CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`7. APPLICATION NUMBER:
`21-880
`
`ADMINISTRATIVE
`
`DO CUMENTS/CORRESPONDENCE
`
`

`

` Form Apprdved: OMB No. 0910-0513
`Department of Health and Human Services
`
`Expiration Date: 7i31I06
`Food and Drug Administration
`
`See OMB Statement on Page 3.
`
`
`
`NDA NUMBER ’
`
`21-880
`
`
`NAME OF APPLICANT] NDA HOLDER
`
`Celgene Corporation
`
`
`
`
`
`
`PATENT INFORMATION SUBMITTED WITH THE
`
`FILING OF AN NDA, AMENDMENT, OR SUPPLEMENT
`For Each Patent That Claims a Drug Substance
`(Active Ingredient), Drug Product (Formulation and
`Composition) andlor Method of Use
`
`
`
`
`
`The following is provided in accordance with Section 505th) and (c) of the Federal Food, Drug, and Cosmetic Act.
`TRADE NAME (OR PROPOSED TRADE NAME)
`REVLIMID® ‘
`
`I
`
`
`
`
`ACTIVE INGREDIENT(S)
`STRENGTH(S)
`1—oxo-2-(2.6-dioxopiperidin-3-yl)—4-aminoisoindollne
`5 mg and 10 mg
`
`
`
`
`
`DOSAGE FORM
`capsules for oral administration
`
`
`
`
`
`
`
`
`
`This patent declaration form is required» to be submitted to the Food and Drug Administration (FDA) with an NDA application.
`amendment, or supplement as required by 21 CFR 314.53 at the address provided in 21 CFR 314.53(d)(4).
`Within thirty (30) days after approval of an NDA or supplement, or within thirty (30) days of issuance of a new patent. a new patent
`declaration must be submitted pursuant to 21 CFR 314.53(c)(2)(ii) with all of the required information based on the approved NDA
`
`or supplement. The information submitted in the declaration form submitted upon or after approval will be the onlyinformation relied
`upon by FDA for listing a patent in the Orange Book.
`
`For hand-written or typewriter versions (only) of this report: If additional space is required for any narrative answer V(i.e., one
`that does not require a 'Yes" or “No" response), please attach an additional page referencing the question number.
`
`
`FDA will not list patent Information if you submit an incomplete patent declaration or the patent declaration Indicates the
`
`patent is not eligible for listing.
`'
`
`
`For each patent submitted for the pending NDA, amendment, or supplement referenced above, you must submit all the
`information described below. If youare not submitting any patents for this pending NDA, amendment, or supplement,
`complete above section and sections 5 and 6.
`1. GENERAL
`
`
`
`
`
`
`b. Issue Date of Patent
`06/03/1997
`
`Address (of Patent Owner)
`86 Morris Avenue
`
`City/State
`
`'
`
`c. Expiration Date of Patent
`07/24/2016
`
`
`
`
`
`
`
`
`
`a. United States Patent Number
`5.635.517
`
`(I. Name of Patent Owner
`Celgene Corporation
`
`FAX Number (if available)
`ZIP Code
`(908) 673-2763
`07901
`
`Telephone Number
`E—Mail Address (if available)
`
`
`(908) 673-9000
`gburton@ceigene.com
`
`Address (of agent or representative named in 1.51.)
`
`
`
`
`
`
`
`
`
`
`City/State
`
`
`
`FAX Number (if available)
`
`
`e. Name of agent or representative who resides or maintains
`a place of business within the United States authorized to
`‘receive notice of patent certification under section 505(b)(3)
`and (i)(2)(8) oi the Federal Food. Drug. and Cosmetic Act
`and 21 CFR 314.52 and 314.95 (it patent owner or NDA
`
`applicant/holder does not reside or have a place of
`business within the United States)
`
`
`W
`
`
`
`f.
`is the patent referenced above a patent that has been submitted previously for the
`
`
`’
`approved NDA or supplement referenced above?
`
`9. if the patent referenced above has been submitted previously for listing. is the expiration
`date a new expiration date?
`
`Telephone Number
`
`E-Mail Address (if available)
`
`
`
`
`
`FORM FDA 3542a (7l03)
`
`[I Yes
`
`
`E No
`D Yes
`
`
`No
`
`'
`Page 1
`rsr: Malia Annual 1 uJ-rmu
`EF
`
`

