(12} INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`CORRECTED VERSION
`
`(19)w ldItlIHt
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`"ori'ahiétiifn mp" "
`lnl‘emati mnl Bureau
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`(10) International Publication Number
`W0 2009007031 A9
`
`(51} International Patent Classification:
`.461K3b’19t2006111}
`AME 31/557t2ilflfiljl}
`.
`{21) International Application iumher:
`
`PCTJ'US2004tfllo4Gl
`
`{22} International Filing Date:
`
`(25, Filing Language:
`
`2-1 May 3004 [24.05.2004]
`
`(20} Publication Languagfi
`_
`_
`l’l'lm'ltl' Dim-‘3
`W471407
`
`(30)
`
`33 M“? 3003 [3105313)
`
`(Tl) Applicant am- nli' designated States- m‘wpt US): UNITED
`’I’HlCRAl’EU‘I'lCS CORPORATION 1USKUS];
`[735
`Columeticul Avenue, N.W.. Third Floor. Washington, [1C .
`30009 (US).
`
`English
`
`English
`
`‘
`“5
`
`(72)
`(TS)
`
`Inventors: and
`{for US only}: PHARES. Ken
`lnventorsMpplieanls
`IUSHUS];
`[94 Amber Wood Run. Chapel Ilill, NC 21516
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`(Uh). . IOT'I‘OLA. Dawd [Ub.Ub]. Ont. Park Dme. RI.
`search Triangle Park NC 27709 {US}.
`
`(74] Agents: MAI‘IBIUS. Stephen. B. gt a]; FOLFY & LARJJ-
`NER LLP. Washington Harbour, 3000 K Slt'eet N.W.,
`Suite Still, Washington, DC 20007-5143 (US).
`
`(81] Designated States rnnt'ess otherwise indicated. tor own
`kind of'nntionnx’ protection mm’t’nblet: AE. AG. AL, AM.
`AT_ AU. AZ, BA. BB, Bt'i‘ BR BW, BY. BZ, CA, CH,
`CN. co. CR. cu. CL DE. DK. DM. DZ. 11c. Eli. 113. ns.
`
`lily {if}: GI), (fla- L1H, GM, Elk- Hug"), l'L‘ IN, IS, 'lP'
`Hi. khaki). lvxll. lui. LC. Lk. .LR' LS. LT, LLL LY. MA
`MD- Mf’ Ml" MN“ MW' ND" MZ' NA' N1; N0' N‘fi'
`OM. Pt]. PH, PL, PT, RO. RU, SC“ SD, SE, SUV SK. SL.
`SY, TJ, TM, TN, TR. 'l'T= TZ, UA, UG, US. UZ, VC, VN.
`YU. ZA, ZM, ZW.
`
`{Continued m: not! page}
`
`(54] Title: COMPOUNDS ANI) METHODS FOR DELIVERY OF PROSTACYCL-[N ANALDGS
`
`.d _
`
`noun}: IA
`
`U
`
`’0
`
`I“
`
`‘in
`
`an
`
`2"
`'l'ul'lnl W}
`
`m
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`3*!
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`OK
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`I!)
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`3“
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`FIG URFS 3 l3
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`-I~ H122
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`a- on)
`+ mat
`
`+ m!
`
`(57) Abstract: This invention pertains generally Io pronto—
`c-yclin analogs nod methods For their use in promoting vns-
`odilotiou, inhibiting platelet aggregation and thrombus fortn-
`ation, stimulatirn:l tltrotobolysis, inhibiting cell proliferation
`(including. vascular remodeling), providing afloprotection,
`preventing nlherogencsis and inducing (utgiogenesis. (Hench
`ally,
`the compounds and methods of the present invention
`increase the oral hioaveilobilily and circulating concentra-
`tions of treproslinil when administered orally. Compounds
`or‘ me present invention have l‘onnnla [I].
`
`Liquidia - Exhibit 1008 - Page 1
`
`
`
`WO2005/007031A9|||||||||||||l|||||||l|||||||||l||||l||l||||||||||1||||||||||llllll||||||||||||||||||||||||l|||
`
`Liquidia - Exhibit 1008 - Page 1
`
`

