[12] United States Patent
`(10) Patent NIL:
`US 8,410,121 32
`
`Sands
`(45) Date of Patent:
`Apr. 2, 2013
`
`U8008410121B2
`
`
`
`
`
`75
`
`1’3
`
`III
`
`21
`
`32
`65
`
`54 MHI‘HODS()F't‘R}:.\'1‘N:PULMONARY
`HYPI‘IR’I‘I‘INSION
`.
`‘
`‘
`'
`1
`.
`Imcntor. Arthur [. Sands,
`(US)
`
`'
`
`'
`'
`f
`|11c Woodlands, IX
`
`Assigncc: Lexicon Pharmaceuticals, Inc.‘ The
`Woodlands. TX (L's)
`
`_
`N I
`nttLe.
`
`II 1"
`I
`I
`d" |
`‘i b'
`lhl. duller: I It: term u I us
`. uII1eLtItutme
`pulenl Iii extended or adjusted Ilntler 35
`U .317. 1540‘} h)” 73 days—
`
`Appl. N0.: 130305592
`
`Filed:
`
`"“11- 14,2011
`Prior Publication Data
`
`1
`US ~01 1’01 12094 Al
`
`May 12. 291 1
`
`Related L'.S. Application Data
`
`arml=uwllls A1
`2004;014:299] Al
`2004.:‘(1l5801'fi Al
`300450209997 Al
`2005056803 At
`2006:0[54936 M
`20093000538] Al
`
`2009-0048280 Al
`200‘)r0054308 Al
`
`10-2003 sum
`7.2004 Nag
`8.2004 Jackson
`100004 Vernier
`11-3005 (Than
`mums Lusty
`[-2009 Brown
`
`33009 BUIEUUH
`263009 Sands
`
`EP
`“.0
`W0
`“(0
`WT)
`W0
`
`FOREIGN PATENT DOCUMENTS
`1091711
`5.-'20t]|
`WOQI'DITM
`1199'
`Wt) 2004:13l7‘l‘l‘a
`3.711114
`“F0 2004f058'f62
`12004
`WU 20053044'ISO
`552005
`W0 20083073928
`(1.52008
`
`{III II-LR PUBLICATIONS
`Driscoll, IA. and Chakinaia. M.M.. Eur}? 0pm. Phammmrtmr.
`
`9(l]:65—Rl (2008].
`Eddahibi. s. et 3.1.. (J'r'tm’au'vn 113t_15):1857-1864 (2006).
`lzikki. M. or aL Am. .I Ph}..¢f0f. 11mg ('01! Mot. Pt:3._rint. 2931.1045-
`]_ IDSE (200?).
`].iu. 0. CI al.. J. l‘harlmicol. 1-317. 1110'. 325(1 ]:47-55 (2008].
`Mac].can.M.R.. I’m. J. C'ttn. Pmn‘. fitt'suppl. 1582731 (200?).
`MacLean. MR. and Dempsie. Y.. Curr. 0pm. th'mrrrot. 9:1-6
`(2009;.
`.
`Moreerafl. I. et at. hit};erten.§mu 49232—236 (ZUUTJ.
`[)Issnn. K.M. :Intl Hneper, MNL Drng Dim Pitta}: 00:10”) (7.008).
`Shi. K-(Iu et al.. J. Med. Chem. .‘3 II_I3]:3684-3fi‘87 (2008].
`Inlernalinnal Search R
`I11 and “’rillcnt
`ininn forfnrrcs omlin
`International Appliealijz l‘ublieatiun WUIEUOS.-0694?1. defied Se:
`12003,
`
`Raymond Henley. III
`Primary lemr'ner
`(74) :1 Emmett. Agent. or Firm Max Bachraeh
`
`(57")
`
`A BS'I‘RAL'T
`
`Methods 01‘ treating pnlmtmary hypertension are disclueetl.
`szictllur methods cuntprixe the administration til :I
`Iryp—
`tnphun hydmxylmie inhihilnmnd n pmstneyciin. Phnmmcctt—
`tical termination-s. are also disclosed.
`
`13 Claims, 1 Drawing Sheet
`
`[63] Continuation of application No. 12t']69.815, filed on
`‘h'l‘ 9‘ 2008, new Pat‘ NU' 1375-621
`Provisional application No. 601949.040. filed on Jul.
`1 l. 2001
`
`[60]
`
`[51]
`
`Int' Cl"
`(20060”
`A61K 310105
`5141069
`[52] U.S. Cl.
`. 514.3269
`[58] Field of Classification Search
`Sec application file for complete search history.
`
`[5(1)
`
`References Cited
`
`U‘b' PAH—lb 1 DUI“ UMEN 15
`4120.34 A
`5"IJ-97? SE0"?
`.
`:gfié'igg 2%
`233% 32:33:31:
`11'2334'5 32
`5.29m Dwamgaynfij
`7.875.622 152
`1520“ Sands
`2003-0130349 A1
`?:'2003 Lubi
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01622
`
`UNITED THERAPEUTICS, EX. 2081
`
`Page 1 of 41
`
`

`

`US. Patent
`
`Apr. 2, 2013
`
`US 3,410,121 132
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`iH—§ MEGEJiNOS :33 33.7
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01622
`
`UNITED THERAPEUTICS, EX. 2081
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`

`US 8,410,]2l B2
`
`1
`METHODS OF 'I‘REA'I‘ING PULMONARY
`HYPERTENSION
`
`This appiieation is a wntinuation UTILS. patent applica—
`lion Ser. No. 12’] 69.81 5. tiled Jul. 9. 2008. now U .5. Pat. No.