`

`For the patent referenced above, provide the following information on the drug substance, drug product andlor method of
`use that”Is the subject of the pending NDA, amendment, or supplement.
`
`2. Drug Substance (Active Ingredient)
`
`2.1 Does the patent claim the drug substance thatIs the active ingredientIn the drug product
`described in the pending NDA, amendment. or supplement?
`
`2.2 Does the patent claim a drug substance that is a different polymorph of the active
`ingredient described In the pending NDA, amendment, or supplement?
`
`2.3 if the answer to question 2.2 is "Yes," do you certify that. as of the date of this declaration, you have test
`data demonstrating that a drug product containing the polymorph will perform the same as the drug
`product described in the NDA? The type of test data required is described at 21 CFR 314.53(b).
`
`2.4 Specify the polymorphic fom1(s) claimed by the patent for which you have the test results described in 2.3.
`
`2.5 Does the patent claim only a metabolite of the active ingredient pending in the NDA or supplement?
`(Complete the information in section 4 below if the patent claims a pending method of using the pending
`ang product to administer the metabolite.)
`
`2.6 Does the patent claim only an intermediate?
`
`2.7 If the patent referenced in 2.1 is a product-by—process patent. is the product claimed in the
`patent novel? (An answer is required only if the patent is a product-by-process patent.)
`
`3.1 Does the patent claim the drug product, as definedIn 21 CFR 314.3 in the pending NDA
`amendment, or supplement?
`
`3.2 Does the patent claim only an intermediate?
`
`3.3 if the patent referenced in 3.1 is a product-by-process patent, is the product claimed in the
`patent novel? (An answer is required only it the patent is a product-by—process patent.)
`
`4. Method of Use
`
`
`
`Sponsors must submit the Information In section 4 separately for each patent claim claiming a method of using the pending drug
`product for which approval'Is being sought. For each method of use claim referenced, provide the following information:
`4.1 Does the patent claim one or more methods of use for which approval'Is being soughtin
`the pending NDA, amendment, or supplement?
`
`4.2 Claim Number (as listed in the patent) Does the patent claim referenced in 4.2 claim a pending method
`of use for which approval is being sought in the pending NDA,
`amendment. or supplement?
`‘
`
`Yes
`
`[:1 No
`
`4.23 if the answer to 4.2 is
`"Yes." identify with speci—
`ficity the use with refer-
`ence to the proposed
`labeling for the drug
`product.
`
`Use: (Submit indication or method of use information as identified specifically in the proposed labeling.)
`Please see attachment for exemplary and relevant sections of proposed labeling.
`
`5. No Relevant Patents
`
`For this pending NDA, amendment, or supplement, there are no relevant patents that claim the dmg substance (active ingredient).
`drug product (formulation or composition) or method(s) of use. for which the applicant is seeking approval and with respect to
`which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in
`the manufacture, use, or sale of the drug product.
`
`FORM FDA 3542a (7/03)
`
`_
`
`Page 2
`
`

