue. Radiation therapy can also often elicit serious
`side effects. Hormonal therapy is rarely given as a single
`agent. Although hormonal therapy can be effective, it is
`often used to prevent or delay recurrence of cancer after
`other treatments have removed the majority of cancer cells.
`Biological therapies and immunotherapies are limited in
`number and may produce side effects such as rashes or
`swellings, flu-like symptoms, including fever, chills and
`fatigue, digestive tract problems or allergic reactions.
`
`[0011] With respect to chemotherapy, there are a variety of
`chemotherapeutic agents available for treatment of cancer. A
`majority of cancer chemotherapeutics act by inhibiting DNA
`synthesis, either directly, or indirectly by inhibiting the
`biosynthesis of deoxyribonucleotide triphosphate precur(cid:173)
`sors, to prevent DNA replication and concomitant cell
`division. Gilman et aI., Goodman and Gilman's: The
`Pharmacological Basis of Therapeutics, Tenth Ed.
`(McGraw Hill, New York).
`
`[0012] Despite availability of a variety of chemotherapeu(cid:173)
`tic agents, chemotherapy has many drawbacks. Stockdale,
`Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12,
`sect. 10, 1998. Almost all chemotherapeutic agents are toxic,
`and chemotherapy causes significant, and often dangerous
`side effects including severe nausea, bone marrow depres(cid:173)
`sion, and immunosuppression. Additionally, even with
`administration of combinations of chemotherapeutic agents,
`many tumor cells are resistant or develop resistance to the
`chemotherapeutic agents. In fact, those cells resistant to the
`
`Apotex Ex. 1004, p. 3
`
`

`

`US 2004/0029832 A1
`
`Feb. 12,2004
`
`2
`
`particular chemotherapeutic agents used in the treatment
`protocol often prove to be resistant to other drugs, even if
`those agents act by different mechanism from those of the
`drugs used in the specific treatment. This phenomenon is
`referred to as pleiotropic drug or multidrug resistance.
`Because of the drug resistance, many cancers prove refrac(cid:173)
`tory to standard chemotherapeutic treatment protocols.
`
`[0013] Other diseases or conditions associated with, or
`characterized by, undesired angiogenesis are also difficult to
`treat. However, some compounds such as protamine, hepain
`and steroids have been proposed to be useful in the treatment
`of certain specific diseases. Taylor et aI., Nature 297:307
`(1982); Folkman et aI., Science 221:719 (1983); and U.S.
`Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain
`derivatives of it 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.
`
`[0014] Still, there is a significant need for safe and effec(cid:173)
`tive methods of treating, preventing and managing cancer
`and other diseases and conditions, particularly for diseases
`that are refractory to standard treatments, such as surgery,
`radiation therapy, chemotherapy and hormonal therapy,
`while reducing or avoiding the toxicities and/or side effects
`associated with the conventional therapies.
`
`[0015] 2.3IMIDSTM
`
`[0016] A number of studies have been conducted with the
`aim of providing compounds that can safely and effectively
`be used to treat diseases associated with abnormal produc(cid:173)
`tion of TNF-a See, e.g., Marriott, J. B., et aI., Expert Opin.
`Bioi. Ther. 1(4):1-8 (2001); G. W. Muller, et aI., Journal of
`Medicinal Chemistry 39(17): 3238-3240 (1996); and G. W.
`Muller, et aI, Bioorganic & Medicinal Chemistry Letters 8:
`2669-2674 (1998). Some studies have focused on a group of
`compounds selected for their capacity to potently inhibit
`TNF-a production by LPS stimulated PBMe. L. G. Corral,
`et aI., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999).
`These compounds, which are referred to as IMiDSTM (Cel(cid:173)
`gene Corporation) or Immunomodulatory Drugs, show not
`only potent inhibition of TNF-a but also marked inhibition
`of LPS induced monocyte IL1~ and IL12 production. LPS
`induced IL6 is also inhibited by immunomodulatory com(cid:173)
`pounds, albeit partially. These compounds are potent stimu(cid:173)
`lators of LPS induced ILlO. Id. Particular examples of
`IMiD™s include, but are not limited to, the substituted
`2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted
`2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described
`in
`U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G. W.
