[12] United States Patent
`(10) Patent NIL:
`US 8,410,121 32
`Sands
`Apr. 2, 2013
`(45) Date of Patent:
`
`U8008410121B2
`
`54 METHODS OF 'l‘Rl-IA'I‘ING PULMONARY
`HYPI‘IR'I‘I‘INSION
`
`2003.-'0l‘)| l IR A1
`2004.-'Ul4299l Al
`2004.:0l5802fi Al
`200420209807 A!
`200520226803 Al
`2000:0[54936 Al
`200920005381 Al
`20095004 82 80 Al
`200990054308 A1
`
`10-2003 Sllcal'
`2:2004 Na}:I
`8-2004 Jack 3011
`100111114 Vernier
`1 330125 (.‘l'lan
`222001“: Lash);
`[-2009 Brown
`3'20 09 Bingo on
`2220 09 Sands
`
`FOREIGN PATENT DOCUMENTS
`1092211
`5.200 I
`“091501224
`2-'199|
`“-1) 2004?” I200?
`3.2004
`WO 2004058262
`2-2004
`WO 2005044280
`5-2005
`Wt] 20083023928
`0.2008
`
`T113
`W0
`Wt '1
`W0
`W0
`W( J
`
`{Ill Il-LR PUBLICATIONS
`
`Driscoll, IA. and Chaklnaia. M.M.. E11202? Om». Phammmmm'.
`9(l]:65—Rl (2008].
`Eddahibi. S. et 21.1.. (.U'r'tm’au'vfl 113t_15):1852-1864 (2006).
`lzikki. M. or aL Am. .2’. Ph}..¢fof. lung ('cHMof. P2:J._rin.‘. 293:1.1045-
`11052 (2002).
`].iu. 0. CI al.. J. l‘harlnncol. l-pr. 111::1'. 325(1 ):42-55 (2008].
`MacI.e.'tn. MR- I’m. .2. CH”. Pmn‘. 1'11 (Suppl. 1561:2231 (2002).
`MacLean. MR. and Dempsie. Y.. Curr. 0pm. Phar'marof. 9:1-6
`{2000).
`Moreerofl. I. et :11. hit};erten.§-iou 49232—236 (2002].
`[)Issnn. K.M. and Hneper, MNL Drag Div. Fido}:00(0010008).
`Shi. K-(Iu el al.. J. Med. Chem. .‘3 I1_l3]:3684-3f282 (2008].
`lnlernalinnal Search Report and “’rillcn Opinion forfnrrespomling
`International Applicalion Publication “02003-069421. dated Sep.
`2. 2008.
`
`Primary Examiner
`Raymond Henley. III
`Max Bachraeh
`(2'4) :1 Homer. Agent. or Firm
`
`A BSTR!“ ."1‘
`
`(52)
`Methods ol‘ treating pulmonary hypertension are diselottcd.
`szieulur melhods eolnpritu: the adminislmtion ol‘ :1
`Iryp—
`lophun liydmxylaee inhihilorand n pmslneyclin. Phnmiaeeu—
`tical tormnlations are also disclosed.
`
`13 Claims, 1 Drawing Sheet
`
`
`
`25
`
`23
`
` 65
`
`21
`
`22
`
`Inventor: Arthur 1‘. Sands. The Woodlands. TX
`(US)
`
`Assignee: Lexicon Pharmaceuticals, Inc“ The
`Woodlands. TX (US)
`
`Notice:
`
`Subject to any disclaimer. the term ul‘lhis
`palcnl ih‘ extended or ndjnsled under 35
`11.017. 15401121)» 23 days.
`
`Appl. No: 132005.592
`
`Filed:
`
`Jan. 14, 2011
`
`Prior Publication Data
`
`US 201120112094.“
`
`May 12. 2011
`
`Related L'.S. Application Data
`[03] Continuation of application No. 122169.815. filed on
`.lul.9.2008,1110“:Pat.No,2.X25.(122.
`
`[60]
`
`Provisional application No. 601949.040. filed on Jul.
`1 l. 2002.
`
`(51)
`
`Im. at.
`A61K 31/505
`5142269
`[52] U.S. Cl.
`. 5142269
`[58] Field of Classification Search
`See application file for complete search history.