`

`6-1 The undersigned declares that this is an accurate and complete submission ofpatent Information for the NDA,
`amendment, or supplement pending under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-
`sensitive patent information Is submitted pursuant to 21 CFR 314.53. lattest that I am familiar with 21 CFR_ 314.53 and
`this submission complies with the requirements of the regulation. l verify under penalty ofperjury that the foregoing
`is true and correct.
`
`Warning: A willfully and knowingly false statement is a criminal offense under 18 U.S.C. 1001.
`
`6.2 Authorized Signature of N '
`other Authorized Official)
`
`~.
`
`licantlHoider or Patent Owner (Attomey. Agent, Representative or
`.- Infonnetion below)
`
`Date Signed
`
`gal "larch st
`
`submit title declaration directly to the FDA. A patent owner who is not the NDA applicant]
`=
`-
`NOTEtOnIy an NBA appllcantlhoid-
`holder ls authorized to sign the -eclaration but may not submit it directly to FDA. 21 CFR 314.53(c)(4) and (d)(4).
`Check applicable box and provide information below.
`
`NDA Applicant/Holder
`
`U NDA Applicant's/Holder's Attorney. Agent (Representative) or other
`Authorized Official
`
`E] Patent Owner
`
`Name
`
`Celgene Corporation
`
`Address
`86 Morris Avenue
`
`ZIP Code
`07901
`
`D Patent Owner's Attorney. Agent (Representative) or Other Authorized
`Oifieial
`
`CitylStete
`Summit/NJ
`
`Telephone Number
`(908) 673-9000
`
`information unless it displays a currenlly mlid 0MB canIro'I number.
`
`E-Mail Address (if available)
`FAX Number (if available)
`gburton@eelgene.eom
`(908) 673-2763
`—-———_———____.—__—_______
`
`'
`
`including the time for reviewing
`The public reporting burden for this collection of infonnation has been estimated to average 9 hours per response.
`instructions. searching existing data sources. gathering and maintaining the data needed. and completing and reviewing the collection of information. Send
`comments regarding this burden estimate or any other aspect of this collection of information. including suggestions for reducing this burden to:
`Food and Drug Administration
`CDER (HFD-007)
`5600 Fishers Lane
`Roekvillc. MD 20857
`
`An agency may no! conduct or sponsor. and a person is rial required to respond to. a collection of
`
`FORM FDA 3542a (7103)
`
`Page 3
`
`

`

`Mechanism of Action:
`
`Lemlidomide affects a number of biological processes.
`
`Lenalidomide inhibits the secretion of pro- inflammatory cytokines including TNF-a, IL-
`IB, and lL-6 and IL— 12 from LPS —stimulated PBMC "2. Lenalidomide increases
`production of the anti-inflammatory cytokine IL- 10 from LPS-stimulated PBMC, and
`
`consequently inhibits the expression but not the enzymatic activity of COX-23A.
`
`APPEARS nus WAY
`0N ORlGli‘iAL
`
`

`

`FORM FDA 3542a
`QUESTION 4.2a
`United States Patent No. 5,635,517
`Celgene Corporation
`
`Claim 2 is related to, for example, the following passages within the proposed labeling:
`
`