`Muller, et ai.
`
`3. SUMMARY OF THE INVENTION
`
`[0017] This invention encompasses methods of treating
`and preventing certain types of cancer, including primary
`and metastatic cancer, as well as cancers that are refractory
`or resistant to conventional chemotherapy. The methods
`comprise administering to a patient in need of such treat(cid:173)
`ment or prevention a therapeutically or prophylactically
`effective amount of an immunomodulatory compound, or a
`pharmaceutically acceptable salt, solvate, hydrate, stereoi(cid:173)
`somer, clathrate, or prodrug thereof. The invention also
`encompasses methods of managing certain cancers (e.g.,
`preventing or prolonging their recurrence, or lengthening the
`time of remission) which comprise administering to a patient
`
`in need of such management a prophylactically effective
`amount of an immunomodulatory compound of the inven(cid:173)
`tion, or a pharmaceutically acceptable salt, solvate, hydrate,
`stereoisomer, clathrate, or prodrug thereof.
`
`In particular methods of the invention, an immu(cid:173)
`[0018]
`nomodulatory compound is administered in combination
`with a therapy 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.
`
`[0019] This invention also encompasses methods of treat(cid:173)
`ing, 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, clathrate, or
`prodrug thereof.
`
`In other methods of the invention, an immuno(cid:173)
`[0020]
`modulatory compound is administered in combination with
`a therapy conventionally used to treat, prevent or manage
`diseases or disorders associated with, or characterized by,
`undesired angiogenesis. Examples of such conventional
`therapies include, but are not limited to, surgery, chemo(cid:173)
`therapy, radiation therapy, hormonal therapy, biological
`therapy and immunotherapy.
`
`[0021] This invention encompasses pharmaceutical com(cid:173)
`positions, single unit dosage forms, dosing regimens and kits
`which comprise an immunomodulatory compound, or a
`pharmaceutically acceptable salt, solvate, hydrate, stereoi(cid:173)
`somer, clathrate, or prodrug thereof, and a second, or addi(cid:173)
`tional, active agent. Second active agents include specific
`combinations, or "cocktails," of drugs.
`
`4. BRIEF DESCRIPTION OF FIGURE
`
`[0022] FIG. 1 shows a comparison of the effects of
`3-( 4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,
`6-dione (Revimid™) and thalidomide in inhibiting the pro(cid:173)
`liferation of multiple myeloma (MM) cell lines in an in vitro
`study. The uptake of [3H]-thymidine by different MM cell
`lines (MM. IS, Hs Sultan, U266 and RPMI-8226) was
`measured as an indicator of the cell proliferation.
`
`5. DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0023] A first embodiment of the invention encompasses
`methods of treating, managing, or preventing cancer which
`comprises administering to a patient in need of such treat(cid:173)
`ment or prevention a therapeutically or prophylactically
`effective amount of an immunomodulatory compound of the
`invention, or a pharmaceutically acceptable salt, solvate,
`hydrate, stereoisomer, clathrate, or prodrug thereof.
`
`In particular methods encompassed by
`[0024]
`this
`embodiment, the immunomodulatory compound is admin(cid:173)
`istered in combination with another drug ("second active
`agent") or method of treating, managing, or preventing
`cancer. Second active agents include small molecules and
`large molecules (e.g., proteins and antibodies), examples of
`which are provided herein, as well as stem cells. Methods,
`
`Apotex Ex. 1004, p. 4
`
`

`

`US 2004/0029832 A1
`
`Feb. 12,2004
`
`3
`
`or therapies, that can be used in combination with the
`the
`immunomodulatory compound
`administration of
`include, but are not limited to, surgery, blood transfusions,
`immunotherapy, biological therapy, radiation therapy, and
`other non-drug based therapies presently used to treat,
`prevent or manage cancer.