`

`WO 2005/007081 A9 ||||1||||||||||||||l||||||1|||1||l||| ||I||| ||[||||||||||||||||||l|lllll|||l|||||||||||l|||||||
`
`{8-0 Designated States (airless otherwise {Mic-mad. __far emu-
`Mad af rt'giaaa! ,ararcctirm amin’abh’fl ARIPU {8W1 (ill.
`GM, Kli. LS, MW. MZR NA. ELL SL, 32. T2“ UG. ZM,
`ZW). Eurasian (AM, AZ‘ BY. KG. KZ. MD, RU. TJ.
`TM ), European (AT, BE, BU, CH1 CY. CZ, DE. DK, L" E
`ES. Fl, FR. GB, GR. HU, IE, IT. LU, MC, NL. PL. PT‘
`RO‘ SE. SI. SK TR)‘ OAPI (BF, BJ. CF. CG. CL CM.
`GA, {'iN, (3Q. (iW, ML. MIL NIB, SN, TD. TU}.
`Pulllished;
`
`with imermmrma! ward} mm” Ma. 2! r3);
`
`(88) Date of puhllcnthm nf the internatinnal search repnrl:
`I4 April 3005
`
`(48') Date of publication of this corrected version:
`26 January EDIT
`
`{15)
`
`Information about Carnation:
`sec Notice oflfi January 2017
`
`Liquidia - Exhibit 1008 - Page 2
`
`Liquidia - Exhibit 1008 - Page 2
`
`

`

`W0 2005/0070!”
`
`PCTI‘ U SZUlI-‘Mll (140]
`
`COMPOUNDS AND METHODS FOR DELIVERY OF PROSTACYCLIN
`ANALOGS
`
`CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
`
`This application claims benefit of US. Provisional Application Serial No.
`
`60f472,407, filed on May 22, 2003, the entire contents of which are incorporated by
`
`reference herein.
`
`FIELD OF THE INVENTION
`
`This invention pertains generally to prostacyclin analogs and methods for their
`
`use in promoting vasodilation, inhibiting platelet aggregation and thrombus
`
`formation, stimulating thrombolysis, inhibiting cell proliferation (including vascular
`
`remodeling), providing cytoprotection, preventing atherogenesis and inducing
`
`angiogenesis. Through these prostacyclin-rnimetic mechanisms, the compounds of
`
`the present invention may be used in the treatment ofi’for: pulmonary hypertension,
`
`ischernic diseases (e.g., peripheral vascular disease, Raynaud’s phenomenon,
`
`Scleroderrna, myocardial ischemia, ischemic stroke, renal insufficiency), heart failure
`
`(including congestive heart failure), conditions requiring anticoagulation (e.g., post
`
`MI, post cardiac surgery), thrombotic microangiopathy, extracorporeal circulation,
`
`central retinal vein occlusion, atherosclerosis, inflammatory diseases (e.g., COPD,
`
`psoriasis), hypertension (e.g., preeclampsia), reproduction and parturition, cancer or
`
`other conditions of unregulated cell growth, cell)Jtissue preservation and other
`
`emerging therapeutic areas where prostacyclin treatment appears to have a beneficial
`
`role. These compounds may also demonstrate additive or synergistic benefit in
`
`Liquidia - Exhibit 1008 - Page 3
`
`Liquidia - Exhibit 1008 - Page 3
`
`

`

`W0 leflfiiflfl'fllfll
`
`PCTI'USZIlfl-lill l64lll
`
`combination with other cardiovascular agents (e. g, calcium channel blockers,
`
`phosphodiesterase inhibitors, endothelial antagonists, antiplatelet agents).
`
`BACKGROUND OF THE INVENTION
`
`Many valuable pharmacologically active compounds cannot be effectively
`
`administered orally for various reasons and are generally administered via intravenous
`
`or intramuscular routes. These routes of administration generally require intervention
`
`by a physician or other health care professional, and can entail considerable
`
`discomfort as well as potential local trauma to the patient.
`
`One example of such a compound is treprostinil, a chemically stable analog of
`
`prostacyclin. Although treprostinil sodium (Remodulin®) is approVed by the Food
`
`and Drug Administration (FDA) for subcutaneous administration, trcprostinil as the
`
`free acid has an absolute oral bioavailability of less than 10%. Accordingly, there is
`
`clinical interest. in providing treprostinil orally.
`
`Thus, there is a need for a safe and effective method for increasing the
`
`systemic availability of treprostinil via administration of treprostinil or treprostinil
`
`analogs.
`
`SUM'MARY OF THE INVENTION
`
`I11 one embodiment, the present invention provides a compound having structure
`
`
`
`OCH2C02R1
`
`Liquidia - Exhibit 1008 - Page 4
`
`Liquidia - Exhibit 1008 - Page 4
`
`