`

`1
`METHOD OF REDUCING TNFa LEVELS
`WITH AMINO SUBSTITUTED 2-(2,6-
`DIOXOPIPERIDIN-3-YL)-l-OX0-AND 1,3-
`DIOXOISOINDOLINFS
`
`5,635,517
`
`2
`
`sarcoidosis patients have also been found to spontaneously
`release massive quantities of Wu as compared with mac-
`rophages from normal donors {Baughman et aL, J. Lab.
`Clin. Med. 115(1), 36-42 (1990)}.
`TNFaisalsoimplicatedintheinflammatoryresponse
`which follows reperfusion, called repcrfusion injury, and is
`a major cause of tissue damage afier loss of blood flow
`{Vedder et al., PNAS 87, 2643—2646 (1990)}. TNFOL also
`alters the properties of endothelial cells and has various
`pro-coagulant activities, such as producing an increase in
`tissue factor pro-coagulant activity and suppression of the
`anticoagulant protein C pathway as well as down—regulating
`the expression of thrombomodulin {Sherry et al., J. Cell
`Biol. 107, 1269-1277 (1988)}. TNFa has pro-inflammatory
`activities which together with is early production (dining
`the initial stage of an inflammatory event) make it a likely
`mediator of tissue injury in several important disorders
`including but not limited to, myocardial infarction, stroke
`and circulatory shock. 0f specific importance may be
`TNFa-induced expression of adhesion molecules, such as
`intercellular adhesion molecule (ICAM) or endothelial leu-
`kocyte adhesion molecule (ELAM) on endothelial cells
`{Munro et al., Am. J. Path. 135(1), 121—132 (1989)}.
`Moreover, it now is known that TNFot is apotent activator
`of retrovirus replication including activation of HIV-1. {Duh
`et al., Pmc. Nat. Acad. Sci. 86. 5974—5978 (1989); Poll et aL,
`Proc. Nat. Acad. Sci. 87, 782—785 (1990); Monto et al.,
`Blood ,791 2670 (1990); Clause et al., J. Immunol. 142,
`431—438 (1989); Poll et al., AIDS Res. Hum. Retrovirus,
`191-197 (1992)}. AIDS results from the infection of T
`lymphocytes with Human Immunodeficiency Virus (HIV).
`At least three types or strains of HIV have been identified,
`i.e., HIV-l, HIV-2 and HIV-3. As a consequence of HIV
`infection, T—cell mediated immunity is impaired and infected
`individuals manifest severe opportunistic infections and/or
`unusual neoplasms. HIV entry into the T lymphocyte
`requires T lymphocyte activation. Other viruses. such as
`HIV-1, HIV-2 infect T lymphocytes after T cell activation
`and sud: virus protein expression and/or replication is
`mediated or maintained by such T cell activation. Once an
`activated T lymphocyte is infected with HIV, the T lympho—
`cyte must continue to be maintained in an activated state to
`permit HIV gene expression and/or HIV replication.
`Cytokines, specifically TNFot, are implicated in activated
`T—cell mediated HIV protein expression and/or virus repli-
`cation by playing a role in maintaining T lymphocyte
`activation. Therefore, interference with cytolcine activity
`such as by prevention or inhibition of cytoldne production,
`notably TNFa, in an HIV-infected individual assists in
`limiting the maintenance of T lymphocyte caused by HIV
`infection.
`
`Monocytes, macrophages, 'and related cells, such as
`knptfer and glial cells, also have been implicated in main-
`tenance of the HIV infection. These cells, like T cells, are
`targets for viral replication and the level of viral replication
`is dependent upon the activation state of the cells. {Rosen—
`berg et al., The Imrnurwpatlwgenesis of HIV Irfection,
`Advances in Immunology, 57 (1989)}. Cytokines, such. as
`TNFot. have been shown to activate HIV replication in
`monocytes and/or macrophages {Poli et aL Prue. Natl. Acad.
`Sci, 87, 782—784 (1990)}, therefore, prevention or inhibi-
`tion of cytokine production or activity aids in limiting HIV