`”£375,622, which claims priority to US. provisional applica—
`tionno.ti(li949.04tl. tiled Jul. l1.2007.tlmentiretiesol‘which
`are irmorporatcd herein by reference,
`
`5
`
`1. I-‘IIEID (Jl-'
`
`'I'I ili lNVIiN'I'ION
`
`This invention relates to methods and compositions for the
`treatment of pulmonary hypertension and related diseases
`and disorders.
`
`2‘ BACKG ROW
`
`IU
`
`15
`
`40
`
`2
`vaseulature sum-nth Inuwlc. thereby preventing the neurohor—
`mone eudotlielin—l (HT—I) from binding to these same recep—
`tor sites and triggering yasoconstriction. 1d. at 76-”. An
`example ol‘an ERA is hosenlan {TRACLl'il'iRt-Ttl).
`Other methods oftrcating 1"” have 130011 investigated. For
`example.- seleclive serotonin reoptake inhibitors (SSRIS)
`reportedly reverse P11 in rats. id. at 3'9. These compounds.
`which are widely used to treat depression. affect the reuptal-Le
`ofthc neurotransmitter serotonin (5-HT).
`Serotonin is syndiesimd in two steps from the amino acid
`tryptophan. Goodman (it Gibson's The Pharmacologicai
`Basis Qi‘iti’icrapcntics, 10'" ed, p. 270 (Mctjraw-llili. 2001).
`The lirst step is rale—linliliug, and is catalyzed by the enzyme
`tryptophan hydroxylasc {‘I‘PI I), which has two known iso—
`Iiirms: 'I‘I’H l_. which is expressed in the periphery, and 'I'I’H 2,
`which is expressed primarily in the brain. Walther. D. J. . et a1.,
`Science 299:76 (2003). Mice genetically deficient for the tpli I
`gene (“knockout mice”) have been reported. in one case. the
`Pulmonary hypertension [Pl 1). or pulmonary artcrial
`mice reportedly expressed normal amounts ol‘ serotonin in
`hypertension (PAH), is a disease characterized by increased
`pulmonary artery pressure and pulmonary vascular rcsis— 3n classic-a] scrotonergie brain rcgions_but]argc1y1ackcd 3cm-
`tance. Harrison '3 Priflcipics inntcmal’ Medicine, 15111 Cd,
`lonin in the periphery. Id.
`In another.
`the knockout mice
`PP- 1505-1507" (MCGFdW-Hills 2001]. Left untreated. PH
`cxhjbitcdabnormal cardiac activity. whichwas attributed toa
`"usually has adistnal prognosis culminating in right ventrieu—
`lack of peripheral gemlonim Cfilé‘ ]'-‘___ ct 211.. PM45 100(23):
`tar lhiitlt‘c and death.“ lJIrich, S“ et at., Swiss Med. Wilt]?
`13525-13530 (2033) Rcccntly_ 'l‘PII knockout lyficc were
`137373—81 73 (2007)-
`T" studied in a hypoxia—induced pulmonary arterial hyperten—
`ln 2003, the world iiealth Organization (Wl l0) sponsored
`sign model. Motocrofi. L! at al._. liypenension 495132.235
`the development ol‘guidelines, called the “Venice classilica—
`(2007), The regulls of Lhasa studies suggest that TPH] and
`mm.“ WhiCh are now HIV-Bil 10 classify [YIN-35 01' PH- httpa"!
`peripheral semtonin “play an essential hole in the develop—
`\vww.traclccr.mmt'dcfault.asp'Epagc—{TouldHavc WHO (80-
`ment of hypoxia—induced elevations in pulmonary pressures
`CCSSL‘d JUH- 29, 200-1")- The fir!“ IYPC‘ WHO Gmllp l-‘- is 3'1 and hypoxia—induced pulmonary vascular remodeling.” 1d. at
`idiopathic pulmonary arterial hypertension (II’AII). This
`231
`refers to PAH that occurs at random. without an apparent
`cause. II‘AII used to bc callcd "primary pulmonary hypcrtcn-
`sion” or PPii. id.
`This invention is directed. in part, to methods of treating
`Thc sccond typc, WI IO Group 1.2, is familial pulmonary 35
`pulmonary hypertension and related diseases and disorders.
`arterial hypertension (FPAi-i). With this type oI‘PAH. a Faulty
`which comprise administering to a patient therapcuticaliy
`gene is passed on through thc family, which causes the PAH
`cfiectiveanlountsofa tryptophanhydroxylase [TH-I) inhibi—
`to develop over time. it is estimated that at
`least 6 to [0
`tor and at least one other aetivc pharmaceutical ingredient.
`pcrccnt of PAH cascs occur in families where at least one
`One embodiment encompasses a method of treating. inan-
`other pcrson has had the disease. 1d.
`aging or preventing pulmonary hypertension, which coin—
`is pulmonary arterial
`'I'hc third type, WI It) (imup 1.3.
`prises administering to a patient in need thereof therapeuti—
`hypcrlcnsion associated with other diseases or conditions
`cally or pmphylactically etiéctive amounts ot'an endotheIin
`{AI’AH}. This used to be called "PAH secondary to other
`receptor antagonist and a tryptophan hydroxylase inhibitor.