`
`(2006.01)
`
`[:20]
`
`References Cited
`
`U.S. PATENT DLX’UML‘N'I'S
`4.156.234 A
`531.929 Stone
`2.553.840 B2
`6-"2009 Demsagaymnj
`2.209.493 B2
`5-2010 Devasagaynraj
`2.223.345 B2
`5-2010 Devasagayaraj
`2.825.622 132
`1:20“ Sands
`2003-0130349 Al
`232003 LU bl
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2081
`
`Page 1 of 41
`
`

`

`US. Patent
`
`Apr. 2, 2013
`
`US 3,410,121 132
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`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2081
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`Page 2 of 41
`
`

`

`US 8,410,12l B2
`
`1
`METHODS OF 'I‘REA'I‘ING PULMONARY
`IIYPERTENSION
`
`This appiication is a continuation ofU.S. patent applica—
`double-rho.121691.815.liledlul.9.2t)(}8.now1J.S.Pal.No.
`"£375,622, which claims priority to ILLS. provisional applica—
`tion no. titlf949,040. lilecl Jul. 1 l, 200?, the ent ireties ofwhieh
`are incorporated herein by reference.
`I. i-‘llil.l) OI" 'I'Iili iNVIiN'I'ION
`
`10
`
`This invention relates to methods and compositions for the
`treatment of pulmonary hypertension and related diseases
`and disorders.
`
`2. BACKGROUND
`
`3|]
`
`9'?
`
`3|]
`
`2
`vasculature smooth tnuwle, there by preventing the neurohor—
`mone endothelin—I (HT—1) from binding to these same recep—
`tor sites and triggering vasoconstriction. 1d. at 76-22. An
`example ofan ERA is hosenlan {TRACI.EER®).
`Other methods of treating PM have been investigated. For
`example, selective serotonin reuptake inhibitors (SSRls)
`reportedly reverse P11 in rats. id. at T9. These compounds.
`which are widely used to treat depression. affect the reuptal-ce
`of the neurotransmitter serotonin (5-HT).
`Serotonin is synflicsimd in two steps from the amino acid
`tryptophan. Goodman (it Gilmeu 's The Pharmacological
`Best's Qthhcrupetm'CS, 10'" ed., p. 270 (McUraw-l till, 2001).
`The Iirst step is rale—lintiliug, and is catalyzed by the enzyme
`tryptophan hydroxyiase {‘I‘PI I), which has two known iso—
`Iiorms: 'l‘l’H l, which is expressed in the periphery, and 'l'l’H 2,
`which is expressed primarily in the brain. Walther. D. J.. eta1.,
`Science 299:76 (2003). Mice genetically deficient thr the tph I
`gene (“knockout mice”) have been reported. in one case. the
`mice reportedly expressed normal amounts of serotonin in
`classical scrotoncrgic brain regions. but largely lacked scro-
`lonin ill the periphery. Id.
`In another.
`the knockout mice
`exhibited abnormal cardiac activity. which was attributed to a
`lack of peripheral serotonin. Céié. F., et al., PN45 100(23):
`13525-13530 (2003). Recently. TPll knockout mice were
`studied in a hypoxia—induced pulmonary arterial hyperten—
`sion model. Morecroft. L, et al., iiypenension 495132—236
`(2007). The results of those studies suggest that TPl-ll and
`peripheral serotonin “play an essential role in the develop—
`ment of hypoxia—induced elevations in pulmonary pressures
`and hypoxia—induced pultnonary vascular remodeling.” 1d. at
`232.
`
`3. SUMMARY Oi" THE INVENTION
`
`This invention is directed. in part, to methods of treating
`pulmonary hypertension and related diseases and disorders,
`which comprise administering to a patient therapeutically
`effective amounts ofa tryptophan hydroxylase (TPH) inhibi—
`tor and at least one other active pharmaceutical ingredient.
`One embodiment encompasses a method of treating, inan-
`aging or preventing pulmonary hypertension, which coin—
`prises administering, to a patient in need thereof therapeuti—
`cally or pmphylaclieally etiéctive amounts ot'an endothelin
`receptor antagonist and a tryptophan hydroxylase inhibitor.
`Another encompasses a method of treating, managing or
`preventing pulmonary hypertension. which comprises
`administering to a patient in need thereof therapeutically or
`prophylactieally effective amounts of an anticoagulant and a
`tryptophan hydroxylase inhibitor.
`Another encompasses a method of treating. managing or
`preventing pulmonary hypenension. which comprises
`administering to a patient in need thereof therapeutically or
`prophylactically effective amounts of a calcium channel
`blocker and a tryptophan hydmxylase inhibitor.