`

`W0 2(Hi5/flil7fl81
`
`PCTIUSZIIfl-llllifielfll
`
`wherein,
`
`R1 is independently selected from the group consisting ofH, substituted and
`1
`
`unsubstituted benzyl groups, and groups wherein OR are substituted or unsubstituted
`
`glycolamide esters;
`
`R2 and R3 may be the same or different and are independently selected from
`
`the group consisting of H, phosphate and groups wherein 017?.2 and OR3 form esters of
`
`amino acids or proteins, with the proviso that all of R‘, R2 and R3 are not H;
`
`an enantiomer of the compound;
`
`and phannaceutically acceptable salts ofthe compound and polymorpbs.
`
`In some ofthese embodiments, RI is a substituted or unsubstituted benzyl
`
`group, such as CHgCEI-Is,
`
`in other embodiments, OR1 is a substituted or unsubstituted
`
`glycolamide ester, R1 is -CH2CONR4R5, R.4 and R5 may be the same or different and
`
`are independently selected fi'om the group consisting of H, OH, substituted and
`
`unsubstituted allcyl groups, -(CH2)mCH3, -CH20H, and -CH;(CH2),,0H, with the
`
`proviso that m is 0,1, 2, 3 or 4, and n is 0,1, 2, 3 or 4.
`
`in certain ofthese
`
`embodiments one or both ofR4 and Rj are independently selected from the group
`
`consisting of H, -0H, -CH3, or -CH3CH;OH. In any of the previously discussed
`
`embodiments, one or both of R2 and R3 can be H. In some enantiomers ofthe
`
`compound R1=R2=R3=H, or R2=R3=H and a1=va1iny1 amide.
`
`In still further embodiments of the present compounds R2 and R3 are
`
`independently selected from phosphate and groups wherein OR1 and OR3 are esters of
`
`amino acids, dipeptides, esters of tripeptides and esters of tetrapeptides. In some
`
`, compounds only one of R2 or 13?.3 is a phosphate group. In other compounds R2 and R3
`
`are independently selected from groups wherein OR2 and OR3 are esters of amino
`
`acids, such as esters of glycine or alanine. In any of the above embodiments, one of
`
`R2 and R3 are H. In certain of the present compounds, the oral bioavailability of the
`
`compound is greater than the oral bioavailability of treprostinil, such as at least 5 0%
`
`or 100% greater than the oral bioavailability of treprostinil. The above compounds
`
`can further comprise an inhibitor ofp-glycoprotein transport. Any of these
`
`compounds can also filrther comprise a pharmaceutically acceptable excipient.
`
`Liquidia - Exhibit 1008 - Page 5
`
`Liquidia - Exhibit 1008 - Page 5
`
`

`

`W0 2005fllfl'fllli I
`
`PCTIUSZIJfl-UII l 6401
`
`The present invention also provides a method of using the above compounds
`
`therapeutically ofi’ for: pulmonary hypertension, ischemic diseases, heart failure,
`
`conditions requiring anticoagulation, thrombotic microangiopathy, extracorporeal
`
`circulation, central retinal vein oCcIusion, atherosclerosis, inflammatory diseases,
`
`hypertension, reproduction and parturition, cancer or other conditions of unregulated
`
`cell growth, cellt’tissuc preservation and other emerging therapeutic areas Where
`
`prostacyclin treatment appears to have a beneficial role. A preferred embodiment is a
`
`method of treating pulmonary hypertension andfor peripheral vascular disease in a
`
`subject comprising orally administering a pharmaceuticali y effective amount of a
`
`compound of structure 11:
`
`
`
`6st
`
`-um+|0R2
`
`
`
`OCHzCOgR-j
`
`wherein,
`
`R] is independently selected from the group consisting of H, substituted and
`
`tmsubstituted alkyl groups, arylallryl groups and groups wherein ORl form a
`
`substituted or unsubstituted glycolarnide ester;
`
`R2 and R3 may be the same or different and are independently selected from
`
`the group consisting of H, phosphate and groups wherein (R2 and OR3 form esters of
`
`amino acids or proteins, with the proviso that all of R1, R1 and R3 are not H;
`
`an enantiomer of the compound; and
`
`a pharmaceutically acceptable salt or polymorph of the compound.
`
`In some of these methods, when OR1 forms a substituted or unsubstituted
`
`glycolamide ester, R1 is -CH3COI\1R4R5, wherein R4 and RS may be the same or
`
`different and are independently selected from the group consisting of H, OH,
`
`Liquidia - Exhibit 1008 - Page 6
`
`Liquidia - Exhibit 1008 - Page 6
`
`