`conditions" or Secondary PAH. This category includes PAH
`Another encompasses a method oftreating. managing or
`associated with collagen vascular disease or “connective tis— 4»
`preventing pulmonary hypertension. which comprises
`sue disease" (e.g..sclerodertm1 (SSe)-including CREST syn-
`administering to a patient in need thereof therapeutically or
`drome-lupus
`(SLED,
`congenital
`systemic-to-pulmonary
`pmphylactically el'l'eetive amounts 01‘ an anticoagulant and a
`shunts (congenital heart disease), portal hypertension, lllV
`tryptophan hydrexylase inhibitor.
`ini‘txtion. drugs and toxins. and other diseases and disorders
`Another encompasses a mcthod of treating. managing or
`(cg... thyroid disorders. glycogcn storage diseases. Gauchcr 50
`preventing pulmonary hypenension. which comprises
`disease. hereditary hemorrhagic telangieclasia. hemoglo-
`administering to a paticnt in need thcrcof therapeutically or
`binopathics. mycloprolifcrativc disorders. splcncctomy). 1d.
`pmphylactically ell‘eelive amounts of a calcium channel
`The fourth type. WI IO Group 1.4. is pulmonary arterial
`blocker and a tryptophan hydroxylasc inhibitor.
`hypertcnsion associated with significant venous or capillary
`Another encompasses a method of treating, managing or
`involvement, and includes pulmonary veno—ooelusive disease 55
`preventing pulmonary hypertension. which comprises
`{PV'OD} and pulmonary capillaryhemangiomalosis (PCH).
`administering to a patient in need thereof therapeutically or
`The Iifth and filial type, WHO Group 1.5.
`is persistent
`pmphylaeticaiiy cfi‘ectivc amounts of a prostacyciin and a
`pulmonary hypertension of the newborn. 1d.
`tryptophan hydroxyiasc inhibitor.
`Drugs currcntly used to treat
`I’ll
`include pulmonary
`Another encompasses a method ot‘trcaling. managing or
`vasodilators, calcium channel blockers, and inhibitors of 50
`preventing pulmonary hypertension. which
`comprises
`platelet aggregation. Theittc'rr.-kMantiai. 17Ihed..pp. HUS—4
`administering to a patient in need thereof therapeuticaIIy or
`(Merck Research I aboratories. I999). Diuretics, nitric oxide,
`prophylactically ellectivc amounts o I‘nilric oxide or a nitric
`phosphodicsterasc 5 inhibitors (cg. sildenalil) and endothc—
`oxide precursor or releasing compound, and a tryptophan
`tin receptor antagonists (HRAs) are also used for its treat—
`ment. Uhich. 3.. et 11].. Swiss Med. Wkii' 137:73-32. 76-7? 65 hydroxyhlse inhibitor.
`(200?). Endothelin receptor antagonists work by binding to
`Another encompasses a method of treating. managing or
`the ETA andfor RTE receptor sites in the endothelilmi and
`preventing pulmonary hypertension. which comprises
`
`3. SUMMARY OF THE INVENTION
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01622
`
`UNITED THERAPEUTICS, EX. 2081
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`
`

`

`US 8,410,]2l B2
`
`3
`administering to a patietit in need thereof therapeutically or
`propliylactieiilly ellectivc amounts iil‘a phosphotliestcmse 5
`inhibitor and a tryptophan liydroxylase inhibitor.
`Another encompasses a method of trailing, managing or
`preventing P11 lnionary
`hyperlcnfiium which compritws
`administering to a patient in need thereof therapeutically or
`prophylactically eflective amounts Ufa diuretic and a WP"
`tophan hydroityiase inhibitor.
`Another encompasses a method of treating. managing or
`.1
`.
`,
`.
`_
`.
`.
`prey cilllilg pulmonary
`hyperteiiSion, which comprises
`.
`.y
`.-
`.
`.
`.
`,
`adniinisteiing to a patient in need thereof therapeutically or
`.
`.
`.
`.
`.
`.
`.
`.
`prophylactieally efiective antouiits 01 a platelet derived
`growthfactorl and a tryptoplian liydroxylasc inhibitor.
`.
`the invention also encompasses pharmaceutical formula-
`tiiiiisteg.1 single unit dosage Iorms) composing a‘
`| I’H
`inhibitor and at 1935‘ 011'? Other 3cm": pharmaceutical ingre-
`client.
`
`4- BRIEF DESCRIPUON OFTHE FIGURE
`
`5
`
`10
`
`4
`Unless otherwise indicated. tiie term “alkyiheteroaryi” or
`“alkyl-heteroaryl” means an alkyi moiety bound to a het-
`eroaryl Inoiely.
`Unless olhem'i Ht: indicated, the term “:ilkylhcterocycie“ or
`“alkyl—hetemcyele" nieunsan silty] moiety bound to :ihetero—
`“Etc": '“U‘L‘IY-
`.
`y
`y
`..
`..
`linless otherwtse lntilctlllltl,-Il'lc term :ilkynyi‘ means a
`straight chain. branched or cyclic hydrocarbon haying Irom 2
`to 20 (cg, 2 to 20 or 2 to ti) carbon atoms. and including at
`least one carbon-carbon triple bond. Representative alkynyl
`.