`
`[0025] Another embodiment of the invention encompasses
`methods of treating, managing or preventing diseases and
`disorders other than cancer that are characterized by undes(cid:173)
`ired angiogenesis. These methods comprise the administra(cid:173)
`tion of a therapeutically or prophylactically effective amount
`of an immunomodulatory compound, or a pharmaceutically
`acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
`prodrug thereof.
`
`[0026] Examples of diseases and disorders 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, retina neovascular diseases, and
`rubeosis (neovascularization of the angle).
`
`In particular methods encompassed by
`[0027]
`this
`embodiment, the immunomodulatory compound is admin(cid:173)
`ister in combination with a second active agent or method of
`treating, managing, or preventing the disease or condition.
`Second active agents include small molecules and large
`molecules (e.g., proteins and antibodies), examples of which
`are provided herein, as well as stem cells. Methods, or
`therapies, that can be used in combination with the admin(cid:173)
`istration of the immunomodulatory compound include, but
`are not limited to, surgery, blood transfusions, immuno(cid:173)
`therapy, biological therapy, radiation therapy, and other
`non-drug based therapies presently used to treat, prevent or
`manage disease and conditions associated with, or charac(cid:173)
`terized by, undesired angiogenesis.
`
`[0028] The invention also encompasses pharmaceutical
`compositions (e.g., single unit dosage forms) that can be
`used in methods disclosed herein. Particular pharmaceutical
`compositions comprise an immunomodulatory compound of
`the invention, or a pharmaceutically acceptable salt, solvate,
`hydrate, stereoisomer, clathrate, or prodrug thereof, and a
`second active agent.
`
`[0029] 5.1 Immunomodulatory Compounds
`
`[0030] Compounds used in the invention include immu(cid:173)
`no modulatory compounds that are racemic, stereomerically
`enriched or stereomerically pure, and pharmaceutically
`acceptable salts, solvates, hydrates, stereoisomers, clath(cid:173)
`rates, and prodrugs thereof. Preferred compounds used in the
`invention are small organic molecules having a molecular
`weight less than about 1,000 g/mol, and are not proteins,
`pep tides, oligonucleotides, oligosaccharides or other mac(cid:173)
`romolecules.
`
`[0031] As used herein and unless otherwise indicated, the
`terms "immunomodulatory compounds" and "IMiDsTM"
`(Celgene Corporation) encompasses small organic mol(cid:173)
`ecules that markedly inhibit TNF-a, LPS induced monocyte
`
`IL1~ and IL12, and partially inhibit IL6 production. Specific
`immunomodulatory compounds are discussed below.
`
`[0032] TNF-a is an inflammatory cytokine produced by
`macrophages and monocytes during acute inflammation.
`TNF-a is responsible for a diverse range of signaling events
`within cells. TNF-a may playa pathological role in cancer.
`Without being limited by theory, one of the biological effects
`exerted by the immunomodulatory compounds of the inven(cid:173)
`tion is the reduction of synthesis of TNF-a. Immunomodu(cid:173)
`latory compounds of the invention enhance the degradation
`of TNF-amRNA.
`
`[0033] Further, without being limited by theory, immuno(cid:173)
`modulatory compounds used in the invention may also be
`potent co-stimulators of T cells and increase cell prolifera(cid:173)
`tion dramatically in a dose dependent manner. Immuno(cid:173)
`modulatory compounds of the invention may also have a
`greater co-stimulatory effect on the CD8+ T cell subset than
`on the CD4+ T cell subset. In addition, the compounds
`preferably have anti-inflammatory properties, and efficiently
`co-stimulate T cells.