`Another encompasses a method of treating, managing, or
`preventing pulmonary lrypettension, which comprises
`administering to a patient in need thereof therapeutically or
`prophylactically efiective amounts oi‘a prostacyclin and a
`tryptophan hydroxylase inhibitor.
`Another encompasses a method of treating. managing or
`preventing pulmonary hypertension. which
`comprises
`athninistering to a patient in need thereot' therapeutically or
`prophylactically ellcctive amounts o [nitric oxide or a nitric
`oxide precursor or releasing compound, and a tryptophan
`hydroxylase inhibitor.
`Another encompasses a method of treating. managing or
`preventing pulmonary hypertension. which comprises
`
`Pulmonary hypertension (P11). or pulmonary arterial
`hypertension (PAH), is a disease characterized by increased
`pulmonary artery pressure and pulmonary vascular resis—
`tance. Harrison '5 i’riueipies ol'intemet’ Medicine, 15111 ed,
`pp. 1506—1507" (Me(imw—Hill, 200]). Left untreated. I’H
`"usually has a dismal prognosis culminating itt right ventricu—
`lar failure and death.“ Ulrich, S.. et al., Swiss Med. Wit-45!
`BITE—82. 13 (2007).
`in 2003, the world iiealth Organization (WI I0) sponsored
`the development of guidelines, called the “Venice classifica—
`tion." which are now used to classify types of PH. https"!
`\vww.tracleer.mnu'default.asp'Epagc—{TouldHave WHO (ac-
`cessed Jun. 29, 2007). The first type, WI IO Group 1.1. is
`idiopathic pulmonary arterial hypertension (ll’All). This
`refers to PAH that occurs at random. without an apparent
`cause. ll‘AII ttsed to be called "primary pulmonary hyperten-
`sion” or PPii. id.
`The second type, WHO Group 1.2, is familial pulmonary
`arterial hypertension (FPAl-l). With this type of PAH. a faulty
`gene is passed on through the family, which causes the PAH
`to develop over time. it is estimated that at
`least 6 to 10
`percent of PAH cases occur in families where at least one
`other person has had the disease. 1d.
`is pulmonary arterial
`The third type, WI It) (iroup 1.3.
`hypertension associated with other diseases or conditions
`{AMH} This used to be called "PAH secondary to other
`conditions" or Secondary PAH. This category includes PAH
`associated with collagen vascular disease or “connective tis—
`sue disease“ (e.g.. sclerodenna (SSc)-including CREST syn-
`drome-lupus
`(SLED,
`congenital
`systemic-to-pulmonary
`shunts (congenital heart disease), portal hypertension, IIIV
`itii‘txtion. drugs and toxins. and other diseases and disorders
`{c.g.. thyroid disorders. glycogen storage diseases. Gaucher .
`disease. hereditary hemorrhagic telangiectasia. hemoglo-
`binopathies. ntyeloproliferative disorders. splenectomy). 1d.
`The fourth type, WI 10 Group 1.4. is pulmonary arterial
`hypertension associated with significant venous or capillary
`involvement, and includes pulmonary veno—ooclusive disease
`(P'VOD) and pulmonary capillary hemangion‘tatosis (PCT-I).
`The Iifth and filial type, WHO Group 1.5,
`is persistent
`pulmonary hypertension of the newborn. 1d.
`Drugs currently used to treat Pit
`include pulmonary
`vasodilators, calcium channel blockers, and inhibitors of
`platelet aggregation. 'Hze Merck Manual. l'i'Ih ed.. pp. ”(13—4
`(Merck Research ] aboratories, I999). Diuretics, nitric oxide,
`phosphodicsterase 5 inhibitors (e.g.. sildenalil) and endothe—
`Iin receptor antagonists (HRAs) are also used for its treat—
`ment. Ulrich. 3.. et al.. Swiss Med. Wkly 137:73-32. 76-7?
`(200?). Endothclin receptor antagonists work by binding to
`the ETA andJ'or FLT,3 receptor sites in the endothelilmi and
`
`40
`
`4)
`
`t4: U:
`
`60
`
`65
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
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`

`

`US 8,410,]2l B2
`
`3
`administering to a patient in need thereof therapeutically or
`prophylactienlly ellcctive amounts ol‘a phosphotlieslemse 5
`inhibitor and a tryptophan hydroxylase inhibitor.