`.
`.
`meietics inclttde aoetylenyl. propynyl. l-butynyl. 2-butynyl.
`_
`l-pentynyl. 2-pentynyl. 3-methyl-l-butynyl. 4-pentynyl.
`eptynyl. _ heptynyl.
`iexyn) .
`i.
`exyn) .
`exyny .
`H
`'I
`“eh
`'1
`57h
`,
`_1
`17h
`.
`9.
`,
`6-11eptynyl.
`1 -octynyl. 2%”me T-octynyl.
`l-nonynyl.
`15 2—iionynyl. Known“: l—decynyi. 2_decyn}.1 and 9—decynyi.
`Unless otherwise indicated. the term “aryi” means an aro-
`tnatic ring or an aromatic or partially aromatic ring system
`composed of carbon and hydrogen atoms. An aiyl moiety
`may comprise multiple rings bound or
`fused together.
`Eu Examples of aryl moieties include antliracenyi. azulenyi,
`biphenyi, lluorcnyl. indan. indenyl. napiithyl, phenantlireiiyi.
`[11.3%,]: l.23_.4—tetniliydru—tiapthaieIie. and 10131
`Unless otherwise indicated. the tertli "aryiaikyl" or "aryi—
`alkyl” means an aryl moiety bound to an alkyl moiety.
`Unless otherwise indicated, the terms ”bioliydrolyznhlc
`amide," “hiohytlrolymble ester." “hioliydrolymhle carham—
`ate." “hiohydrolymble carbonate." “biohydrolyrable ilreido11
`and “hitthydmlrmhlc phosphate" mean 5'“ amide. ester, car—
`baniate. carbonate, ureido. or phosphate. respectively. of a
`3:1 compo Lind that either: ljdoes not interfere with the biological
`activity of the compound but can confer upon that compound
`advantageous properties in vivo. such as uptake. duration of
`
`Aspects ol‘ tiic invention may be understood with reference
`10 the 11118011611 figure. FIG.
`I ShttWS the Ell-WIS ol' 3 11016111
`TPH] itihibitor of the invention in the mouse gastrointestinal
`tract Elndhfllil‘i al‘lcrortiladministration.Alldata arepresentcd )i
`as percentage ol‘ the mean ol‘ the control [vehicle—dosed]
`group. Error bars are ELEM. N—5 per group. The syn'jbqlg; are
`*_. pa‘tltlfi vs control group. For the brain data1 p—tJ.5. one—way
`ANOVA.
`
`5_ DETAILED DESCRIPTION
`
`action. or OPS“ ofaction: or 2) ‘5 b}°1°31°31]§' inactive but 13
`'Ihisinvention is based. in part. on studies of tplil knockout
`converted ll'i- vivo to the biologically active compound.
`mi“. and the discovery ol'colnpountls lltul inhibit lryptophan
`35 Examples of btohydrolyzablc esters include lower alkyi
`hydrexylase (e_g__ THU).
`esters, alitoxyacyioity estets. alkyi acylanimo alkyi esters.
`' 5'], Definitions
`Fwd choline esters. haaniples (if biohydrolyzable amides
`Unless otherwise indicated. the term “alkenvl” means a
`include lower alkyl amides, a—amiiio aeid amides, alkoxyaeyl
`_‘
`.
`.
`y
`.
`y
`.
`_ .. .
`_
`.. '
`_
`.
`.
`‘
`y
`.
`. 1.
`‘.
`all'dlgl‘il chain, branched auditor cyclic hydrocarbon having
`amides, and alkylaniinoalkle-carbonyi amides. aninples of
`from 2 to 20 (cg. 2 to 10 or 2 to 6} carbon atonis. and
`10 bioliydrolyzable carbaniates include lower alkylaniincs, sub-
`.
`.
`slituted etltylenediamines, aminoacids, Iiydmxyalkylani ines.
`"mjlu‘hug at 1‘32””an “firbuuwalb‘m duuble hu'ld‘ Rupmm"
`heterocyclie (Ind heleroaromatic amines. and polyether
`tative aikenyi moieties Include Vinyl, ally], l—butenyl. 2—butc—
`amines.
`nyl.
`isobutylenyl.
`l—pentetiyi1 _2—pentenyl_. 3—inethyl—l—bute—
`the terms “halogen" and
`Unless otherwise indicated,
`“Fl.- Z'Ilwlhlf'l'z'bulefllr'ls 2~3'dmmhyl'2'huleul'ls l‘hexefllfL
`2'11‘3x‘3'13’1: 3419““er l'hcl‘lcnyL z'ht‘l’lcnyla 3'hci‘lcnlt']: 4» “halo“ encompass fluorine, chlorine, bromine, and iodine.
`1'0‘51‘3113'1-
`2'0‘51‘31131‘
`3'0‘51‘313'1-
`I'WDCRYL 24101191131
`Unless othenvise indicattxl. the term “heterotilkyi” refers to
`3410116154: lilecellyl: 24606134 and 3-deoel'lyL
`an alkyl moiety (cg... linear. branched or cyclic) in which at
`[Iiiiess otherwise indicated,
`the term “alkyl” means a
`least one ol‘ its carbon atoms has been replaced with a bet—
`straight chain. branched andt'or cyclic (“cycloalkyl”) hydrio—
`eroatom (e.g., N, 0 or S).
