throbber
IIIII
`US005233036A
`[ii] Patent Number:
`[45] Date of Patent:
`
`ABSTRACT
`[57]
`A compxiund of the structure
`
`.5,233,036
`Aug. 3, 1993
`
`United States Patent m
`Hughes
`
`[54] RAPAMYCIN ALKOXYESTERS
`
`[75]
`
`Inventor: Philip F. Hughes, Hopewell, N.J.
`
`[73] Assignee: American Home Products
`
`Corporation, New York, N.Y.
`
`[21] Appl. No.: 839,653
`
`[22] Filed:
`
`Feb. 20,1992
`
`Related U.S. Application Data
`[63] Continuation of Ser. No. 598.270, Oct. 16, 1990, aban(cid:173)
`doned.
`
`[51] Int. Cl.5
`[52] U.S. Cl
`[58] Field of Search
`
`C07D 269/00; A61K 31/33
`540/455
`540/455; 514/183
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,929,992 12/1975
`Sehga! et al
`3,993.749 11/1976
`Sehgal et al
`4,316.885 2/1982
`Rakhit et al
`4,401,653 4/1983
`Maruyama et al
`4,650,803 3/1987
`Stella et al
`4.885.171 12/1989
`Sehgal et al
`4,929,611 5/1990 Okuhava
`OTHER PUBLICATIONS
`Can. J. Physiol. Pharmacol. 55, 48 (1977).
`FASEB 3, 3411 (1989).
`FASEB 3, 5256 (1989).
`Lancet, 1183,(1978).
`J. Am. Chem. Soc. 103, 3215 (1981).
`J. Am. Chem. Soc. 104, 6787 (1982).
`J. Antibiot. 28, 721-726 (1975).
`J. Antibiot. 28, 727-732 (1975).
`J. Antibiot. 31, 539-545 (1978).
`
`Primary Examiner—C. Warren Ivy
`Assistant Examiner—Celia Chang
`Attorney, Agent, or Firm—Arnold S. Milowsky
`
`wherein R1 is
`
`424/122
`424/122
`424/122
`424/122
`546/90
`424/122
`514/183
`
`o
`II
`—CH2COR-:
`
`R2 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of
`3-8 carbon atoms which is optionally unsaturated,
`aralkyl of 7-10 carbon atoms, or phenyl which is
`optionally mono-, di-, or tri-substituted with a substit(cid:173)
`uent selected from alkyl of 1-6 carbon atoms, alkoxy
`of 1-6 carbon atoms, hydroxy, cyano, halo, nitro,
`carbalkoxy of 2-7 carbon atoms, trifluoromethyl,
`amino, or a carboxylic acid;
`or a pharmaceutically acceptable salt thereof when R2is
`hydrogen, which are useful in the treatment of trans(cid:173)
`plantation rejection, host vs. graft disease, autoimmune
`diseases, diseases of inflammation, or fungal infections.
`
`4 Oaims, No Drawings
`
`West-Ward Pharm.
`Exhibit 1045
`Page 001
`
`

`

`5,233,036
`
`RAPAMYON ALKOXYESTERS
`
`OR1
`
`This is a continuation of application Ser. No. 5
`07/598,270 filed Oct. 16, 1990 now abandoned.
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to novel ethers of rapamycin
`and a method for using them in the treatment of trans(cid:173)
`plantation rejection, host vs. graft disease, autoimmune
`diseases, diseases of inflammation or fungal infections.
`Rapamycin is a macrocyclic triene antibiotic pro(cid:173)
`duced by Streptomyces hygroscopicus, which was found
`to have antifungal activity, particularly against Candida
`albicans, both in vitro and in vivo [C. Vezina et al., J.
`Antibiot. 28, 721 (1975); S. N. Seghal et al., J. Antibiot.
`28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539
`(1978); U.S. Pat. No. 3,929,992; and U.S Pat. No.
`3,993,749].