`Another encompasses a method of trailing. Inanaging or
`preventing pulmonary
`hypertension. which compriws
`administering to a patient in need thereof therapeutically or
`prophylactically effective amounts of a diuretic and a try}:—
`tophan hydroxylase inhibitor.
`Another encompasses a method of treating. managing or
`preventing pulmonary hypertension. which comprises
`administering to a patient in need thereof therapeutically or
`prophylactieally effective amounts of a platelet derived
`growth factor and a tryptophan hydroxylasc inhibitor.
`'Ihe invention also encompasses pharmaceutical formula-
`tions (e.g., single Imit dosage limos) comprising a 'I‘I’H
`inhibitor and at least one other active pharmaceutical ingre-
`client.
`
`4. BRIEF DESCRIPTION OF TIIE FIGURE
`
`Aspects ol‘ the invention may be tinderstood with reference
`to the attached figure. FIG.
`I shows the eli'ects of a potent
`TI’I—Il inhibitor of the invention in the mouse gastrointestinal
`tract and brain al‘leroral administration. All data are presented
`as percentage ol‘ the mean of the control [vehicle—dosed]
`group. Error bars are ELEM. N—5 per group. The symbols are
`{1141.05 vs control group. For the brain data, p—IJ.5. one—way
`ANOVA.
`
`5. DETAILED DESCRIPTION
`
`5
`
`10
`
`Eli
`
`Pi
`
`3|]
`
`4
`Unless otherwise indicated. the term “alkylheteroaryl” or
`“alkyl-hcteroaryl” means an alkyl moiety bound to a het-
`eroaryl moiety.
`Unless othem'i He indicated, the term “:ilkylheterocyele“ or
`“alkyl—hetemeyele" means an alkyl moiety bound to a hetero—
`cycle moiety.
`Unless otherwise indicated, the term “:ilkynyl" means a
`straight chain. branched or cyclic hydrocarbon having from 2
`to 20 (eg, 2 to 20 or 2 to ti) carbon atoms. and including at
`least one carbon-carbon triple bond. Representative alkynyl
`moieties include acctylenyl. propynyl. l-butynyl. 2-butyriyl.
`1-pcntynyl. 2-pentynyl. 3-methyl-l-butynyl. 4-pentyriyl.
`liltexynyl. lhexynyl. Sihexynyl.
`liheptynyl. 2*heptynyl.
`6-11cptynyl.
`l-octynyl. 2-octynyl. T-octynyl.
`l-nonyriyl.
`2—nonynyl. 8—nonynyl. l—decynyl. 2—decynyl and 9—decynyl.
`Unless otherwise indicated. the term “aryl” means an aro-
`matic 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.
`Examples of aryl moieties include anthracenyl. azulenyl,
`biphenyl, lIuorenyl. indan. indcnyl. naphthyi, phenanthrcnyi.
`plleliyl. l2.3.4—tetniltydro—naphthalene. and tolyl.
`Unless otherwise indicated. the tertli "arylaikyl" or "aryi—
`alkyl” means an aryl moiety bound to an alkyl moiety.
`Unless otherwise indicated, the terms ”hiohydrolyzahle
`amide," “hiohydrolymhle ester." “hiohydrolymhle carhaln—
`ate." “hiohydrolymhle carbonate." “biohydrolymblc ureido11
`and “hiohyth'olymhle phosphate" Inean an amide. ester, ear—
`bamate. carbonate, ureido. or phosphate. respectively. of a
`compound 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
`action. or onset of action: or 2) is biologically inactive but is
`converted in vivo to the biologically active cotnpound.
`Examples of biohydrolyzablc esters include lower alkyl
`esters. alkoxyacyloity esters. alkyl acylamino alkyl esters.
`and choline esters. Examples of biohydrolyzablc amides
`include lower alkyl amides, a—amino acid amides. alkoxyacyl
`amides, and alkylaminoalkyl-carbonyl amides. Examples of
`biohydrolyzable carbamates include lower alkylantincs, sub-
`stituted ethylenediamines, aminoaciLLs, Iiydroxyalkylam incs.
`heterocyclie and helcroaromatic amines. and polyether
`entities.
`the terms “halogen" and
`Unless otherwise indicated.
`“halo“ encompass fluorine. chlorine. bromine. and iodine.