`progression for T cells. Additional studies have identified
`TNFa as a common factor in the activation of HIV in vitro
`and has provided a clear mechanism of action via a nuclear
`regulatory protein found in the cytoplasm of cells (Osborn,
`et al., PNAS 86 2336—2340). This evidence suggests that a
`
`The present inventionrelates a method ofreducing levels
`of tumor necrosis factor or in a mammal through the admin-
`istration of an amino substituted 2—(2,6-dioxopiperidin-3-yl)
`-1-oxoisoindolines and lj-dioxoisoindolines and to phar-
`maceutical compositions of such amino substituted indoline
`derivatives.
`
`‘ BACKGROUND OF THE INVENTION
`
`Tumor necrosis factor a. or mm, is a cytokine which is
`released primarily by mononuclear phagocytes in response
`to a number immunostimulators. When administered to
`animals or humans, it causes inflammation, feva, cardio-
`' vascular eifects. hemorrhage, coagulation, and acute phase
`responses similar to those seen during acute infections and
`shock states. Excessive or unregulated TNFa production
`thus has been implicated in a number of disease conditions.
`These include endotoxemia and/or toxic shock syndrome
`{'lracey et al., Nature 330, 662—664 (1987) and Hinshaw et
`al., Circ. Shock 30, 279—292 (1990)}; cachexia {Dezube et
`al., Lancet, 335 (8690), 662 (1990)} and Adult Respiratory
`Distress Syndrome where TNFot concentration in excess of
`12.000 pgmL have been detected in pulmonary aspirates
`from ARDS patients {Millar et al., lancer 2(8665), 712-714
`(1989)}. Systemic infusion of recombinant TNFa also
`resulted in changes typically seen in ARDS {Ferrai-
`Baliviera et al., Arch. Surg. 12402), 1400—1405 (1989)}.
`'I‘NFot appears to be involved in bone resorption diseases,
`including arthritis. When activated, leukocytes will produce
`bone-resorption, an activity to which the data suggest TNFoL
`contributes. {Bertolini et al., Nature 319, 516—518 (1986)
`and Johnson et al., Endocrinology 124(3), 1424—1427
`(1989).} TNFa also has been shown to stimulate bone
`resorption and inhibit bone formation in vitro and in vivo
`through stimulation of osteoclast formation and activation
`combined with inhibition of osteoblast function. Although
`TNFa may be involved in many bone resorption diseases,
`including arthritis, the most compelling link with disease is
`the association between production of 'I'N'Fa by tumor or
`host
`tissues and malignancy associated hypercalcemia
`{Calci Tissue Int. (US) 46(Suppl.), 53—10 (1990)}. In Graft
`versus Host Reaction, increased serum TNFa levels have
`been associated with major complication following acute
`allogcnic bone marrow transplants {Holler et al., Blood
`75(4), 1011—1016 (1990)}.
`Cerebral malaria is a lethal hyperacute neurological syn-
`drome associated with high blood levels of TNth and the
`most severe complication occurring in malaria patients.
`Levels of serum TNFot correlated directly with the severity
`of disease and the prognosis in patients with acute malaria
`attacks {Grau et at, N. EngL J. Med. 320(24). 1586—1591
`(1989)}.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`TNFa also plays a role in the area of chronic pulmonary
`inflammatory diseases. The deposition of silica particles
`leads to silicosis. a disease of progressive respiratory failure
`caused by a fibrotic reaction. Antibody to TNFa completely
`blocked the silica-induced lung fibrosis in mice {Pignet et
`al., Nature, 344:245—247 (1990)}. High levels of TNFot
`production (in the serum and in isolated macrophages) have
`been demonstrated in animal models of silica and asbestos
`induced fibrosis {Bissonnette et al., Inflammation 13(3),
`329—339 (1989)}. Alveolar macrophages from pulmonary
`
`65
`
`