`
`[0034] Specific examples of immunomodulatory com(cid:173)
`pounds of the invention, include, but are not limited to,
`cyano and carboxy derivatives of substituted styrenes such
`as those disclosed in U.S. Pat. No. 5,929,117; 1-oxo-2-(2,
`6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-
`2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as
`those described in U.S. Pat. No. 5,874,448; the tetra substi(cid:173)
`tuted
`2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines
`described in U.S. Pat. No. 5,798,368; l-oxo and 1,3-dioxo-
`2-(2,6-dioxopiperidin-3-yl)
`isoindolines
`(e.g., 4-methyl
`derivatives of thalidomide and EM-12), including, but not
`limited to, those disclosed in U.S. Pat. No. 5,635,517; and a
`class of non-polypeptide cyclic amides disclosed in U.S. Pat.
`Nos. 5,698,579 and 5,877,200; analogs and derivatives of
`thalidomide, including hydrolysis products, metabolites,
`derivatives and precursors of thalidomide, such as those
`described in U.S. Pat. Nos. 5,593,990, 5,629,327, and 6,071,
`948 to D' Amato; aminothalidomide, as well as analogs,
`hydrolysis products, metabolites, derivatives and precursors
`of aminothalidomide, and substituted 2-(2,6-dioxopiperidin-
`3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-
`yl)-l-oxoisoindoles such as those described in U.S. Pat. Nos.
`6,281,230 and 6,316,471; isoindole-imide compounds such
`as those described in U.S. patent application Ser. No.
`09/972,487 filed on Oct. 5,2001, U.S. patent application Ser.
`No. 10/032,286 filed on Dec. 21, 2001, and International
`Application No. PCT/USOl/50401 (International Publica(cid:173)
`tion No. WO 02/059106). The entireties of each of the
`patents and patent applications identified herein are incor(cid:173)
`porated herein by reference. Immunomodulatory com(cid:173)
`pounds of the invention do not include thalidomide.
`
`[0035] Other specific immunomodulatory compounds of
`the invention include, but are not limited to, l-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 the structure I:
`
`Apotex Ex. 1004, p. 5
`
`

`

`US 2004/0029832 A1
`
`Feb. 12,2004
`
`4
`
`-continued
`o
`\
`I
`N
`~ l
`
`H2
`
`NH2
`
`C;XM;:XIO
`
`/H
`N
`
`0
`
`in which one of X and Y is C=O, the other of X
`[0036]
`and Y is c=o or CH2, and R2 is hydrogen or lower alkyl,
`in particular methyl. Specific immunomodulatory com(cid:173)
`pounds include, but are not limited to:
`
`l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-ami(cid:173)
`[0037]
`noisoindoline;
`
`l-oxo-2-(2,6-dioxopiperidin-3-yl)-5-ami(cid:173)
`[0038]
`noisoindoline;
`
`l-oxo-2-(2,6-dioxopiperidin-3-yl)-6-ami(cid:173)
`[0039]
`noisoindoline;
`
`l-oxo-2-(2,6-dioxopiperidin-3-yl)-7-ami(cid:173)
`[0040]
`noisoindoline;
`
`[0041] 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-ami(cid:173)
`noisoindoline; and
`
`[0042] 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-ami(cid:173)
`noisoindoline.
`
`[0043] Other specific immunomodulatory compounds of
`the invention belong to a class of substituted 2-(2,6-diox(cid:173)
`opiperidin-3-yl) phthalimides and substituted 2-(2,6-diox(cid:173)
`opiperidin-3-yl)-I-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 No. PCT/US97/
`13375 (International Publication No. WO 98/03502), each
`of which is incorporated herein by reference. Compounds
`representative of this class are of the formulas:
`
`[0044] wherein Rl is hydrogen or methyl. In a separate
`embodiment, the invention encompasses the use of enantio(cid:173)
`merically pure forms (e.g. optically pure (R) or (S) enanti(cid:173)
`omers) of these compounds.