`Unless othcnvise indicnttxl. the term “heteroallryl” refers to
`an alkyl moiety (cg... linear. branched or cyclic) in whieh at
`least one ol‘ its carbon atoms has been replaced with a het—
`eroatom (e.g., N, 0 or S).
`Unless otherwise indicated. the term “heteroaryl” means
`an aryl moiety wherein at least one oi'its carbon atoms has
`been replaced with a heteroatom (e.g.. N. O or 8). Examples
`include
`acridinyl. benzimidazolyl. benzofuranyl.
`hen—
`zoisothiazolyl. benzoisoxazolyl. benzoquinazolinyi, ben-
`mthiamlyl. henmxazolyl. l‘nryl. imidazolyl. indolyl. isothia—
`mlyl,
`isoxazolyl. oxadiamlyl.
`oxazolyl. phthalaxinyl.
`pyrazinyl. pyramlyl. pyridazinyl, pyridyl. pyrimidinyl,
`pyriinidyl, pyrrolyl. quinazolinyl. quinolinyl, tetrazolyl, thia-
`zolyl, and triazinyl.
`Unless otherwise indicated. the term “lteteroarylalkyl” or
`“‘hetemuryl—alkyl” means a heteroaryl moiety bound to an
`alkyl moiety.
`Unless otherwise indicated. the tcmi ”heterocyclc“ refers
`to an aromatic. partially aromatic or non—aromatic monoey—
`clic or polycyclic ring or ring, system comprised of carbon.
`hydrogen and at least one heteroatom (e.g.. N. 0 or S). A
`heterocycle may comprise multiple {i.e., two or more) rings
`
`'Ihis invention is based. in part. on studies of tphl knockout
`mice and the discovery ol'colnpounds that inhibit tryptophan
`hydroxylase (e.g.. TPI Il ).
`5 .1. Definitions
`Unless otherwise indicated. the term “alkenyl” means a
`straight chain, branched andfor cyclic hydrocarbon having
`from 2 to 20 (cg. 2 to 10 or 2 to 6} carbon atoms. and
`ilicluding at least one carbon—carbondouble bond. Represen—
`tative alkenyl moieties include vinyl, a Ily]. l—butenyl. 2—hute—
`nyl,
`isobutylenyl.
`l—pentenyL 2—pentenyl, 3—methyl—l—bute—
`nyl. Z—rnethyl—IZ—butenyl, 2.3—dimetliy|—2—hutenyl.
`l—hexenyl.
`2—hexenyl, 3—hexcnyl.
`l—heptenyl. 2—heptenyi, 3—hepteny].
`l—octenyl.
`2—octenyl.
`3—octenyl.
`l—uonenyl.
`2—noncnyl.
`3—nonenyl, ldecenyl. 2—decenyl and 3—decenyl.
`[Inless otherwise indicated,
`the term “alkyl” means a
`straight chain. branched andi'or cyclic (“cycloalkyl”) hydro—
`carbon having from 1 to 20 (e.g..
`l to 10 or ] to 4) carbon .
`atoms. Alkyl moieties having from 1 to 4 carbons are referred
`to as “lower alkyl." Examples ofa lkyl groups include methyl.
`ethyl. propyl.
`isopropyl. n—hutyl.
`t—butyl.
`isohutyl. pentyl.
`hexyi. isohcxyl. heptyl. 4.4-dimethylpentyl. octy]. 2.2.4-tri-
`methylpentyl. nonyl. decyl. undecyl and dodecyl. Cycloalkyl
`moieties may be monocyclic or multicyclic. and examples
`include cyclopropyl, cyclobutyl. cyclopentyl. cyclohexyl.
`and adamantyl. Additional examples of alkyl moieties have
`linear, branched andJor cyclic portions (cg, 1-cthyl-4-mc-
`tlin—cyclohexyl). 'I'lte tertn “alkyd“ includes saturated hydro—
`carbons as well as alkcnyl and alkynyl moieties.
`Unless otherwise indicated. the term “alkoxy” means an
`O—alkyl group. Examples of alkoxy groups
`include
`t)cH.._
`(XTH._(‘H._.
`tittiH.).t‘H..
`0((TH.)1(‘H.,
`0(CH2)_,CI-I_.. and OtCngsCI-I..
`Unless otherwise indicated. the term “alkylaryl” or “alkyl-
`aryl” means an alkyl moiety bound to an aryl moiety.
`
`~10
`
`4)
`
`t4: U:
`
`60
`
`65
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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. Ed.