`
`Rapamycin alone (U.S. Pat. No. 4,885,171) or in com(cid:173)
`bination with picibanil (U.S. Pat. No. 4,401,653) has
`been shown to have antitumor activity. R. Martel et al.
`[Can. J. Physiol. Pharmacol. 55. 48 (1977)] disclosed
`that rapamycin is effective in the experimental allergic
`encephalomyelitis model, a model for multiple sclerosis;
`in the adjuvant arthritis model, a model for rheumatoid
`arthritis; and effectively inhibited the formation of IgE-
`like antibodies.
`
`The immunosuppressive effects of rapamycin have
`been disclosed in FASEB 3, 3411 (1989). Cyclosporin A
`and FK-506, other macrocyclic molecules, also have
`been shown to be effective as immunosuppressive
`agents, therefore useful in preventing transplant rejec(cid:173)
`tion [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); and
`R. Y. Calne et al., Lancet 1183 (1978)].
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Mono- and diacylated derivatives of rapamycin (es(cid:173)
`terified at the 28 and 43 positions) have been shown to
`be useful as antifungal agents (U.S. Pat. No. 4,316,885)
`and used to make water soluble prodrugs of rapamycin
`(U.S. Pat. No. 4,650,803). Recently, the numbering
`convention for rapamycin has been changed; therefore
`according to Chemical Abstracts nomenclature, the
`esters described above would be at the 31- and 42- posi(cid:173)
`tions.
`
`50
`
`55
`
`60
`
`DESCRIPTION OF THE INVENTION
`
`This invention provides derivatives of rapamycin 65
`which are useful as immunosuppressive, anti-inflamma(cid:173)
`tory, or antifungal agents having the structure
`
`wherein R' is
`
`O
`II
`—CH2COR2;
`
`R2is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of
`3-8 carbon atoms which is optionally unsaturated,
`aralkyl of 7-10 carbon atoms, or phenyl which is
`optionally mono-, di-, or tri-substituted with a substit(cid:173)
`uent selected from alkyl of 1-6 carbon atoms, alkoxy
`of 1-6 carbon atoms, hydroxy, cyano, halo, nitro,
`carbalkoxy of 2-7 carbon atoms, trifluoromethyl,
`amino, or a carboxylic acid;
`or a pharmaceutically acceptable salt thereof when R2is
`hydrogen.
`Of the compounds, preferred members are those in
`which R2 is alkyl Of 1-6 carbon atoms.
`The pharmaceutically acceptable salts may be formed
`from inorganic cations such as sodium, potassium, cal(cid:173)
`cium, magnesium and the like or may be in the form of
`a quaternary ammonium salt.
`The compounds of this invention can be prepared by
`reacting rapamycin with the appropriately substituted
`ester of diazoacetic acid in the presence of a divalent
`cation salt, such as rhodium (II) diacetate dimer or
`copper (II) triflate, as shown below.
`
`HN2CCO2R2 ^
`OH M(I1)
`> ">
`
`•>
`
`OCH2CO2R2
`
`This method of preparing alkoxyesters has been de(cid:173)
`scribed by B. Ganem et al., J. Am. Chem. Soc. 104,6787
`(1982). The starting materials utilized are either com(cid:173)
`mercially available or can be prepared by methods dis(cid:173)
`closed in the literature.
`The compounds of this invention, rapamycin-42-
`ethers, provide stability against hydrolysis ofthe 42-side
`chain by virtue of the ether moiety connecting the side
`chain to rapamycin at the 42-position.
`Immunosuppressive activity was evaluated in an in
`vitro sUndard pharmacological test procedure to mea(cid:173)
`sure lymphocyte proliferation (LAF) and in two in vivo
`standard pharmacological test procedures. The first in
`vivo procedure was a popliteal lymph node (PLN) test
`procedure which measured the effect of compounds of
`this invention on a mixed lymphocyte reaction and the
`
`West-Ward Pharm.
`Exhibit 1045
`Page 002
`
`

`

`• 4
`3
`The following table summarizes the results of repre-
`second in vivo procedure evaluated the survival time of
`sentative compounds of this invention in these three
`a pinch skin graft.