`

`0
`
`X\N
`Y
`
`0
`
`H/N@Ifl
`
`0,,N
`
`5,635,517
`
`-
`
`6
`istration. Rectal administration can be dfected through the
`use of suppositories formulated from conventional carriers
`such as cocoa butter.
`Pharmaceutical compositions thus comprise one or more
`compounds of Formula I associated with at least one phar-
`maceutically acceptable carrier, diluent or excipient.
`In
`preparing such compositions,
`the active ingredients are
`usually mixed with tr diluted by an excipient or endosed
`within such a carrier whidr can be in the form of a capsule
`or sachet. When the excipient serves as a diluent, it may be
`a solid, semi-solid. or liquid material which acts as a vehicle,
`carrier, or medium for the active ingredient. Thus,
`the
`compositions can be in the form of tablets, pills, powders,
`elixirs, suspensions, emulsions, solutions, syrups, soft and
`hard gelatin capsules, suppositories, sterile injectable solu-
`tions and sterile packaged powders. Examples of suitable
`excipients include lactose, dextrose, sucrose, sorbitol,
`mannitol, starch, gum acacia, calcium silicate, microcrys-
`talline cellulose. polyvinylpyn'olidinone, cellulose, water,
`syrup, and methyl cellulose, the ftrmulations can addition-
`ally include lubricating agents such as talc, magnesium
`stearate and mineral oil, wetting agents, emulsifying and
`suspending agents, preserving agents such as methyl- and
`propylhydroxybenzoates, sweetening agents or flavoring
`agents.
`The compositions preferably are formulated'in unit dos-
`age form, meaning physically discrete units suitable as a
`unitary dosage, or apredcteunined fraction of a unitary dose
`to be administn'edin a single or multiple dosage regimen to
`human subjects and other mammals, each unit containing a
`predetermined quantity of active material calculated to pro-
`duce the desired therapeutic effect in association with a
`suitable pharmaceutical excipient. The compositions can be
`formulated so as to provide an immediate, sustained or
`delayed release of active ingredient after administration to
`the patient by employing procedures well known'in the art.
`Oral dosage forms include tablets, capsules, dragees, and
`similar shaped, compressed pharmaceutical forms contain-
`ing from 1 to 100 mg of drug per unit dosage. Botanic saline
`solutions containing from 20 to 100 mg/mL can be used for
`.parentm'al administration which includes intramuscular,
`intratheea], intravenous and intra-artetial routes of admin—
`istration. Rectal administration can be reflected through the
`use of suppositories formulated from conventional carriers
`such as cocoa butter.
`Phannaceutical compositions thus comprise one or more
`compounds of Formula I associated with at least one phar-
`maeeutically acceptable came; diluent or excipient. In
`preparing such compositions,
`the active ingredients are
`usually mixed with or diluted by an excipient or enclosed
`within sucha canierwhich canbein lhefonnofacapsule
`or sachet. When the excipient serves as a diluent, it may be
`a solid, semi-solid, or liquid material which acts as a vehicle,
`carrier, or medium for the active ingredient. Thus,
`the
`compositions can be in the form of tablets, pills, powders,
`elixirs, suspensions, emulsions, solutions, syrups, soft and
`hard gelatin capsules, suppositories, sterile injectable solu-
`tions and sterile packaged powders. Examples of suitable
`excipients include lactose, dextrose, sucrose, sorbitol,
`mannitol, starch, gum acacia, calcium silicate, microa'ys-
`talline cellulose, polyvinylpyrrolidinone, cellulose, water,
`syrup, and methyl cellulose, the formulations can addition-
`ally include lubricating agents such as talc, magnesium
`stearate and mineral oil, wetting agents, emulsifying and
`suspending agents, preserving agents such as methyl- and
`propylhydroxybenzoates, sweetening agents or flavoring
`agents.
`The compositions preferably are formulated in unit dos-
`age form, meaning physically discrete units suitable as a
`
`10
`
`15
`
`20
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`The nitro intermediates of Formula II are known or can be
`obtained though conventional processes. For example, a
`nitrophthalic anhydride is allowed to react with
`ot-aminoglutarimide hydrochloride {alternatively named as
`2.6-dioxopiperidin—3—ylammonium chloride} in the pres-
`ence of sodium acetate and glacial acetic acid to yield an
`intermediate of Formula II in which X andY are both C=O.
`In a second route, a lower alkyl ester of nitro—ortho—toluic
`acid is brominated with N-hromosuccinimide under the
`influence of light to yield a lower alkyl 2—(bromomethyl)
`nitrobenzoate. This is allowed to react with 2,6-
`dioxopipaidin—3—ammonium chloride in, for example. dim-
`ethylformamide in the presence of triethylamine to yield an
`intermediate of Formula II in which one of X is C=O and
`the other is CH2.
`The compounds of Formula Ipossess a center of chirality
`and can exist as optical isomers. Both the racemates of these
`isomers and the individual isomers themselves, as well as
`diastereomers when there are two chiral centers, are within
`the scope of the present invention. The racemates can be
`used as such or can be separated into their individual isomers
`mechanically as by chromatography using a chiral absor—
`bant. Alternatively, the individual isomers can beprepared in
`chiral form or separated chemically from a mixture by
`forming salts with a chiral acid, such as the individual
`enantiomers of lO-camphorsulfonic acid, camphoric acid,
`a-bromocamphoric acid, methoxyacetic acid, tartaric acid,
`diacetyltartaric acid, malic acid, pyrrolidone—S—carboxylic
`acid, and the like, and then freeing one or both of the
`resolved bases, optionally repeating the process, so as obtain
`either or both substantially free of the other, i.e., in a form
`having an optical purity of >95%.
`Alternatively, the compounds can be stereopreferentially
`synthesized by allowing the lower alkyl 2-(bromomethyl)
`nitrobenzoate intermediate discussed above to react with
`either
`(R)-l-benzyloxy—2,6-dioxo—3-tert.—
`butoxycarbonylaminopiperidine or (S)-l-benzyloxy-2,6—
`dioxo-3-tut-butoxycerbonylaminopiperidine analogous to
`the method described by Robin et al., Tetrahedron
`Asymmetry, 6. 1249 (1995). Hydrogenation in this case not
`only reduces the nitro group to an amino group but also
`converts the N—benzyloxy group to an N-hydroxy group
`whidt can be removed with bromoacetophenone uiethy—
`lamine and dimethylaminopyridine to yield the correspond-
`ing (R) or (S) enantiomer of Formula I.
`The present invention also pertains to the physiologically
`acceptable non-toxic acid addition salts of the compounds of
`Formula I. Such salts include those derived from organic and
`inorganic acids such as, without limitation, hydrodrloric
`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, embonic
`acid. enanthic acid, and the like.
`Oral dosage forms include tablets, capsules, dragees, and
`similar shaped, compressed pharmaceutical forms contain—
`ing from 1 to 100 mg of drug per unit dosage. Isotonic saline
`solutions containing from 20 to 100 mg/mL can be used for
`parenteral administration which includes intramuscular,
`intrathecal, intravenous and intra-arterial routes of admin-
`
`'
`
`