`

`W0 2005filllfllfl I
`
`PCTIUSZIHl-Ull l 6401
`
`substituted and unsubstituted alkyl groups, -(CH2)mCH3, "CH20H, and -
`
`CH3(CH2)nOH, with the proviso that m is 0, l, 2, 3 or 4, and n is O, 1, 2, 3 or 4.
`
`In
`
`other methods R1 is a C1-C4 alkyl group, such as methyl, ethyl, propyl or butyl. In the
`
`disclosed methods, R1 can also be a substituted or unsubstituted benzyl group. In
`
`other methods, R‘ can be -cm or magmas. In still other methods a“ and R5 are the
`
`same or different and are independently selected from the group consisting of H, OH,
`
`-CH;, and -CHzCHgOI-I. In yet other methods, one or both of FL2 and R3 are H.
`
`Alternatively, one or both ofR2 and R3 are not H and R2 and R3 are independently
`
`selected from phosphate and groups wherein OR2 and OR3 are esters of amino acids,
`
`dipeptides, esters of tripeptides and esters of tetrapeptides. In some methods, only
`
`one of R2 or R3 is a phosphate group. In additional methods, R2 and R3 are
`
`independently selected iii-om groups wherein OR2 and OR3 are esters of amino acids,
`
`such as esters of glycine or alanine. In further methods one ofR1 and R2 is H. In
`
`some methods, enantiomers of the compound where R1=R2=R3=H, or R2=R3=H and
`
`R1=valinyl amide are used.
`
`In various methods the oral bioavailability of the compound is greater than the
`
`oral bioavailability of treprostinil, such as at least 50% or 100% greater than the oral
`
`bioavailahility of treprostinil. The present methods can also comprise administering
`
`pharmaceutically effective amount of a p-glycoprotein inhibitor, simultaneously,
`
`sequentially, or prior to administration of the compound of structure II.
`
`In some
`
`embodiments the p-glycoprotein inhibitor is administered orally or intravenously.
`
`The disclosed methods can be used to treat pulmonary hypertension.
`
`The present invention also provides a method of increasing the oral
`
`bioavailability of treprostinil or pharmaceutically acceptable salt thereof, comprising
`
`administering a pharmaceutically effective amount of a p-glycoprotein inhibitor and
`
`orally administering a pharmaceutically effective amount of treprostinil to a subject.
`In certain of these embodiments the p-glycoprotein inhibitor is administered prior to
`
`or simultaneously with the treprostinil. The route of the p—glycoprotein inhibitor
`
`administration can Vary, such as orally or intravenously. The present invention also
`
`provides a composition comprising treprostinil or a phannaceutically acceptable salt
`
`thereof and a p-glycoprotein inhibitor.
`
`Liquidia - Exhibit 1008 - Page 7
`
`Liquidia - Exhibit 1008 - Page 7
`
`

`

`W0 2t|05fllll7ll31
`
`PCTIUSZIIO-lill l64ll|
`
`The present compound can also be administered topically or transdermally,
`
`Pharmaceutical formulations according to the present invention are provided
`
`which include any of the compounds described above in combination with a
`
`pha1rnaceutically acceptable carrier.
`
`The compounds described above can also be used to treat cancer.
`
`Further objects, features and advantages of the invention will be apparent fi'om
`
`the following detailed descn'ption.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figures 1A and 1B respectively show plasma concentration versus time curves
`
`for intravenous and intraportal dosing of treprostinil diethanolamine salt in rats as
`
`described in Example 1;
`
`Figures 2A, 213 and 2C respectively show plasma concentration versus time
`
`curves for intraduodenal, intracolonic and oral dosing of treprostinil diethanol amine
`
`salt in rats as described in Example 1;
`
`Figure 3 shows on a logarithmic scle the average plasma concentration versus
`
`time curves for the routes of administration described in Example 1 ;
`
`Figure 4 is a graphical representation of the plasma concentration versus time
`
`curve for treprostinil in rat following oral administration in rats of treprostinil methyl
`
`ester as described in Example 2;
`
`Figure 5 is a graphical representation cfthe plasma concentration versus time
`
`curve for treprcstinil in rat following oral administration in rats of treprostinil benzyl
`
`ester as described in Example 2;
`
`Figure 6 is a graphical representation of the plasma concentration versus time
`
`curve for treprostinil in rat following oral administration in rats of treprostinil
`
`diglycine as described in Example 2;
`
`Figure 7 is a graphical representation of the plasma concentration versus time
`
`curve for treprostinil in rat following oral administration in rates of treprostinil benzyl
`
`Liquidia - Exhibit 1008 - Page 8
`
`Liquidia - Exhibit 1008 - Page 8
`
`