`standard test procedures,
`The comitogen-induced thymocyte proliferation pro-
`cedure (LAF) was used as an in vitro measure of the __
`TABLE 1
`immunosuppressive effects of representative com(cid:173)
`PLN*
`L A F*
`pounds. Briefly, cells from
`the thymus of normal
`(ratio)
`(ratio)
`BALB/c mice are cultured for 72 hours with PHA and
`0.74**
`IL-1 and pulsed with tritiated thymidine during the last
`+
`1.0
`six hours. Cells are cultured with and without various
`concentrations of rapamycin, cyclosporin A, or test
`compound. Cells are harvested and incorporated; radio(cid:173)
`activity is determined. Inhibition of lymphoprolifera-
`tion is assessed in percent change in counts per minute
`from non-drug treated controls. The results are ex- iS
`pressed by the following ratio, or as the percent inhibi-
`tion of lymphoproliferation of 1 pM.
`
`5,233,036
`
`Compound
`Example 1
`Exampie 2
`Rapamycin
`
`0.46
`0.27
`1.0
`
`•Calculation of ratios was
`. described supra.
`••A result of -0.14 also
`was obtained for Example 1.
`-rNot evaluated
`
`10
`
`Skin Graft
`(days + SD)
`7.5 ± 1.2
`+
`12.0 ± 1.7
`
`The results of the LAF standard pharmacological
`test procedure demonstrates that the compound of Ex(cid:173)
`ample 2 suppressed T-cell proliferation, and is therefore
`useful as an immunosuppressive agent. Based on the
`results of the in vitro and in vivo standard pharmaco(cid:173)
`logical test procedures, it was unclear whether the com-
`p o u nd 0f Example 1 had immunosuppressive activity. A
`r a t io of QM ^
`t he L AF a nd Q 74 in t he pLN
`t e st p r o c e.
`dures indicates that the compound of Example 1 sup-
`preSSed T-cell proliferation; however, the -0.14 ratio
`A mixed lymphocyte reaction (MLR) occurs when
`t h at w as ajso obtained in the PLN test procedure could
`lymphoid cells from genetically distinct animals are
`combined in tissue culture. Each stimulates the other to 25 be indicative of immunostimulation.
`undergo blast transformation which results in increased
`Antifungal activity of the compounds of this inven-
`DNA synthesis that can be quantified by the incorpora-
`tion was measured against 5 strains of Candida albicans
`tion of tritiated thymidine. Since stimulating a MLR is a
`using a plate test procedure for measurement of inhibi-
`function of disparity at Major Histocompatibility anti-
`tion. The following represents the typical procedure
`gens, as in vivo popliteal lymph node (PLN) test proce- 3Q used. Compound to be tested was placed on sterile dried
`dure closely correlates to host vs. graft disease. Briefly,
`J" plate disks, and allowed to dry. Agar plates were
`irradiated spleen cells from BALB/c donors are in-
`seeded with fungi and allowed to solidify. The impreg-
`jected into the right hind foot pad of recipient C3H
`nated disks were placed on the seeded Agar surface and
`mice The drug is given daily, p.o. from Day 0 to Day
`incubated for the time required for the particular cul-
`4 On Day 3 and Day 4, tritiated thymidine is given i.p., 35 t u r e- R e s u l ts a re expressed in MIC (pg/ml)
`to inhibit
`b i.d.. On Day 5, the hind popliteal lymph nodes are
`growth. The results of this test procedure showed that
`?he compounds of this invention have antifungal activ-
`removed and dissolved, and radioactivity counted. The
`corresponding left PLN serves as the control for the
`"y-
`PLN from the injected hind foot. Percent suppression is
`calculated using the non-drug treated animals as allo(cid:173)
`genic control. Rapamycin at a dose of 6 mgAg, p.o.