`Elseview, 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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`

`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. ehetnical
`moiety or functional group such as. but not limited to. alco-
`hol. aldehylde, alkoxy. alkanoyloxy. alkoxycarhonyl. alk—
`enyl. ulkyl (cg, methyl, ethyl, propyl, I—hutyl). alkynyl, alky—
`lcarbonyloxy ( OC(O)alkyl}. amide { C(O)NH-alkyl- or
`—alky1NHC(O)alkyl).
`amidinyl
`(—CfN'I-I)NH—al.kyl
`cr
`LitNRJNllgj. amine (primary, secondary and tertiary such
`as alkylamino, arylamino, arylalkylamino}. aroyl. aryl, ary-
`loxy. azo, carbamoyl E NIIC(O)O-alkyl- or OC(O)N'I]-
`alkyl), carbamyl (cg, CONttz, as well as CUNll-alkyl,
`CONH-aryl, and CONH-arylalkyl). carbonyl, carboxy], car-
`boxylic acid. carboxylic acid anhydride. carboxylic acid
`chloride, cyano. ester, epoxide, ether {e.g.. methoity, ethosy),
`guanidino,halo,haloall-tyl(e411,.T
`(‘t‘lh
`(#1,,
`(‘((‘F_,)_,).
`heteroallxyl. herniacetal. imine {primary and secondary). iso-
`cyanate. isothlocyanate, ketone. nitrile. uitro, oxygen (i.c.. to
`provide an oxo group), phosphodiester. sullide, sullonamido
`{e.g.. SOlel; ). sull'one. sultonyl [including alkylsullimyl.
`arylsulfonyl and arylalkylsuilonyll, sulloxidc.
`thic] (cg.
`sullhydryl. t|1ioet|ier)attd urw( NH{T()NH—a|ky|—).
`Unless otherwise indicated. a "therapeutically effective
`amount“ ot'a compound is an amount sullicieut to provide a
`therapeutic benefit in the treatment or management ot'a dis—
`ease or condition. or to delay or minimize one or more symp—
`toms associated with the disease or condition. A therapeuti—
`cally effective amount of a compound is an atnount o I‘
`therapeutic agent. alone or in combination with other thera—
`pies, which provides a therapeutic benefit in the treatment or
`management o I‘ the disease or condition. The term “therapeu—
`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 therapeutic
`efficacy of another therapeutic agent.
`Unless otherwise indicated. the term “'l't’Hl_I(_‘5,_,“ is the
`1C5” ofa compound for 'I'Ptll as determined usingthc in vitro
`inhibition assay described in the Examples, below.
`Unless otherwise indicated. the term ‘”l'Pll2_I(_‘SU” is the
`ItTSU of a compound [or 'l'l’HZ as determined using tile in
`vitro inhibition assay described in the Examples. below.
`Unless otherwise indicated, the terms “treat." “treating,"
`and “treatment" contemplate an action that occurs while a
`patient is suffering from the specified disease or disorder.
`which reduces the severity ot'the disease ortlisorder. or one or
`more of its symptoms. or retards or slows the progression o I‘
`the disease or disorder.
`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 term “such as.
`but not limited to.”
`
`Unless otherwise indicated, one or more adjectives innue-
`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-
`tuted aryl, or optionally substituted hetemaryl.”
`It should be noted that a chemical moiety that forms part of
`a larger compound may be described herein using a name
`commonly accented it when it exists as a single. molecule. or
`a name commonly accorded its radical. For example. the
`terms “pyridine" and “pyridyl” are accorded the same merm—
`
`10
`
`Eli
`
`Pi
`
`3|]
`
`~10
`
`4)
`
`u: VI
`
`60
`
`65
`
`8
`ing, when used to describe a moiety attached to otherchemical
`moieties. Thus, the two phrases “X01 1, wherein X is pyridyl“
`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 it the stereochemistry of a
`structure or a portion ol‘a structure is not indicated with. for
`example, bold or dashed lines. the structure or the portion of
`the structure is to be interpreted as encompassing all stereoi-
`sotners of it. Similarly. names ot'compounds having one or
`more chiral centers that do not specify the stereochemistry of
`[11058 centers CDCUIUPHSS pure stet‘eoisorners and mixtures
`thereol'. Moreover. any atom shown in a drawing with unsat—
`islied valences is assumed to be attached to enough hydrogen
`atoms to satisfy the valences. In addition, chemical bonds
`depicted with title solid line parallel
`to one dashed lirte
`encompass both single and double (cg... aromatic) bonds, if'
`valences permit.