`

`W0 200500708!
`
`I’CT.Jr [15200410 I64!”
`
`ester (0.5-mg/lcg) and treprostinil diglycine (0.5 mg/kg) as described in Example 2
`
`compared to treprostini] (l rag/per kg).
`
`Figure 8 is a graphical representation of the plasma concentration versus time
`
`curve for treprostinil in rat following intraduodenal administration of treprostinil
`
`monophosphate (ring) as described in Example 3;
`
`Figure 9 is a graphical representation of the plasma concentration versus time
`
`curve for treprostinil in rat following intraduodcual administration of [reprostinil
`
`monovaline (ring) as described in Example 3;
`
`Figure 10 is a graphical representation of the plasma concentration versus time
`
`curVe for neprostinil in rat following intraduodenal administration oftreprostinil
`
`monoalanine (ring) as described in Example 3;
`
`Figure I l is a graphical representation of' the plasma concentration versus time
`
`curve for treprostinil in rat foliowing intraduodenal administration of treprostinil
`
`monoalanine (chain) as described in Example 3', and
`
`Figure 12 is a graphical representation of the avergage plasma concentration
`
`Versus time curve for each prcdrug compared to treprostinil alone from Example 1, as
`
`described in Example 3. Treprostinil was dosed at l mgl'kg whereas the prodrugs were
`
`dosed at 0.5 mg/kg.
`
`Figures 13A— 1313 respectively show doses, administered every two hours fer
`
`four doses, for either 0.05 mg per dose (total = 0.2 mg), 0.125 mg per dose (total = 0.5
`
`mg), 0.25 mg per dose (total = 1.0 mg), or 0.5 mg per dose (total = 2.0 mg).
`
`Figure 14 shows pharmacokinetic profiles of UT-l 5C sustained release tablets
`
`and sustained release capsules, fasted and fed state.
`
`Figure 15 shows an X ray powder diffraction spectrum of the polymorph Form
`
`Figure 16 shows an IR Spectnnn of the polymorph Form A.
`
`Figure 1'? shows a Raman spectrum of the polymorph Form A,
`
`Figure 18 shows then'nal data of the polymorph Form A.
`
`Liquidia - Exhibit 1008 - Page 9
`
`Liquidia - Exhibit 1008 - Page 9
`
`

`

`W0 200500708!
`
`PCTJ'USZIIIJMH lti-‘llll
`
`Figure 19 shows moisture sorption data of the polymorph Form A.
`
`Figure 20 shows an X ray powder diffraction Spectrum of the polymorph Form
`
`Figure 2] shows thermal data of the polymorph Form B.
`
`Figure 22 shows moisture sorption data of the polymorpll Form B..
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Unless otherwise specified, “a” or “no” means “One or more". The present
`
`inVention provides compounds and methods for inducing prostacyclin—like efiects in a
`
`subject or patient. The compounds provided herein can be formulated into
`
`pharmaceutical formulations and medicaments that are useful in the methods of the
`
`invention. The invention also provides for the use of the compounds in preparing
`
`medicaments and pharmaceutical formulations and for use of the compounds in
`
`treating biological conditions related to insufficient prostacyclin activity as outlined in
`
`the Field of Invention. The present invention also provides compounds and methods
`
`for the treatment of cancer and cancer related disorders.
`
`In some embodiments, the present compounds are chemical derivatives of (+)-
`
`treprostinil, which has the following structure:
`
`
`
`OCHECOQH
`
`Tteprostinil is a chemically stable analog of prostacy'clin, and as such is a
`
`potent vasodilator and inhibitor of platelet aggregation. The sodium salt of
`
`treprostioil, (1R,2R,3aS,9&S)—[[2,3,3 a,4,9.9a —Hexahydro-2—hydroxy —-1-[(3S)-3—
`
`hydroxyoctyl}lH—bcnz[t]inclen-5-yi] oxy]acetic acid monosodiurn salt, is sold as a
`
`Liquidia - Exhibit 1008 - Page 10
`
`Liquidia - Exhibit 1008 - Page 10
`
`

`

`W0 2005,1007"!!!
`
`PCTIUSZIlfl-lr‘ll l64ll|
`
`solution for injection as Remodulin® which has been approved by the Food and Drug
`
`Administration (FDA) for treatment of puhnonary hypertension. In some
`
`embodiments, the present compounds are derivatives of (-)«treprostinil, the
`
`enantiomer of (+)-treprostini1. A preferred embodiment of the present invention is the
`
`diethanolamine salt of treprostinil. The present invention further includes pclymorphs
`
`of the above compounds, with two forms, A and B, being described in the examples
`
`below. Of the two forms, B is preferred. A particularly preferred embodiment of the
`
`present invention is form B of treprostinil diethanolamine.
`
`In some embodiments, the present compounds are generally classified as
`
`prodrugs of treprostinil that convert to treprostinil after administration to a patient,
`
`such as through ingestion. In some embodiments, the prodrugs have little or no
`
`activity themselves and only show activity after being converted to treprostinil. In
`
`some embodiments, the present compounds were produced by chemically derivatizing
`
`treprostiuil to make stable esters, and in some instances, the compounds were
`
`derivatized from the hydroxyl groups. Compounds of the present invention can also
`
`be provided by modifying the compounds found in US. Patent Nos. 4,306,075 and
`
`5,153,222 in like manner.
`
`In one embodiment, the present invention provides compounds of structure I:
`
`
`
`0C H2002R1
`
`wherein,
`
`R1 is independently selected from the group consisting of H, substituted and
`
`unsubstituted benzyl groups and groups wherein OR] are substituted or unsubstituted
`
`glycolaroide esters;
`
`Liquidia - Exhibit 1008 - Page 11
`
`Liquidia - Exhibit 1008 - Page 11
`
`