`carbon having from 1 to 20 (e.g..
`l to 10 or J to 4) carbon 50
`Unless otherwise indicated. the term “ltcteroaryl” means
`atomsAllryi moieties having. from 1 [04 carbons are referred
`an aryl moiety wherein at least one oi'its carbon atoms has
`to as “lower alkyl." Examples ofalkyl groups include methyl.
`been replaced with a heteroatom (e.g.. N. O or 8). Examples
`ethyl. propyl.
`isopropyl. n—butyi.
`t—butyi.
`isobutyl, pentyi.
`include
`acridinyl. benzimidazolyi. benzofuranyl.
`ben—
`iiexyl. isohcxyl. heptyl. 4.4-dimethylpcntyl. octyl. 2.2,4-tri-
`zoisothiazoiyi. benzoisoxazoiyl. benzoquinazolinyl, ben-
`nieliiylpentyl. nonyi. decyi. undecyl and dodecyl. Cycioalkyi 55 mthiamiyl, benmxazolyi, l‘nryl. imidazolyi. incloiyi. isothia—
`moieties may be monocyciic or mullicyclic. and examples
`mlyl,
`isoxamlyl. oxadiamiyi,
`oxazolyl,
`plithaiaxinyi.
`include cyciopropyi, cyciohutyi. cyciopentyl. cycloliexyi.
`pyrazinyl. pyramlyl. pyridazinyi, pyridyi. pyritnidinyi,
`and adamantyi. Additional examples of alkyl moieties have
`pyrimidyl, pyrrolyl. quinazolinyl. quinolinyl, tetrazolyi, thia-
`linear, branched andJor cyclic portions (e.g., l-ctltyi-4-inc-
`zolyl,and triaziiiyl.
`tlin—cycloliexyl). 'l'lic term “alkyl‘” includes saturated Itydrti— so
`Unless otherwise indicated. the term “lieteroarylalkyl” or
`carbons as well as alkenyl antlalkynyl Inoielics.
`“helemaryl—alkyl” means a lieteroaryl moiety bound to an
`Unless otherwise indicated. the term “alkoxy” means an
`alkyl moiety.
`O—alkyl group.
`liiitimplcs
`ol‘ alkoxy groups
`include
`Unless otherwise indicated. the term ”heterocycle“ rel'crs
`()(TH.._
`(XTH?_(‘H.,
`()(tTH3)_1(‘H..
`()(t‘.I-l_.).(‘I-lb
`to an aromatic. partially aromatic or non—aromatic monocy—
`0(CH2‘J4CI-Ij. and
`OtiCHgisCl-Ij.
`65 clic or polycyclic ring or ring system comprised of carbon.
`L'iilcss otherwise indicated. the term “alkylaryl” or “alkyl-
`hydrogen and at least one heteroatom (c.g.. N. O or S). A
`aryl” means an alkyl moiety bound to an aryi moiety.
`helerocycie may comprise iiiuitipie {i.e., two or more) rings
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01622
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`

`

`US 8,410,121 B2
`
`10
`
`Eli
`
`3|]
`
`5
`fused or bound together. Heterocycles include heteroaryls.
`Examples include bcnzo[l,3jdioaolyl, 2.3-dihydro-bcnaoll,
`4]dioxinyl. cinnolitiyl,
`litranyl, hydariloinyl. Iuorplioliiiyl.
`oxetnnyl, oxiranyl, pipera'zinyl. piperidinyl, pymtlidinouyl.
`pymilidinyl,
`tetrahydrotiiranyl.
`telrahydropyranyl, tetrahy—
`dropyridinyl,
`tetrahydropyrimidinyl,
`tetrahydmlhiophenyl.
`tetml‘iydrothiopyranyl and valentlactamyl.
`Unless otherwise indicated. the term “heterocyclealkyl” or
`“lietertwycle—alkyl" refers to a heterocycle moiety bound to
`an allryl moiety.
`Unless otherwise indicated. the ternt “lteterocycloalkyl”
`refers to a non-aromatic heterocycle.
`Unless otherwise indicated. the term “helerocycloalkylas
`lkyl" or “heterocycloalkyl-alkyl” refers to a heterocycloallql
`moiety bound to an alkyl moiety.
`Unless otherwise indicated, the term “pharmaceutically
`acceptable salts” Defers to salts prepared from phannaceuti—
`cally acceptable non-toxic acids or bases including inorganic
`acids and bases and organic acids and bases. Suitable phar-
`maceutically acceptable base addition salts include metallic
`salts made li'oni aluminum, calcium, lithium, magnesium,
`potassium. sodium and zinc or organic salts iiuide li'oin
`lysine. N.N'—dibenzyletliylenedianiiue, cliloropmcaine. cho—
`line, dielhanolnmine, ethylenediantine, meglnmine (N—metlt—
`ylglucamine) and procaine. Suitable non—toxic acids include .
`
`inorganic and organic acids such as aceticT algini . anthra—
`nilic. benzenesulfonic. henzoic, camphorsulliinic. citric.
`ethenesulfonic, formic,
`litmaric, f'umic, galacluronic. glu—
`conic. glucuronic, glutamic. glycolic, hydrobromic. hydro-
`chloric. isethionic. lactic. maleic, malic, tnandelic. methane—
`sulfonic. mttcic. nitric. pantoic. pantothenie. phenylaectic.