`5.2. TPIl inhibitors
`Particular embodiments of this invention utilize coin—
`pounds capable ol‘ inhibiting tryptophan hydroxylase [TPI I).
`Preferred manpoLmds are potent TPHI inhibitors. Examples
`ol'p-otent TPlll inhibitors are disclosed in US. patent appli—
`cation Ser. No.
`1 [3638.671 filed Dec. 12. 2006.
`
`Particular embodiments utilize cotnpounds of l'ornmla l:
`
`and phartnaceutically acceptable salts and solvates thereof,
`wherein: A is optionally substituted cycloalkyl, aryl, or het-
`erocycle:xisabond. U .
`S
`,
`(2(0)
`,
`t'(R4)
`(.‘(Ra
`.
`truck.)
`.
`{1a,} out.)
`.
`t‘
`t.‘
`MM)
`3
`Ntksli-‘(O‘JMRQ .
`(‘tRsRQNtRsI
`.
`N(R,)(1(R,R,)
`,
`()Nt‘(R.}
`t‘(R.)No ,
`5(01)
`FOUL)”
`,
`()C(RIR4)
`=
`Stem!
`. 0r
`(Rs)
`NtRsl-‘HOQ
`C(RJR4)S(OE)
`S(O,)C
`(R3R4)
`: D is optionally substituted aryl or heterocycle; RL
`is hydrogen or optionally substituted alkyl. alkyl—aryl. alkyl—
`heterocycle, aryl, or hetero cycle; R2 is hydrogen or optionally
`substituted alkyl. allxyl-aryl. alkyl-heterocycle. aryl. or het-
`erocycle: R3 is hydrogen. alkoxy. amino. cyano. halogen.
`hydroxyl. or optionally substituted allq'l: R,,
`is hydrogen.
`alkoxy. amino. eyano. halogen. liydroxy]. or optionally sub—
`stituted alkyl or aryl; each R5 is independently hydrogen or
`optionally substituted alley] or zuyl; and n is 0—3.
`Particular compounds are of formula HA):
`
`Q
`
`U
`
`/ R3
`
`HA]
`
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`

`US 8,410,]2l B2
`
`Others are of formula II;
`
`9
`
`:
`
`R2
`
`0
`
`HN
`
`"R
`
`and pharmaceutically acceptable salts and solvatcs thereof,
`wherein: A is optionally substituted eyu::loalkyl1 aryl. or het—
`erocycleixisabond. 0 .
`S
`. C(O)
`C(Rq)—.
`=(‘(Rt)
`(TtRJRs)
`_
`(‘{R,.)=(7(R,)
`,
`(‘Ec ,
`
`..
`N(Rs)(3(0JN{RsJ
`,
`(rtktmwtks)
`MR5]
`.
`ONC(R3)
`("(R_,,)N0
`—N(R5]C(R3R_1}
`5(03)
`C(1t,R_,)0
`.
`0033114)
`.
`S(UZ)N
`- 0r
`(Rs)
`N(RS)S(02)
`C(RJqusloz)
`St‘JQIC
`{R34}
`; |)is optionally substituted aryl or heterocycle; His
`optionally substituted aryl or hetemcyclc: R,
`is hydrogen or
`optionally substituted alkyl. alkyl—aryl. alkyI—heterocycle.
`aryl. or lteterocyele: R1 is hydrogen or optionally substituted
`alkyl. alkyl—aryl. alkyl—heterocyele, aryl, or hetcmcycle: R3 is
`hydrogen. alkoxy, amino. cyano, halogen, hydroxyl, or
`optionally substituted all-Lyl'. R4 is hydrogen. alkoxy. amino.
`cyano. halogen, hydroxy]. or optionally substituted alkyl or
`aryl; R5 is hydrogen or optionally substituted alkyl or aryl;
`and n is 0-3.
`Particular compounds are of formula ”(A):
`
`{NA}
`
`:
`x o 0 H
`
`I {N
`
`0
`
`x‘ R
`
`lt_-
`
`0/
`
`Willi regard to tlte fortitulae disclosed herein (e.g.. l. [{A).
`II and II(A))._ particular compounds include those wherein A
`is optionally substituted eyeloalltyl [c.g.. 6-men1bered and
`5-membered). In some, A is