`gave 86% suppression, whereas cyclosporin A at the
`same dose gave 43% suppression. Results are expressed
`by the following ratio:
`
`^H-controi thymus cells - H^-rapamYcin-ireated thymus cells
`-'H-control thymus cells - H'-test compound-treated cells
`
`40
`
`45
`
`Compound
`Example 1
`Example 2
`Rapamycin
`
`TABLE 2*
`Strain of Candida albicans
`ATCC
`ATCC
`ATCC
`10231
`38246
`38247
`0.5
`0.1
`0.2
`0.05
`0.2
`0.05
`0.003
`0.025
`0.003
`
`ATCC
`38248
`0.1
`0.1 •
`0.006
`
`3669
`
`0.05
`0.2
`0.025
`
`•expressed as MIC (fig/ml)
`
`-'H-PLN cells control C3H mouse -
`3H-PLN cells ranamvcin-treated C3H mouse—
`3U D,3^"PnN c e"s c o m r o li:,-, H,m^^?lr „,...
`jH-PLN cells test compound-treated C3H mouse
`
`Based on the results of these standard pharmacologi-
`cal test procedures, the compounds are useful in the
`r
`.
`K .
`'
`.
`50 treatment of transplantation rejection such as, heart,
`k i d n ey> "^ ^nt marrow and skin transplants; auto-
`The second in vivo test procedure is designed to
`" ™e dlsf,a
`ses s u ch «*• ^
`rheumatoid arthntis,
`determine the survival time of pinch skin graft from
`f
`diabetes mellitus, myasthenia gravis, and multiple scle-
`, X^TW /-. J
`-
`1
`.
`_ I T > A I D /„
`.A
`.
`male DBA/2 donors transplanted to male BALB/c
`, • „
`.•
`x.
`• •
`rosis; and diseases of inflammation such as, psoriasis,
`. •
`j
`, c
`n-ii-
`t.
`r>
`L,
`.
`. ^ i^
`recipients. The method is adapted from BdhnghamR. 55 d e n n a t i ti
`e c z e m ai
`inf la m m a t o r£
`^wel
`E. and Medawar P. B., J Exp. Biol. 28:385-402, (1951).
`d i s e a s e; or f
`i n f e c t i o ns
`Briefly, a pinch skin graft from the donor is grafted on
`T he c o m p o u n ds m ay ^
`a d ministered neat or with a
`the dorsum of the recipient as a homograft, and an
`pharmaceutical carner to a mammal in need thereof,
`autograft is used as control in the same region. The
`^g pharmaceutical carrier may be solid or liquid,
`recipients are treated with either varymg concentra- ^
`substances
`A s o l id c a r r i er c an jn ciu de o ne or m0Tt
`tions of cyclosporin A as test control or the test com-
`whjch may also act as flavoring agents, lubricants, solu-
`pound, intraperitoneally. Untreated recipients serve as
`bilizers, suspending agents, flllers, glidants, compression
`rejection control. The graft is monitored daily and ob-
`ajds, binders or tablet-disintegrating agents; it can also
`servations are recorded until the graft becomes dry and
`be an encapsulating material. In powders, the carrier is
`forms a blackened scab. This is considered as the rejec- 65 a finely divided solid which is in admixture with the
`tion day. The mean graft survival time (number of
`finely divided active ingredient. In tablets, the active
`days±S.D.) of the drug treatment group is compared
`ingredients is mixed with a carrier having the necessary
`with the control group.
`compression properties in suitable proportions and
`
`West-Ward Pharm.
`Exhibit 1045
`Page 003
`
`

`

`5,233,036
`
`10
`
`15
`
`30
`
`35
`
`compacted in the shape and size desired. The powders
`chloride for 3 d to yield a white powder which was
`and tablets preferably contain up to 99% of the active
`filtered
`to give 42-deoxy-42-(2-ethoxy-2-oxoethoxy)-
`ingredient. Suitable solid carriers include, for example,
`rapamycin (496 mg, 23%). The product was isolated as
`calcium phosphate, magnesium stearate, talc, sugars,
`the hemihydrate. IR (KBr) 1680, 1730, 2920, 3430
`lactose, dextrin, starch, gelatin, cellulose, methyl cellu(cid:173)
`c m - '; IH-NMR (CDCL3)81.28 (3H, t, J=7.14 Hz),
`lose, sodium carboxymethyl cellulose, polyvinylpyr-
`1.65 (3H, s), 1.74 (3H, s) 3.14 (3H, s), 3.34 (3H, s), 3. 41
`rolidine, low melting waxes and ion exchange resins.