`

`W0 2005,1007"!!!
`
`PCTIUSZIIII-lill l64ll|
`
`R2 and R3 may be the same or different and are independently selected from
`
`the group consisting ofH, phosphate and groups wherein OR1 and OR3 fonn esters of
`
`amino acids or proteins, with the proviso that all of R] , R2 and R3 are not H;
`
`enantiomers of the compound; and
`
`pharmaceutically acceptable salts of the compound
`
`In some embodiments wherein ORl are substituted or unsubstituted
`
`glycolamide esters, RI is -CH1CONR4R5 and FL4 and R5 maybe the same or different
`
`and are independently selected from the group consisting of H, OH, substituted and
`
`unsubstituted alkyl groups, —(CH1)mCH3, -CH20H, and —CH2(CH2),,OH, with the
`
`proviso that m is 0,1, 2, 3 or4, andnis 0,1, 2, 3 or4.
`
`One skilled in the art will also readily recognize that where members are
`
`grouped together in a common manner, such as in a Markush group or the groups
`
`described in the R of structures I and II above and below,' the present invention
`
`encompasses not only the entire group listed as a whole, but each member of the
`
`group individually and all possible subgroups of the main group. Accordingly, for all
`
`proposes, the present invention encompasses not only the main group, but also the
`
`main groupabsent one or more of the group members. The present invention also
`
`envisages the explicit exclusion of one or more of any of the group members in the
`
`claimed invention. For example, R1 can specifically exclude H, substituted and
`
`unsubstituted benzyl groups, or groups wherein ORI are substituted. or unsubstituted
`
`glycoiarnide esters.
`
`In some embodiments, R1 is a substituted or unsubstituted benzyl groups, such
`
`as -CH2C5H5, -CH2CGI-14N03, -CH2C5H40CH3, -CH2C5H4C1, -CH:C5H4CNO;)2, or -
`
`CH2C5H4F. The benzyl group can be ortho, meta, para, ortho/para substituted and
`
`combinations thereof. Suitable substituents on the aromatic ring include halogens
`
`(fluorine, chlorine, bromine, iodine), -N03 groups, #038.“ groups wherein R"5 is H or
`
`a C1-C4 alkyl group, and combinations thereof.
`
`Alternatively, when R1 is -CH;CONR4R5 then R4 and R5 may be the same or different
`
`and are independently selected from the group consisting of H, OH, -CH3, and -
`
`ID
`
`Liquidia - Exhibit 1008 - Page 12
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`Liquidia - Exhibit 1008 - Page 12
`
`

`

`W0 ZIIOSIfli‘ITIIBI
`
`PCT! [152004.10 l6-llll
`
`CHZCHEOH. In these compounds where R' is not H, generally one or both ofR1 and
`
`R3 are H.
`
`In some embodiment one or both ot'R2 and R3 are H and R1 is -CH;CONR4R5,
`
`and one or both of R4 and Rs are H, -OH, -CH3, -CH2CH20H.
`
`In compounds where one or both of R2 and R3 are not H, R2 and R3 can be
`
`independently selected from phosphate and groups wherein OR2 and OR3 are esters of
`
`amino acids, dipeptides, esters of tripeptides and esters of tetrapeptides. In some
`
`embodiments, only one of R2 or R3 is a phosphate group.
`
`In compounds where at
`
`least one of R2 and R3 is not H, generally R' is H. In additional embodiments, one of
`
`R2 and R3 are H and thus the compound of structure I is derivatized at only one of R2
`
`and R3. In particular compounds, R2 is H and R3 is defined as above.
`
`In additional
`
`embodiments, R1 and R3 are H and R2 is a group wherein OR2 is an ester of an amino
`
`acid or a dipeptide. 1n flirther embodiments, R' and R2 are H and R3 is a group
`
`wherein OR3 is an ester of an amino acid or a dipeptide.
`
`When one or both of the OR2 and OR3 groups form esters of amino acids or
`
`peptides, i.e., dipeptides, tripeptides or tetrapeptides, these can be depicted genetically
`
`as «COCHRGNRTRa wherein R6 is selected fiom ”the group consisting of amino acid
`
`side chains, R7 and RE may be the same or different and are independently selected
`
`iron: the group consisting of H, and -COCl-IR9NR'°R”. Generally, reference to
`
`amino acids or peptides refers to the naturally occurring, or L—isomer, of the amino
`
`acids or peptides. However, the present compounds and methods are not limited
`
`thereto and D-isomer amino acid residues can take the place of some or all of L—
`
`amino acids. In like manner, mixtures of D— and L-isomers can also be used. In the
`
`embodiments wherein the amino acid is proline, R7 together with R6 forms a
`
`pyn‘olidine ring structure. Rti can be any ofthe naturally occurring amino acid side
`
`chains, liar example —CH3 (alanine), -(CH2)3NHCNH;NH (arginine), -CH2CONH2
`
`(asparagine), -CH2COOH (asparfic acid,), —CH2$H (cysteine), -(CH2)2CONH2
`
`(glutamine), —(CH2)2COOH (glutamic acid), -H (glycine), ~CHCH3CH2CH3
`
`(isoleucine), -CH;CH(CH3)2 (leucine), «(CH3)4NH2 (lysine), -(CHg)28CH3
`(methionine), —CHZPh (phenylalanine), «CHZOH (serine), -CHOHCH3 (threonine), -
`
`CH(CH3)2 (valine),
`
`ll
`
`Liquidia - Exhibit 1008 - Page 13
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`Liquidia - Exhibit 1008 - Page 13
`
`