`phosphoric. propionic. salicylic. stcaric. succinic. sull'anilic.
`sulfuric. tartaric acid. and p-toluencsulfonic acid. Specific
`non—toxic acids include hydmchloric. hydrobroinic. phos—
`phoric, sulfuric, and methancsulfonic acids. Examples ofspc-
`cilic salts thus include hydrochloride and mesylate salts. Oth—
`ers are well-known in the art. See, e.g., Rwairrgton ’s
`Pharmacurrrirui Sciences. 18”1 ed. (Mack Publishing, Faston
`Pa; 1 990) and Remington: ”it: Science am! Practice qfl’irur—
`”met; 19“" cd. (Mack Publishing, L-‘aston Pa.: 1995).
`Unless otherwise indicaletL the term “potent 'I'Pl ll inhibi—
`tor" is a compound that has a 'l 'P} l l_]( 15,, ol‘lcss titan about It!
`th.
`linless otherwise indicated, the term “prodrng” encom—
`passes pharmaceutically acceptable esters, carbonates, thio—
`carbonates, N-acyl derivatives. Netcyloxyalkyl derivatives,
`quraernary derivatives of tertiary amines. N-Mannich bases,
`Schill‘ bases. amino acid conjugates, phosphate esters, metal
`salts and suli'onate esters of compounds disclosed herein.
`Examples of prodrttgs include compounds that comprise a
`biohydrolyzable moiety (cg. a biohydrolyzablc amide. bio-
`hydrolyzable earbamatc. biohydrolyzablc carbonate. biohy-
`drolyzable ester. biohydmlyyahle phosphate. or biohydrolyz—
`able ureidc analog). Prodrugs ofcompounds disclosed herein
`are readily envisioned and prepared by those of ordinary skill
`in the art. See. e.g.. Design omed'rttgs. Bundgaard. A. Pd.
`Flseview, 1985; Bundgaard, 1-1., "Design and Application o I'
`Prodrugs," A chtbow‘i offlmg Design and ikivm’oprrrcrrt,
`Krosgtard-Larscn and ll. Bundgaard. Lid" 1991, Chapter 5, p.
`ll3—I‘Jl; and Bundgaard,
`||.._ Admitted Drag Deliwcv
`Review. 1992, it, 1-33.
`Unless otherwise indicated. a “prophylacticully eltective
`amount“ ol'a compound is an amount sullicicnl to prevent a
`disease or condition, or one or more symptoms associated
`with the disease or condition. or prevent its recurrence. A
`prophylactically effective amount of a contpotind is an
`amount of therapeutic agent. alone or in combination with
`
`~10
`
`4)
`
`u:C)
`
`t4: U:
`
`60
`
`6
`other agents. which provides a prophylactic benefit in the
`prevention of the disease. 'l'llc 1cm] "prophylacticall).r cllcc-
`tive amount" can encompass an amount that improves overall
`prophylaxis or enhances the prophylactic etlicacy ol'nnother
`prophylactic agent.
`Unless othenvi He indicated, the term “protecting group“ or
`“pmtective group," when used to refer to part ol'a molecule
`subjected to a chemical reaction, means a chemical moiety
`that
`is not reactive under the conditions of that chemical
`reaction, and which may he removed to provide a moiety that
`is reactive under those conditions. Protecting groups are well
`known in the art. Sec. c.g.. Greene. '1‘. W. and Wuts. 1’. G. M..
`Protective Groups in Organic Si-‘miierir {3"If ed.. John Wiley
`& Sons: 1999): Larcck. R. C.. Comprehensive Organic
`Thinsbrinariom (23"! ed._. John Wiley & Sons: 1999]. Some
`examples include benzyl. diphcnylmcthyl. trityl, Cbz, Boc,
`Fntoc, Inethoxycarbonyl, ethoxycarbonyl, and pthalimido.
`Unless otherwise indicated, the term "pseudohalogen"
`refers to a polyatomic anion that resembles a halide ion in its
`acid—base. substitution. and redox chemistry, generally has
`low basicity, and forms a tree radical under atom transfer
`radical polymerization conditions. Examples ol'pseudolialo—
`gens include a7ide ions. cyanide, cyauule. tliiocyanate. tliio—
`sulfate, sultiinates, and sultonyl halides.
`Unless otherwise indicated,
`the term “selective TPlil
`inhibitor" is a compound that has a Tl:"l'l2_l("in that is at least
`about 10 times greater than its TPlll_lC5n.
`Unless otherwise indicated. the term “serotonin—mediated
`adverse effect" refers to an adverse effect that is attributable
`to increased levels of peripheral S—hydroxytryptamine
`(5-1 11'].
`the term “stereomerically
`Unless otherwise indicated.
`enriched composition of“ a compound refers to a mixture of
`the named compound and its stereoisomer(s} that contains
`more of the named compound than its stcrcoisomerfis). For
`example, a stereoisomerically enriched composition of (5)—
`butan-Z-ol encompasses mixtures of (S)—btttar1-Zol and (R)-
`hutan—E—ol in ratios of, e.g._. about 60340. 70i30. 80120. L30310,
`9515, and 98:2.
`Unless otherwise indicated, the term “stercoisomeric mix-
`ture“ encompasses racemic mixtures as well as stereomeri—
`cally enriched mixtures (cg, RES—BUM). Siiofi. Ammo,
`45:55, SSE-15, 6W4”, 6585 and 7080).