`(3H, s), 4.20 (2H, q, J = 7.14 Hz), 4.30 (2H, dd); Mass
`Liquid carriers are used in preparing solutions, sus(cid:173)
`Spect (neg. ion FAB) m/z 999 (94%), 590 (15%), 407
`pensions, emulsions, syrups, elixirs and pressurized
`(16%), 379 (4%), 253 (6%), 167 (100%).
`compositions. The active ingredient can be dissolved or
`Analysis Calcd for C55 Hgs N Ou .0.5 H20:C, 65.45;
`suspended in a pharmaceutically acceptable liquid car(cid:173)
`H, 8.59; N, 1.39 Found: C, 65.29; H, 8.64; N, 1.60.
`rier such as water, an organic solvent, a mixture of both
`The following representative compounds can be pre(cid:173)
`or pharmaceutically acceptable oils or fats. The liquid
`pared from rapamycin and the appropriately substituted
`carrier can contain other suitable pharmaceutical addi(cid:173)
`ester of diazoacetic acid by employing the method used
`tives such as solubilizers, emulsifiers, buffers, preserva(cid:173)
`to prepare the title compound in Example 1. 42-Deoxy-
`tives, sweeteners, flavoring agents, suspending agents,
`42-(2-phenoxy-2-oxoethoxy)rapamycin
`42-Deoxy-42-
`thickening agents, colors, viscosity regulators, stabiliz(cid:173)
`ers or osmo-regulators. Suitable examples of liquid car(cid:173)
`[2-(4-chlorophenoxy)-2-oxoethoxy]rapamycin
`42-
`riers for oral and parenteral administration include
`Deoxy-42-(2-phenylmethoxy)-2-oxoethoxy)rapamycin
`water (partially containing additives as above, e.g. cel- 20 42-Deoxy-42-(2-cyclobotoxy)-2-oxoethoxy)rapamycin
`lulose derivatives, preferably sodium carboxymethyl
`42-Deoxy-42-[2-(cyclohex-2-enyloxy)-2-oxoethoxy]-
`cellulose solution), alcohols (including monohydric
`rapamycin
`alcohols and polyhydric alcohols, e.g. glycols) and their
`derivatives, and oils (e.g. fractionated coconut oil and
`arachis oil). For parenteral administration, the carrier 25
`can also be an oily ester such as ethyl oleate and isopro(cid:173)
`pyl myristate. Sterile liquid carriers are useful in sterile
`liquid form compositions for parenteral administration.
`The liquid carrier for pressurized compositions can be
`halogenated hydrocarbon or other pharmaceutically
`acceptable propellent.
`Liquid pharmaceutical compositions which are sterile
`solutions or suspensions can be utilized by, for example,
`intramuscular, intraperitoneal or subcutaneous injec(cid:173)
`tion. Sterile solutions can also be administered intrave(cid:173)
`nously. The compound can also be administered orally
`either in liquid or solid composition form.
`Preferably, the pharmaceutical composition is in unit
`dosage form, e.g. as tablets or capsules. In such form,
`the composition is sub-divided in unit dose containing ^
`appropriate quantities of the active ingredient; the unit
`dosage forms can be packaged compositions, for exam(cid:173)
`ple, packeted powders, vials, ampoules, prefilled syrin(cid:173)
`ges or sachets containing liquids. The unit dosage form
`can be, for example, a capsule or tablet itself, or it can be
`the appropriate number of any such compositions in
`package form. The dosage to be used in the treatment
`must be subjectively determined by the attending physi(cid:173)
`cian.