`

`W0 leflfimll'l'lliil
`
`PC T! USleflaH'OlG-Ifll
`
`H2 / NH
`-—C
`
`[lfisfidinel@
`
`Hz
`
`21'
`
`tenement
`
`—‘3
`
`0“
`
`(W6).
`
`~(CH2)3NHCONH3 (citrulline) or -(CH3)3NH3 (omithine'). Ph designates a phenyl
`
`group.
`
`In the above compounds, R1' and Rl'I may be the same or different and are
`
`selected fi'om the group consisting of H, and HCOCHRBNRI uRl 1, wherein R9 is a side
`
`chain of amino acid, R'” and RIl may be the same or different and are selected from
`
`the group consisting of H, and —COCHR12NR”RI4, wherein R12 is an amino acid side
`
`chain, R13 and RM may be the same or different and are independently selected from
`
`the group consisting of H, and —COCHRIENH2. One skilled in the art will realize that
`
`the peptide chains can be extended on the following scheme to the desired length and
`
`include the desired amino acid residues.
`
`In the embodiments where either or both of OR2 and OR3 groups form an ester
`
`of apeptide, such as dipeptide, tripeptide, tetrapeptide, etc. the peptides can be either
`
`homopeptides, i.e., repeats of the same amino acid, such as arginyl-arginine, or
`
`heteropeptides, '1.e., made up of different combinations of amino acids. Examples of
`
`heterodipeptides include alanyl-glutamine, glycyl—glutamine, lysyI-arginine, etc.
`
`As will be understood by the skilled artisan when only one R7 and RB includes
`
`apeptide bond to further amino acid, such as in the di, tri and tetrapeptides, the
`
`resulting peptide chain will be linear. When both R7 and R3 include a peptide bond,
`
`then the peptide can be branched.
`
`12
`
`Liquidia - Exhibit 1008 - Page 14
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`Liquidia - Exhibit 1008 - Page 14
`
`

`

`W0 2tl05fflll'l'll81
`
`PCTI'USZIIfl-HII l64lll
`
`In still other embodiments of the present compounds R1 is H and one of R2 or
`
`R3 is a phosphate group or H while the other R;1 or R3 is a group such the OR2 or OR3
`
`is an ester of an amino acid, such as an ester of glycine or alanine.
`
`Phannaceutically acceptable salts of these compounds as well as
`
`pharmaceutical formulation of these compounds are also provided.
`
`Generally, the compounds described herein have enhanced oral bioavailability
`
`compared to the oral bioavailability of treprostinil, either in flee acid or salt form.
`
`The described compounds can have oral bioavailability that is at least 25%, 50%
`
`100%, 200%, 400% or more compared to the oral bioavailability of treprostinil. The
`
`absolute oral bioavailability of these compounds can range between 10%, 15%, 20%,
`
`25%, 30% and 40%, 45%, 50%, 55%, 60% or more when administered orally. For
`
`comparison, the absolute oral bioavailability of treprostinil is on the order of 10%,
`
`although treprostinil sodium has an absolute bioavailability approximating 100%
`
`when administered by subcutaneous infusion.
`
`As will be understood by one skilled in the art, for any and all purposes,
`
`particularly in terms of providing a written description, all ranges disclosed herein,
`
`and in particular the bioavailability ranges described herein also encompass any and
`
`all possible subranges and combinations of subranges thereof. As only one example,
`
`a range of 20% to 40%, can be broken down into ranges of20% to 32.5% and 32.5%
`
`to 40%, 20% to 27.5% and 27.5% to 40%, etc. Any listed range can be easily
`
`recognized as sufficiently describing and enabling the same range being broken down
`
`into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting
`
`example, each range discussed herein can be readily broken down into a loWer third,
`
`middle third and upper third, etc. As will also be understood by one skilled in the art
`1} 0‘
`all language such as “up to,” “at least,” “greater than,” “less than, more than” and
`
`the like include the number recited and refer to ranges which can be subsequently
`
`broken down into subranges as discussed above. In the same manner, all ratios
`
`disclosed herein also include all subratios falling within the broader ratio.
`
`Administration of these compounds can be by any route by which the
`
`compound will be bioavaflable in effective amounts including oral and parenteral
`
`13
`
`Liquidia - Exhibit 1008 - Page 15
`
`Liquidia - Exhibit 1008 - Page 15
`
`