`Unless otherwise indicated,
`the term “stereomerically
`pure” means a composition that comprises one stereoisomer
`ol'a compound and is substantially free ol‘other stereoisomers
`of that compound. For example. a stereomerically pttre com-
`position ol'a compound having one stercocenter will be sub—
`stant ially free ofthc opposite stereoisomer ofthc cotnpound.
`A stercomciically pure composition of a compound having
`two stercocentcrs will be substantially free ol'other diastere-
`enters of the compound. A typical stercomerically pure coin-
`pound comprises greater than about 80% by weight of one
`stereoisomcr of the compound and less than about 20% by
`weight ol‘other stereoison‘iers of the compound, greater than
`about 90% by weight of one steieoisomer of the compound
`and less than about 10% by weight ofthc other stereoisomers
`ofthc compound, greater titan about 95% by weight of one
`stereoisoincr of the compound and less than about 5% by
`weight ofthc other sterwisomers of the compound, greater
`than about 97% by weight of one stereoisomer of the coin—
`pound and less than about 3% by weight of the other stereoi —
`somcrs ot‘thccontpound. or greater titan about 99% by weight
`ot‘one stereoisomer ofthc compound and less than about ] %
`by weight of the other stereoisomers of the compound.
`Unless otherwise indicated, the term “substituted," when
`used to describe a chemical structure or moiety, refers to a
`
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`
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`

`US 8,410,]2l B2
`
`7
`derivative of that structure or moiety wherein one or more o I'
`its hydrogen atoms is substituted with an atom. chemical
`moiety or functional group such as. but not limited to. alco-
`hol. aldeliylde, alkoxy. alkanoyloxy. alkoxycarhonyl. alk—
`eiiyl.alkyl (e.g.._ methyl. etliyl.pnipyl, I—hutyl).alkynyl,a|ky— 5
`
`8
`ing, when used to describe a moiety attached to otlierchernical
`moieties. Thus. the two phrases “XOI l, wherein X is pyriilyl“
`and “KO“. wherein X is pyridine" are accorded the same
`meaning. and encompass the compounds pyridin—Z—ol. pyri—
`din—3—ol and pyridind—ol.
`
`it should also he noted that if the steroieheinistry of a
`learbonyloxy( OC(O)alkyl}: amide{ C(O)NH-alkyl- or
`structure or a portion (1 I‘ a structure is not indicated with. liir
`—ztlky1NHC(O)alkyl).
`‘Fmdmyl
`(—CfN'l-I)NH—al.kyl or
`example. bold or dashed lilies. the structure or the portion of
`LINK)!“ 12)‘ aminetprimary, 5&9“an and tertiary Slwh
`as alkylamino. arylamino. arylalkylamino}. army]. aryl, ary- w the structure is to be interpreted as encompassing all stereoi-
`1033’- azo. carbanioyl E NIIC(O)O-alkyl- 0"
`0C(0)N“'
`soiiiers of it. Similarly. names ol'coiiipounds having one or
`alkyl). carbamyl
`(0‘9"! CON“?! as we“ as CONll-alkyl,
`more chiral centers that do not specify the stereocheinistry of
`CONH'arY‘lr and CONH'amlfll‘yl)‘ carlmnylr carboxyl. car
`those centers encompass pui‘e stereoisomers and mixtures
`boxylic acid. carbexylic {field anliydride. carboxylic acid
`tliereot'. Moreover. any atom shown in a drawing with unsat—
`chloride, eyano. 05ml" cwmdc' etlter (0%" methoity, cmOXYL ts islied valences is assumed to be attached to enough hydrogen
`3'“‘“'d"mvh“l"!1]“1‘m1k5f](fig-r pm.“
`”I?!
`C((‘Ffi-L).
`atoms to satisfy the valences. In addition, chemical bonds
`heteroallxyl. hemiacetal. 11111110 {primary and secondary). 150'
`depicted with one solid line parallel
`to one dashed line
`Cywalc' isotlnocyanate. ketone. thrilc. “Jim! oxygen (1'0" to
`encompass hotlt single and double (egg... aromatic) bonds, if'
`provide an oxo group), phosphodiester. sultide, sullonamido
`“lenses perntit.
`,
`(e.
`.. SO Nil2 ). sull'one. sullon 'l [includin _ alk 'lsulliin 'l. 3“
`,
`aryiisulfufiyl and arylalkylsulloiiyl], sull‘oxildc.
`lhiol (CL.
`5‘2‘ TP“ Inhibitors
`sullltydryl. tliioetlier)aud urui( NHCONH—alkyl—l
`Particular embodiments of this invention utilize coin—
`Unless otherwise indicated. a "therapeutically effective
`pouttds capable ol‘inhibiting tryptophaifliydroxylase (THU.
`amount“ ol'a compound is an amount sullicient to provide a
`_ Preferred “““P‘Tm‘fis, are potent TPHl lfl'hlhllurs‘ Examples
`therapeutic benefit in the treatment or management 01.2] dis— ?\ ol potent TPlll inhibitors are disclosed in US. patent appli—
`.
`.
`.
`.
`.
`cation Ser. No. ll.’638,677, filed Dec. 12. 2006.