`

`5,635,517
`
`continued
`
`Constihnnts (for 1000 tablets)
`
`lactou
`100.0 3
`what starch
`47.0 g
`
`magnesium stearate 3.0 g
`
`All the solid ingredients are first forced through a sieve of
`0.6 mm mesh width. The active ingredient, lactose, magne-
`sium stearate and half of the starch then are mixed. The other
`half of the starch is suspended in 40 mL of water and this
`suspension is added to 100 mL of boiling water. The
`resulting paste is added to the pulverulent substances and the
`mixture is granulated, if necessary with the addition of
`water. The granulate is dried ovu'night at 35° C.. forced
`through a sieve of 1.2 mm mesh width and compressed to
`form tablets of approximame 6 mm diameter which are
`concave on both sides.
`
`10
`
`15
`
`EXAMPLES
`
`Tablets for chewing, each containing 75 mg of l-oxo—2—
`(2,6-dioxopiperidin—3-y1)-4-aminoisoindoline, can be pre-
`pared in the following manner:
`
` Composition (for 1000 tablets)
`l-oxo-Z-(Z.6-dioxo-
`75.0 g
`piperidin-S—ylH—amino—
`isoindnline
`7.30.0 g
`mannitol
`150.0 g
`lactose
`21.0 g
`talc
`12.5 3
`glycine
`10.0 g
`static acid
`1.5 g
`saccharin
`
`5% gelatin solution q.s.
`
`'
`
`All the solid ingredients are first forced through a sieve of
`0.25 mm mesh width. The mannitol and the lactose are
`mixed, granulated with the addition of gelatin solution,
`forced through a sieve of 2 mm mesh width, dried at 50° C.
`and again forced through a sieve of 1.7 mm mesh width.
`l-Oxo-2—(2,6—dioxopipaidin-3-yl)—4-aminoisoindoline,
`the
`'11
`ycine and the saccharin are carefully mixed. the mannitol,
`the lactose granulate, the stearic acid and the tale are added
`and the whole is mixed thoroughly and compressed to form
`tablets of approximately 10 mm diameter which are concave
`on both sides and have a breaking groove on the upper side.
`EXAMPLE 6
`
`Tablets. each containing 10 mg of l—oxo-2-(2,6-
`dioxopipcaidin—S-yl)-5-aminoisoindoline. can be prepared in
`the following manner:
`
`Composition (for 10(1) tablets)
`l-oxo-Z-(L6-dioxo—
`10.0 g
`piperidin—3-yl)—5~amino-
`
`328.5 3
`lactose
`17.5 g
`corn stand]
`5.0 g
`polyethylene glycol 6000
`25.0 g
`talc
`4.0 g
`magnesium steerate
`
`demineralized water qs.
`
`The solid ingredients are first forced through a sieve of 0.6
`mm mesh width. Then the active irnide ingredient, lactose,
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`10
`talc, magnesium steamte and half of the starch are intimately
`mixed. The otha' half ofthe starch is suspended in 65 mL of
`water and this suspension is added to a boiling solution of
`the polyethylene glycol in 260 mL of water. The resulting
`paste is added to the pulverulent substances, and the whole
`is mixed and granulated, if necessary with the addition of
`water. The granulate is dried ova’night at 35° C., forced
`through a sieve of 1.2 mm mesh width and compressed to
`form tablets of approximately 10 mm diameter which are
`concave on both sides and have a hrealdng notch on the
`upper side.
`
`EXAMPLE 7
`
`Gelatin dry-filled capsules, each containing 100 mg of
`l-oxo—2—(2.6-dioxopiperidin-3—yl)-6-aminoisoindoline, can
`be prepared in the following manner:
`
` Composition (fior 11110 capsules)
`l-oxo-H2,64:lioxo-
`1010 g
`piperidin—3—yl)—6~amino—
`
`30.0 g
`microcrystalline cellulose
`2.0 g
`sodium lauryl sulfate
`
`mayresium smarate 8.0 g
`
`The sodium lauryl sulfate is sieved into the 1—0xo-2-(2,
`6—dioxopiperidin-3-y1)-6-aminoisoindoline through a sieve
`of 0.2 mm mesh width and the two components are inti—
`mately mixed for 10 minutes. The microcrystalline cellulose
`is then added through a sieve of 0.9 mmmesh width and the
`whole is again intimately mixed for 10 minutes. Finally, the
`magnesium stearate is added through a sieve of 0.8 mm
`Width and, after mixing for a further 3 minutes, the mixture
`is introduced in portions of 140 mg each into size 0
`(elongated) gelatin dry-fill capsules.
`
`EXAMPLES
`
`A 0.2% injection or infusion solution can be prepared, for
`example, in the following manner:
`
`1-0xo-2-(2,6-dioxo~
`5.0 g
`pipeddin-a-yDJ-amino-
`
`sodium chloride
`phosphate heifer pH 7.4
`demineralized water
`
`22.5 g
`300.0 g
`to 2500.0 mL
`
`l-0xo—2{2.6—dioxopiperidin—3-yl)-7-aminoisoindoline is
`dissolved in 1000 mL of water and filtered through a
`microfilter. The buffer solution is added and the whole is
`made up to 2500 mL with water. To prepare dosage unit
`forms. portions of 1.0 or 2.5 mL each are introduced into
`glass ampoules (each containing respectively 2.0 or 5.0 mg
`of imide).
`What is claimed is:
`
`1. The method of reducing undesirable levels ofTNFa in
`a mammal which comprises administering thereto an effec-
`tive amount of a compound of the formula:
`
`