`

`W0 2005/0070“ I
`
`PCTI‘ U SZUII-‘lflll 640]
`
`routes. The compounds can be administered intravenously, topically, subcutaneously,
`
`intranasally, rectally, intramuscularly, transdennally or by other parenteral routes.
`
`When administered orally, the compounds can be administered in any convenient
`
`dosage form including, for example, capsule, tablet, liquid, susPension, and the like.
`
`Testing has shown that that treprostinil can be irritating upon skin contact. In
`
`contrast, some of the compounds disclosed herein, generally as prodrugs of
`
`treprostini], are not irritating to the skin. Accordingly. the present compounds are
`
`well suited for topical or transdennal administration
`
`When administered to a subject, the above compounds, and in particular the
`
`compounds of structure I, are prostacyclin—mirnetic and are useful in treating
`
`conditions or disorders where vasodilation and/or inhibition of platelet aggregation or
`
`other disorders where prostacyclin has shown benefit, such as in treating pulmonary
`
`hypertension. Accordingly, the present invention provides methods for inducing
`
`prostacyclin~like effects in a subject comprising administering a phannaceutically
`
`effective amount of one or more of the compounds described herein, such as those of
`
`structure I above, preferably orally, to a patient in need of such treatment. As an
`
`example, the vasodilating effects of the present compounds can be used to treat
`
`pulmonary hypertension, which result from various forms of connective tissue
`
`disease, such as lupus, sclenodenna or mixed connective tissue disease. These
`
`compounds are thus useful for the treatment of pulmonary hypertension.
`
`In another embodiment, the present invention also provides methods of
`
`promoting prostacyclin—like effect in a subject by administering a phannaceutically
`
`effective amount of a compound of sttucuu‘e II:
`
`
` 6R3
`
`.uIIIIIIQR2
`
`OCHZCOER1
`
`14
`
`Liquidia - Exhibit 1008 - Page 16
`
`Liquidia - Exhibit 1008 - Page 16
`
`

`

`W0 2005,1007"!!!
`
`PCTIUSZIIO-lill l64ll|
`
`wherein,
`
`R' is independently selected from the group consisting ofH, substituted and
`
`unsubstituted alkyl groups, aiylalkyl groups and groups wherein OR] form a
`
`substituted or unsubstituted glycoiarnide. ester;
`
`RI and R3 may be the same or different and are independently selected fiorn
`
`the group consisting of H, phosphate and groups wherein OR2 and OR3 form esters of
`
`amino acids or proteins, with the proviso that all of R1, R2 and R3 are not B;
`
`an cnantiomcr of the compound; and
`
`e phannaceutically acceptable salt of the compound.
`
`In groups wherein OR' form a substituted or unsubstituted glycolamide ester,
`
`R1 can be -CH2CONR4R5, wherein R4 and R5 may be the same or different and are
`
`independently selected from the group consisting of H, OH, substituted and
`
`unsubstituted alkyl groups, -(CH2)mCH3, ~CH30H, and -CH2(CH2),,OH, with the
`
`proviso that m is 0, 1, 2, 3 or 4, and n is 0, 1, 2, 3 or 4.
`
`In other methods of inducing vasodilation or treating hypertension, R1 can be a
`
`C1—C4 alkyl group, such as methyl, ethyl, propyl or butyl. In other methods R1 is a
`
`substituted or unsubstituted benzyl groups, such as -CH;C5H5, -CH2C5H4N02, ~
`
`CH3C5H40CH3, -CH2C5H4C1, ~CH3C5H4CNOfl2, or -CH2C5H4F. The benzyl group
`
`can be ortho, meta, para, orthofpara substituted and combinations thereof. Suitable