`ease or COIIdlIlOIL or to delay or minimize one or more symp—
`toms ugh-“dated Willt [he disease N condition. A tlierapeuti—
`cally effective amount of a compound is an amount o I‘
`therapeutic agent. alone or in combination with other thera— 3”
`plus. which provides a therapeutic benefit in the treatment or
`management 0 I‘ the disease or eondi lion. The term “thempeii—
`tically effective amount" can encompass an amount
`that
`improves overall therapy, reduces or avoids symptoms or
`causes o l‘ a disease or condition, or enhances the thenipeulic 35
`efficacy ol‘ another therapeutic agent.
`Unless otherwise indicated. the term “'l'l’Hl_I(_‘5._.“ is the
`1C5” ofa compound for 'l'Plll as determined usingthe in vitro
`inhibition assay described in the Examples, below.
`_
`.
`_
`.
`W _
`‘ ” _
`Enless otlierWise indicated. the term l-Pll2_I(_I5U is the
`Iticllyol a compound [or l‘lJHZIEIS determined using the in
`Vitro inhibition assay described in the Examples. below.
`Unless otherwise indicated, the terms “Ii-mil." “treating,"
`and “treatment" contemplate an action that occurs while a 4"
`patient is suffering from the specified disease or disorder.
`which reduces the severity ol'the disease ortlisorder. or one or
`more of its symptoms. or retards or slows the progression o I‘
`the disease or disorder.
`
`Particular embodiments utilize compounds of l'ornntla l:
`
`1
`
`x
`
`”
`
`HF
`
`/R3
`
`0
`
`O
`
`“-1.11
`
`,
`and pharinaceutically acceptable salts and solvates thereof.
`10 wherein: A is optionally substituted cycloalkyl, aryl, or het-
`erocycle: X is a bond. 0 '
`g
`’
`(3(0)
`,
`['(Rfl
`(“{4}
`,
`C(RJR‘)
`.
`{5(qu
`(1R4)
`'
`f (j
`_
`Nlel
`,
`N(R5)(.‘(O)N(R5)
`(‘KR3R4)N(R5)
`~
`NlelC-(RiRal
`.
`()Nt‘lk1}
`(“{1an =
`8(01)
`FOUL)”
`s
`()(1-(R1R4)
`:
`50:39)“.
`‘ or
`(R5)
`N(_RS)S(_OE)
`C(RJRA)S(02)
`S(O;)C
`OER-t)
`: D '3 optionally substituted “3’1 or lieteroeycle; Rt
`15 hydrogen or ”131101121111! SUbSUlllICd alkyl. alkyl—aryl. alkyl—
`heterocycle, aryl,or beterocycle'. R215 hydrogen oroptionally
`50 substituted alkyl. allqu-aryl. alltyl-heterocycle. aryl. or het-
`Irpm-w“: R3 is hydrogen. alkoxy. amino. cyano. halogen.
`hydroxyl. or optionally substituted allq'l: Rd is hydrogen.
`alkoxy. amino. cyano. halogen. hydroxylf or optionally sub—
`stituted alkyl or aryl; each R5 is independently hydrogen or
`is optionally substituted alkyl or aiyl; and n is 0—3.
`Particular compounds are of formula HA):
`
`Unless otherwise indicated. the term “include” has the
`same meaning as "include” and the term "includes” has the
`same meaning as “includes. but is not limited to.” Similarly.
`the term “such as” has the same meaning as the temt “such as.
`but not limited to.”
`Unless otherwise indicated. one or more adjectives immc-
`diately preceding a series of nouns is to be construed as
`applying to each ol' the nouns. For example,
`the phrase
`“optionally substituted alky. aryl. or heteroaryl" has the same
`.
`..
`.
`.
`.
`.
`meaning as optionally substituted alky. optionally substi-
`
`titted aryl. or optionally substituted ltetemaryl.”
`
`it should be noted that a chemical moiety that forms part of
`a larger compound may be described herein using a name
`commonly accorded it when it exists as a single molecule. or 65
`a name commonly accorded its radical. For example. the
`terms “pyridine" and “pyridyl” are accorded the saute meani—
`
`an
`
`Q
`
`X
`
`HA]
`
`K;
`
`0/
`
`0
`
`"
`
`up
`
`a. to
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01622
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`

`

`Others are of lormula lI;
`
`9
`
`US 8,410,]2l B2
`
`:
`
`R2
`
`0
`
`HN
`
`"R
`
`IU
`
`10
`fi—Inelnbered and 5—nieiiibered). In some, A; andfor A: is
`optionally stihslitlilularyl (Lag... phenyl or naphthyl). In oth—
`ers. A. andz'orA1 is optionally substituted lieterocyele (e. g...
`fi—Inelnbered and 5—rnembered}. Examples of fi—membered
`helerocycles include pyridine. pyridazine, pyrimidine, pyra—
`zirie. and triazine. Examples of S-Jneinbered heteroeyeles
`include pyn’ole. imidamle. lriazole. thiazole, thiopliene, and
`furim. hi some compounds, AI andforz’li2 is aromatic. In oth—
`ers. Al andl'orA2 is not aromatic.
`Willi regard to the formulae disclosed herein, particular
`compounds include those wherein I) is optionally substituted
`and pharniaceutically acceptable salts and solvatcs thereof,
`ary] (e.g., pheliy] or naphthyl). In others, I) is optionally
`wherein: A is optionallyr substituted e'\h::loalkyl1 aryl. or liet—
`substituted helemcycle (e.