`

`Inventors: George W. Muller, Bridgewater, NJ
`(US); David I. Stirling, Branchburg, NJ
`(US); Roger Shen-Chu Chen, Edison,
`NJ (US)
`
`Assignee: Celgene' Corporation, Warren, NJ (US)
`
`Notice:
`'
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`
`W0
`
`6,046,221 A
`6,071,948 A
`6,335,349 Bl “
`XIII/0056113 A1
`2001/0056114 A1
`2002/0049231 A1
`2002/(IJ52398 A1
`200210061911 A1
`2002/0082290 A1
`
`4/20“) Muller et al.
`6/2000 D’Amato
`1/2002 Muller et al.
`12/2001 D’Amato
`12/2001 D'Amato
`4/2002 D’Amato
`512002 D‘Amato
`5/2002 D'Amato
`6/2002 D'Amato
`
`514/323
`
`FOREIGN PATENT DOCUMENTS
`
`[/1995
`WO 95/01348
`OTHER PUBLICATIONS
`
`(75)
`
`(73)
`
`< * >
`
`(21)
`
`(22)
`
`(65)
`
`(63)
`
`(60)
`
`(51)
`' (52)
`(58)
`
`(56)
`
`llllllillllllIlllllllllllllllllllillllllllillllllilllllllllllllllllllllll
`USOO6555554BZ
`
`(12)
`
`United States Patent
`Muller et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,555,554 B2
`*Apr. 29, 2003
`
`(54)
`
`ISOINDOLINES, METHOD OF USE, AND
`PHARMACEUTICAL COMPOSITIONS
`
`This patent is subject to a terminal dis-
`claimer.
`
`Appl. No.: 09/781,179
`
`Filed:
`
`Feb. 12, 2001
`Prior Publication Data
`
`US 2002/0045643 A1 Apr. 18, 2002
`
`Related US. Application Data
`
`Continuation of application No. 09/543,809, filed on Apr. 6,
`2000, now Pat. No. 6,281,230, which is a division of
`application No. 09/230,389, filed as applimtion No. PCT/ ’
`US97/13375 on Jul. 24, 1997, now abandoned, which is a
`continuation of application No. 08/690,258, filed on Jul. 24,
`1996, now Pat. No. 5,635,517, and a continuation of appli»
`cation No. 08/701,494, filed on Aug. 22, 1996, now Pat. No.
`5,798,368.
`Provisional application No. 60/048,278, filed on May 30,
`1997.
`
`Int. Cl.7 ..................... A61K 31/454; CO7D 401/04
`US. Cl.
`........................................ 514/323; 546/201
`Field of Search ........................... 514/323; 546/201.
`
`,
`
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