`
`[0045] Still other specific immunomodulatory compounds
`of the invention belong to a class of isoindole-imides
`disclosed in U.S. patent application Ser. Nos. 10/032,286
`and 09/972,487, and International Application No. PCT/
`USOl/50401
`(International
`Publication No. WO
`02/059106), each of which are incorporated herein by ref(cid:173)
`erence. Representative compounds are of formula II:
`
`II
`
`salts,
`acceptable
`pharmaceutically
`[0046] and
`hydrates, solvates, clathrates, enantiomers, diastere(cid:173)
`omers, racemates, and mixtures of stereo isomers
`thereof, wherein:
`
`2
`
`[0047] one of X and Y is c=o and the other is
`orC=O;
`CH
`[0048] Rl is H, (C1-Cg)alkyl, (C3-C7)cycloalkyl,
`(C2-Cg)alkenyl, (C2-Cg)alkynyl, benzyl, aryl, (Co-
`C4)alkyl-(C1 -C6)heterocycloalkyl, (Co-C4)alkyl(cid:173)
`(C2-Cs)heteroaryl, C(O)R3, C(S)R3, C(O)OR4,
`(C1 -Cg)alkyl-N(R6)2'
`(C1-Cg)alkyl-ORS,
`(C1 -
`Cg)alkyl-C(O)ORS, C(O)NHR3, C(S)NHR3,
`C(O)NR3R3', C(S)NR3R3' or
`(C1-Cg)alkyl(cid:173)
`O(CO)RS;
`[0049] R2 is H, F, benzyl, (C1 -Cg)alkyl, (C2-
`Cg)alkenyl, or (C2-Cg)alkynyl;
`[0050] R3 and R3' are independently (C1-Cg)alkyl,
`(C2-Cg)alkenyl,
`(C2-
`(C3-C7)cycloalkyl,
`Cg)alkynyl,
`benzyl,
`aryl,
`(Co-C4)alkyl(C1 -
`C6)heterocycloalkyl,
`(Co-C4)alkyl-(C2-
`(Co-Cg)alkyl-N(R 6)2'
`(C1 -
`Cs)heteroaryl,
`Cg)alkyl-ORS,
`(C-Cg)alkyl-C(O)ORS,
`(C1 -
`Cg)alkyl-O(CO)Rs, or C(O)ORs;
`[0051] R4 is (C1-Cg)alkyl, (C2-Cg)alkenyl, (C2-
`Cg)alkynyl, (C1 -C4)alkyl-ORS, benzyl, aryl, (Co-
`C4)alkyl-(C1 -C6)heterocycloalkyl,
`or
`(Co-
`C4)alkyl-(C2-Cs)heteroaryl;
`
`Apotex Ex. 1004, p. 6
`
`

`

`US 2004/0029832 A1
`
`Feb. 12,2004
`
`5
`
`[0052] RS is (C1-Cg)alkyl, (C2-Cg)alkenyl, (C2-
`Cg)alkynyl, benzyl, aryl, or (C2-Cs)heteroaryl;
`[0053] each occurrence of R6 is independently H,
`(C1-Cg)alkyl,
`(C2-Cg)alkenyl,
`(C2-Cg)alkynyl,
`benzyl, aryl, (C2-Cs)heteroaryl, or (CO-Cg)alkyl(cid:173)
`C(O)O-Rs or the R6 groups can join to form a
`heterocycloalkyl group;
`
`[0054] n is 0 or 1; and
`[0055] * represents a chiral-carbon center.
`
`In specific compounds of formula II, when n is 0
`[0056]
`then Rl
`is
`(C3-C7)cycloalkyl,
`(C2-Cg)alkenyl,
`(C2-
`Cg)alkynyl,
`benzyl,
`aryl,
`(Co-C4)alkyl-(C1-
`C6)heterocycloalky 1,
`(Co-C 4)alky 1-( C2 -Cs)heteroary 1,
`C(0)R3, C(0)OR4, (C1-Cg)alkyl-N(R6)2'
`(C1-Cg)alkyl(cid:173)
`ORs, (C1-Cg)alkyl-C(0)ORs, C(S)NHR3, or (C1-Cg)alkyl
`O(CO)Rs;
`
`[0057] R2 is H or (C1-Cg)alkyl; and
`[0058] R3 is (C1-Cg)alkyl, (C3-C7)cycloalkyl, (C2-
`Cg)alkenyl,
`(C2-Cg)alkynyl, benzyl, aryl,
`(Co-
`C 4)alky 1-( C1 -C6)heterocycloalky 1,
`(Co -C 4)alkyl(cid:173)
`(C2-Cs)heteroaryl,
`(Cs-Cg)alkyl-N(R6)2;
`(Co-
`Cg)alkyl-NH-C(O)O-RS; (C1-Cg)alkyl-ORS, (C1-
`Cg)alkyl-C(O)ORs,
`or
`(C1-Cg)alkyl-0(CO)Rs,
`C(O)ORS; and the other variables have the same
`definitions.
`
`In other specific compounds of formula II, R2 is H
`[0059]
`or (C1-C4)alkyl.
`In other specific compounds of formula II, Rl is
`[0060]
`(C1-Cg)alkyl or benzyl.
`In other specific compounds of formula II, R 1 is H,
`[0061]
`(C1-Cg)alkyl, benzyl, CH20CH3, CH2CH20CH3, or
`
`In another embodiment of the compounds of for(cid:173)
`[0062]
`mula II, R 1 is
`
`[0063] wherein Q is 0 or S, and each occurrence of R7 is
`independently H, (C1-Cg)alkyl, benzyl, CH20CH3, or
`CH2CH20CH3·
`In other specific compounds of formula II, Rl is
`[0064]
`C(0)R3.
`
`In other specific compounds of formula II, R3 is
`[0065]
`(Co-C4)alkyl-(C2-Cs)heteroaryl, (C1-Cs)alkyl, aryl, or (Co-
`C4)alkyl-ORs.
`[0066]
`In other specific compounds of formula II, het(cid:173)
`eroaryl is pyridyl, furyl, or thienyl.
`In other specific compounds of formula II, R 1 is
`[0067]
`C(0)OR4.
`
`In other specific compounds of formula II, the H of
`[0068]
`C(O)NHC(O) can be replaced with (C1-C4)alkyl, aryl, or
`benzyl.
`
`[0069] Still other specific immunomodulatory compounds
`of the invention belong to a class of isoindole-imides
`disclosed in U.S. patent application Ser. No. 091781,179,
`International Publication No. WO 98/54170, and U.S. Pat.
`No. 6,395,754, each of which are incorporated herein by
`reference. Representative compounds are of formula III:
`
`III
`
`[0070] and pharmaceutically acceptable salts, hydrates,
`solvates, clathrates, enantiomers, diastereomers, race mates,
`and mixtures of stereo isomers thereof, wherein:
`[0071] one of X and Y is c=o and the other is CH2
`or C=O;
`[0072] R is H or CH20COR';
`(i) each of Rl, R2, R3, or R4, independently of
`[0073]
`the others, is halo, alkyl of 1 to 4 carbon atoms, or
`alkoxy of 1 to 4 carbon atoms or (ii) one of R\ R2,
`R3, or R4 is nitro or -NHRs and the remaining of
`Rl, R2, R3, or R4 are hydrogen;
`[0074] RS is hydrogen or alkyl of 1 to 8 carbons
`[0075] R 6 hydrogen, alkyl of 1 to 8 carbon atoms,
`benzo, chloro, or fiuoro;
`[0076] R' is R7-CHR10-N(RgR9);
`
`is m-phenylene or p-phenylene or
`[0077] R7
`-(Cn H2n)- in which n has a value of 0 to 4;
`g
`[0078] each of R
`and R9 taken independently of the
`other is hydrogen or alkyl of 1 to 8 carbon atoms, or
`g
`R
`and R9 taken together are tetramethylene, pen(cid:173)
`tamethylene, hexamethylene, or -CH2CH2[X]
`in which [X]Xl is -0-, -S-, or
`Xl CH2CH2-
`-NH-;
`
`[0079] R 10 is hydrogen, alkyl of to 8 carbon atoms, or
`phenyl; and
`[0080] * represents a chiral-carbon center.
`[0081] The most preferred
`immunomodulatory com(cid:173)
`pounds of the invention are 4-( amino )-2-(2,6-dioxo(3-pip(cid:173)
`eridyl))-isoindoline-l,3-dione and 3-( 4-amino-l-oxo-l,3-di-
`
`Apotex Ex. 1004, p. 7
`
`

`

`US 2004/0029832 A1
`
`Feb. 12,2004
`
`6
`
`hydro-isoindol-2-yl)-piperidine-2,6-dione. The compounds
`can be obtained via standard, synthetic methods (see e.g.,
`U.S. Pat. No. 5,635,517, incorporated herein by reference).
`The compounds are available from Celgene Corporation,
`Warren, N.J. 4-(Amino )-2-(2,6-dioxo(3-piperidyl))-isoindo(cid:173)
`line-1,3-dione (ACTIMIDTM) has the following chemical
`structure:
`
`[0082] The compound 3-( 4-amino-1-oxo-1,3-dihydro(cid:173)
`isoindol-2-yl)-piperidine-2,6-dione (REVIMIDTM) has the
`following chemical structure:
`
`[0083] Compounds of the invention can either be com(cid:173)
`mercially purchased or prepared according to the methods
`described in the patents or patent publications disclosed
`herein. Further, optically pure compounds can be asym(cid:173)
`metrically synthesized or resolved using known resolving
`agents or chiral columns as well as other standard synthetic
`organic chemistry techniques.
`[0084] As used herein and unless otherwise indicated, the
`term "pharmaceutically acceptable salt" encompasses non(cid:173)
`toxic acid and base addition salts of the compound to which
`the term refers. Acceptable non-toxic acid addition salts
`include those derived from organic and inorganic acids or
`bases know in the art, which include, for example, hydro(cid:173)
`chloric acid, hydrobromic acid, phosphoric acid, sulfuric
`acid, methanesulphonic acid, acetic acid, tartaric acid, lactic
`acid, succinic acid, citric acid, malic acid, maleic acid,
`sorbic acid, aconitic acid, salicylic acid, phthalic acid,
`embolic acid, enanthic acid, and the like.
`[0085] Compounds that are acidic in nature are capable of
`forming salts with various pharmaceutically acceptable
`bases. The bases that can be used to prepare pharmaceuti(cid:173)
`cally acceptable base addition salts of such acidic com(cid:173)
`pounds are those that form non-toxic base addition salts, i.e.,
`salts containing pharmacologically acceptable cations such
`as, but not limited to, alkali metal or alkaline earth metal
`salts and the calcium, magnesium, sodium or potassium salts
`in particular. Suitable organic bases include, but are not
`limited to, N,N-dibenzylethylenediamine, chloroprocaine,
`choline, diethanolamine, ethylenediamine, meglumaine
`(N-methylglucamine), lysine, and procaine.
`[0086] As used herein and unless otherwise indicated, the
`term "prodrug" means a derivative of a compound that can
`
`hydrolyze, oxidize, or otherwise react under biological con(cid:173)
`ditions (in vitro or in vivo) to provide the compound.
`Examples of prodrugs include, but are not limited to, deriva(cid:173)
`tives of immunomodulatory compounds of the invention
`that comprise biohydrolyzable moieties such as biohydro(cid:173)
`lyzable amides, biohydrolyzable esters, biohydrolyzable
`carbamates, biohydrolyzable carbonates, biohydrolyzable
`ureides, and biohydrolyzable phosphate analogues. Other
`examples of prodrugs include derivatives of immunomodu(cid:173)
`latory compounds of the invention that comprise -NO,
`-N02 , -ONO, or -ON0 2 moieties. Prodrugs can typi(cid:173)
`cally be prepared using well-known methods, such as those
`described in 1 Burger's Medicinal Chemistry and Drug
`Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.
`1995), and Design of Prod rugs (H. Bundgaard ed., Elselvier,
`New York 1985).
`
`[0087] As used herein and unless otherwise indic