`In addition, the compounds of this invention may be
`employed as a solution, cream, or lotion by formulation
`with pharmaceutically acceptable vehicles containing
`0.1-0.5 percent, preferably 2%, of active compound
`which may be administered to a fungally affected area.
`The following examples illustrate the preparation of 55
`representative compounds of this invention.
`
`EXAMPLE 2
`42-Deoxy-42-[2-(l,l-dimethylethoxy)-2-oxoethoxy]-
`rapamycin
`To solution of rapamycin (2.0 g, 2.187 mmol) and
`rhodium (H) diacetate (20 mg, 0.04 mmol) in methylen
`chloride (50 mL) was added with t-butyl diazoacetate
`(750 mg, 690 pL, 6.56 mmol) in methylene chloride (20
`mL) over 1.5 h and the reaction mixture was allowed to
`stir overnight. The mixture was concentrated and puri(cid:173)
`fied by chromatography (silica gel, ethyl acetate-hex(cid:173)
`ane, 4:6) to give the product as a glass. The product was
`dissolved with methylene chloride and concentrated to
`give the product as a while solid (588 mg, 26%). The
`product was then dried in vacua at 68° C. overnight and
`isolated as the hemihydrate. IR (KBr) 1650, 1725, 1750,
`2940, 3440 c m - '; 'H-NMR (CDCL3)81.47 (9H, s), 1.65
`(3H, s), 1.74 (3H, s), 3.14 (3H, s) 3.34 (3H, s) 3.34 (3H, s),
`4.20 (2H, dd); Mass spect (neg. ion FAB) m/z 1027
`(32%), 590 (13%), 435 (9%), 167 (100%).
`Analysis Calcd for C57H89N Oi5«0.5 H20:C, 66.00;
`H, 8.74; N, 1.35 Found: C, 65.83; H, 8.60; N, 1.29.
`What is claimed is:
`1. A compound of the structure
`
`.,
`
`50
`
`EXAMPLE "l
`42-Deoxy-42-(2-ethoxy-2-oxoethoxy)rapamycin
`A solution of rapamycin (2.0 g, 2.187 mmol) and
`rhodium (II) diacetate (37 mg, 0.08 mmol) in benzene
`(50 mL) was heated to reflux and ethyl diazoacetate
`(750 mg, 690 ^iL, 6.56 mmol) in benzene (10 mL) was
`added over 10 min. The mixture was concentrated and
`purified by chromatography (silica gel, ethyl acetate-
`hexane, 1:1) to give 700 mg of product (32%) as a glass.
`The product was stirred with hexane with the addition
`of small amounts of ethyl acetate, ether and methylene
`
`60
`
`65
`
`wherein R1 is
`
`West-Ward Pharm.
`Exhibit 1045
`Page 004
`
`

`

`5,233,036
`
`—CH:COR-:
`
`R2 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of
`3-8 carbon atoms which is optionally unsaturated
`phenylalkyl of 7-10 carbon atoms, or phenyl which is
`optionally mono-, di-, or tri-substituted with a substit(cid:173)
`uent selected from alkyl of 1-6 carbon atoms, alkoxy
`of 1-6 carbon atoms, hydroxy, cyano, halo, nitro,
`
`• 8
`carbalkoxy of 2-7 carbon atoms, trifluoromethyl,
`amino, or a carboxylic acid;
`or a pharmaceutically acceptable salt thereof when R2is
`hydrogen.
`2. A compound of claim 1 where R2 is alkyl of 1-6
`carbon atoms.
`3. A compound of claim 1 which is 42-deoxy-42-(2-
`ethoxy-2-oxoethoxy)rapamycin.
`4. A compound of claim 1 which is 42-deoxy-42-[2-
`10 (1,1 -dimethylethoxy)-2-oxoethoxy]-rapamycin.
`
`5
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`West-Ward Pharm.
`Exhibit 1045
`Page 005
`
`

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket