WO 2009/149278
`
`PCT/US2009/046287
`
`hydrochloride (2-Propanol, 1 -(2-cvelohexyiphenoxzy}-3 - [( 1 -methylethyliamine-,
`
`hydrochioride CAS RIN 59333-90-3), Hestolol sulfate (Bonzoic acid, 2-fhuro-,3-[[2-
`
`jamunocarbonyljamino |- - dimethylethyllamine|-2-hydroxypropyl cater, (+}- sulfate (1 <b} (salt).
`
`CAS RN 88844-73-9: metalol hydrochloride (Methancoulfonamide, N-[4-[l-hydrosy-2-
`
`imethviaminojpropyliphenryl|-, monohydrochionde CAS RIN 7701-65-7}, metoprolol 2-
`
`Propanol, 1-[4-(2- methoxyethyliphenoxy|-3-l]-methylethylhaming]-; CAS RN 37350-S8-63,
`
`metoprofol tartrate (such as 2-Propanol, 1-[4-(2~methoxyethyliphenosy [-3-[G-
`
`methylethylaminol, ¢y., Lopressor®, Novartis}, parnatolol sulfate (Oarbamue acid, [2-/4-[2-
`
`hydroxy-3-[C- methyleth yjarninefpropoxyliphenyi-eth yl, methyl ester, (4) sulfate (aalt) (2:13,
`
`CAS RN 599354-01-7), penbutelol sulfate @-Propanol, |-4(2-cyclopentyiphenosy}-3-[LL-
`
`dimoethyle- thyljaminol |. (S)-, sulfate (2:1) (aalt}), CAS RN 38363-32-5), practolol (Acotamide,
`
`h-[4-[2- nydroxy-3-[il-methyiethylaminoi-propoxy|phenyvif-, CAS RN 6673-35-40) tiprenolol
`
`hydrochloride (Propanol, |-iti-mothviethylamino!-3-[2-(methyithio}-phenoxyl-, hydrochloride,
`
`(2), CAS RN 39832-43-4) tolamolal (Senzamide, 4-[2-[[2-hvdroxy-3-(2-methyinhenoxy}-
`
`propyif amino | ethoxyiP, CAS RN 38163-61-6), bopindolol, indenolol, pindolol, propanolol,
`
`tertatolol, and tiliselol, and the like; calchim channel blockers such as besylate salt of amlodipine
`
`fsuch as 3-ethyi-5-methyl-2-(2-aminoothoxymethyl)-4-(2-chiorophenyD-1 ,4-dihvdro-6-methyl-
`
`3S-pyridinedicarboxylate peazenestiphonace, é.2., Norvasc®, Pfizer}, clentiarom maicate (1,5-
`
`Benrothiazenin-4{Sh}-one, 3-(acctyloxy)-&-chioro-4-]2-{(dimethylaminoietivy!|-23-dilyydra-2-
`
`(4-methoxyphenyi-(28-cis}-. (4}-2-butenedioate (1 114, seo also US4567 195}, isradipine {3,5-
`
`Pyridinedicarboxylic acid, 4-(4-benzoturazanyl}-L4-dihvdro-2.4-dimethyl-, methyl i-
`
`methylethyl ester, (+)-4(4-benzofurazany)- | 4-cdihydre-2,6-dimethyl-3 3 -
`
`OFF
`wyridinedicarboxylate, see also US4466972)} nimodipine (such as is isopropyl (2- methoxyethy)
`
`1, 4- dilvydro -2,6- dimethyl -4- (3-nttrophenyl} -3,5- pyridine - dicarboxylate, eg. er
`nytidinedicarboxylate- 2.2, Plendil® Extended-Release, Astrawencea LP), nilvadipine BS.
`
`Bayer), folodipme (such as cthyl methyl 4-(2,3-dichloropheny])-L4-dibydro-2,6-dimethyi-3
`
`Pyridinedicarboxylic acid, 2-cyano-}4-dihydro-6-methyl-4-€3 -nitraphery lb 3-methyl 5-(-
`
`methylethy) ester, alse see US3799934), nifedrpine (such as 3, 5 -pyridinedicarboxyheacid}
`
`dihydro-2 ,6-dumethy1-4-(2-nitrophenyl)-, dunethy] ester, e.g., Procardia XL&®Extended Release
`
`Tablets, Pfizer}, diltiazern hydrochloride (euch as 1.S-Benzothiaxepin-4(SH)-one.3-(acetyloxyv}
`
`5[2-(dimethylaminojethy]]-2,-3-dithydro-2(4-methosyphenyl)-, monobydrochloride, (4}-cis., eg.,
`
`44
`
`20
`
`25
`
`30
`
`MYLAN - EXHIBIT 1022 Part 11 of 16
`3418
`
`3418
`
`MYLAN - EXHIBIT 1022 Part 11 of 16
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`

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`
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`
`Tiazac®, Forest}, verapamil hydrochloride (such as benzencacetronitrilc, Calpha}-[f5-fP2-(3,4-
`
`dimothoxyphony)) cthylimethylamino ipropyl} -3 .4-dirmethoxy-(aiphal | -methylethyh
`
`hydrochloride, ¢.¢.,lsoptin® SR, Knoll Labs}, teladipine hydrochloride (3.5-
`
`Pyridinedicarboxylic acid, 2-[(dimethylaminojmethyil4-[2-[(TE}-3-Li-dimethylethoxy}-3-oano- |
`
`propenyl[phenyl ]-14-dibydro-G-metivi, diethyl ester, monohyvdrochloride} CAS RN 1G8700-
`
`03-4}, belfosdil (Phosphonic acid, [2-(2-phenoxy ethyl}- 1,3 ~propane- diyijhis-, tetrabuty! ester
`
`CAS BRN 105486-79-9}, fostedif (Phosphonie acid, [[4-(2-benzothiazolyphenyl imethyll,
`
`diethyl ester CAS RN 75889-62-2}, aranidipine, azelnidipine, barucdipine, benidipme, bepridil,
`
`cinaldipine, clevidipime, efonidipine, gallaparmul, lacidipine, lemildipine, lerearudipine, monatepil
`
`maleaic (1-Piperazinebutanamide, N-(6, 11 -dihydrodibenzo(b,eyhiepim 11 -yib.-(4-
`
`Huorophenyli-, (+)}-, (4)-2-butonedioate (1:1) (4)-N-(6 5 1-Dibrydrodibonzo(bchihten- tn-d [-yi}-4-
`
`(p- flucrophenyii-l-piperazinebutyramide mafeate (1 1} CAS RN 132046-06-1}, nicardipine,
`
`nisoldiping, nitrondipine, manidipine, pranidipine, and the Hke; P-channel calcium antagonists
`
`such as mibefradil; aneictensin converting enzyme (ACE) inhibitors such as benazepril,
`
`benazepril hydrochioride (such as 3-[]l-(ethoxycarbonyl}-3- phenyl-(¢ 1 S}-propyliamine}-23
`
`4,5-tetrahydro-2-oxo- | H- 1-3 S}-benzazepine- | -acetic acid monobydrochloride, e.g.,
`
`Lotrel®, Novartis}, captopril (such as 1-](2S)-3-mercapto-2- methylpropiony!}-L-proling, ¢.x.,
`
`Captopril, Mylan, CAS RN G2571-86-2 and others disclosed in US4O4G889), ccranapril (and
`
`others disclosed in US4452700), cetapril (alacepril, Dainippon disclosed in Hur. Therap. Kes.
`
`SO:671 €1986); 40/543 (1980)}, cilazapril GHofiman-Lakoche} disciosed im J. Cardiovasc.
`
`Pharmacel. 9:39 (1987). indalapril Gelapril aydrochloride (2H-1,2.4- Benzothiadiazine-7-
`
`sulfonamide, 3-bicveio[?.2.1 Thept-3-en-2-yl-6-chloro-3 4-dihydro-, f,i- dioxide CAS RN 2ES9-
`
`96-3), disclosed in US438504513, enalapril (and others disclosed in US437482%3, enalonril,
`
`enaloprilat, fosinopril, ((sucn as L-proline, 4-cyclohexyl-L-[[f2-methyl- l-(L-oxopropoxy}
`
`propoxyH4-phenyibuty) phosphinyllacetyl|-, sodiur salt, e.g., Monopril, Bristol-Myers Squibb
`
`and others disclosed in US41 68267), fosinopril sodium(L- Proline, 4-cyclohexyLT-[[(R}IGS}-2-
`
`methyl-1-(l-ox- opropoxyyoropox), trudapril, mdotapril (Schering, disclosed in J, Cardicvasc.
`
`Pharmacel, 5:643, 6454 (1983)}, lsinopril (Merck), losinopril, mocxipril, moexipril bydrochiloride
`
`(3-lsoquinolinccarboxyhe acid, 2-[(25)}-2-]]0S})1 -fethoxyearbory!}-3~phenyvipropyllaramo}- 1 -
`
`oxopropyll |
`
`.- 2.3.4-tetrahydro-6,7-dimethoxy-. monohydrochloride, (45}- CAS RN &2586-S2-
`
`5}, quinapril, quinaprilat, ramipril (Hoechssi) disclosed in EP 79022 and Curr, Ther. Res. 40:74
`
`45
`
`20
`
`25
`
`30
`
`3419
`
`3419
`
`

`

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`
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`
`(1986), perindopril erbummine (such as 28,3a5,7aS- 1 -[(S)-N-[(5} 1 -
`
`Carboxybuty alanyhbeoxahydro’-indolincearboxvlic acid, | -cthyl ester, compound withtert-
`
`butylarnine (1 :-L} eg, Aceon®, Solvay}, perindopril (Servier, disclosed in Fur. J. clin.
`
`Pharmacol 31 319 C1987}), quanipril (disclosed in US4344949) snirapril (Schering, disclosed
`
`in Acta. Pharmacol. Toxicol. 39 (Supp. 43}: 173 (19&6)}, tenocapril, trandolapril, zofenonril Cand
`
`others disclosed in US43169063, rentiapril Gentiapril, disclosed in Clin. Exp. Pharmacol,
`
`Physiol 1131 (i983), pivopril, YS98G, teprotide (Bradviinin potentigitor BPPG9a CAS RIN
`
`35115-60-7), BRL 36,378 (South Kime Beecham, see EPROS22 and EPO0668}, MC-R3&
`
`iChupai, see CA. 1032-72588and Jap. J. Pharmacol 46:373 (19863, CGS 14824 (Ciba-Geigy, 3-
`
`Ol-ethoaycarbonyl-3-phenyi-{i5propyllaminae)}-2 3 ,4.5-tetrahydre-2 -ox- o-1-(35}-benzazepine-]
`
`acelic acid HCL see LK. Patent No. 2104614), CGS 16,617 (Ciba- Gergey, 3(5}-[70S)-5-amino-L-
`
`carboxvpentyljamino |-2,3.4.- 3-tetrahydro-2-oxo-lH-l- benzazepune-l-ethanoic acid, see
`
`LIS4473575), Bu 44576 (Hoechst, sce Arzneimittelforschune 34:1254 (1985), BR 31-2201
`
`(Hoffman-Lakache sce FEBS Lett. 1645:201 (984), CIGZS @Pharmacclogist 26:243, 266
`
`{19843}, WY-44221 Wyeth, sec F Med. Chem. 26:394 (19833), and those disclosed in
`
`US2003006922 (paragraph 28}, US4337201, US84432971 fohosphonamidates}: neutral
`
`endopeptidase inhibitors such as omepatrilat (VVanlev®), CGS 30440), cadoxatril and ecadotril,
`
`fasidotril (also known as aladotril or alatriopril}, sampatrilat, mixanpril, and gcmopatrilat,
`
`AVET6SS, ER4030, and those disclosed in USS362727, USS366973, US5225461, OS4 722210,
`
`USS223516, USA749688, US5552397, USS504080, US5612359, US5525723, BPOS99444,
`
`EPO48 1522, EPOSS0444, BPOSOSeLO, EPOS34363, BP534396, EP534492, EPO629627;
`
`endothelin antagonists such as tezosentan, AS08165, and YM62ZS899, and the like; vasodilators
`
`such as hydralazine (aprescline}, clonidine (clonidine hydrochloride (1H-lmidazol- 2-amine, N-
`
`(2,6-dichloropheny]}4,5-dihydro-, monohydrochioride CAS RN 4205-91-8), catapres, mincaidil
`
`Joniten), ricotinyl alochol (roniacol, diltiazom hydrochloride (such as 1 ,5- Bonzothiazepin-
`
`AC3Hpone 3-acetyloxy }-S[2-(dimethyviaminajethyt]-2,-3-dibydro-2(4- methoxyphenyh-,
`
`monohydrochloride, (+)}-cis, e.g., Tiazac®), Forest}, isosorbide dinitrate (such as 1,4:3,4-
`
`diankiydro-D-glucitel 2,5-dinitrate e2., Iserdul® Titradose®, Wyeth- Ayerst}, soserbide
`
`monortrate (such as 14:3,6-dianhydro-D-gluctto~ 1,3-nitrate, an organic nitrate, eg., isamo®,
`
`Wvyeth-Averst}, nitroglveerin (seach as 2.3 propanctriol trinitrate. ag, Nrtrostat® Parke- Davis),
`
`verapamil hydrochloride (such as benzencaectonitrile, C£)-talpha}[3-[[2-G4 dimethoxypheny
`
`20
`
`25
`
`30
`
`46
`
`3420
`
`3420
`
`

`

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`PCT/US2009/046287
`
`Dethyl imethvlarmino tpropyl] -3 .4-dimethoxy-(aipha}- ( 1 -methvicthy)} hydrochloride, 2g.,
`
`Covera HS® Extended-Rcloasc, Searic}, chromonar Qvhich may be prepared as disclosed im
`
`L832 82948), clonitate (Annalen 1870 155}, droprenilamine (which mav be prepared as disclosed
`
`in DE2521113), lideflazine (which may be prepared as disclosed in LIS3267104); prenylamine
`
`iwhich may be prepared as disclosed in US31452173}, propatyl nitrate Gvhich may be prepared as
`
`disclosed in French Patent No. 1,103,113), mioflazine bydrochloride €1
`
`-Piperazineacetamide, 3-
`
`faminocarbony)-]4,4-bis(4-fluoropheny butyl-N-(2,6- dichiorophenyD-, dihydrochloride CAS
`
`RIN 83898-67-3), mixidine (Renzeneethanamine, 3,4- dimethoxy-N-C-methy1-2-
`
`pyrrolidinylidenc)}- Pyrrolidine, 2-[(3,4-dimethoxyphenethyDunine|- 1 -rmethyl bMethyl-2- 1G,
`
`4.dimethoxyphenethyinnine[pyrrolidine CAS RN 27737-38-8), molsidomine (1,2,3-
`
`Oxaciazohlum, 5-[(othoxvcarborybamuino f-3-(4-morpholiny!-, inner salf CAS KN 28717-80-0},
`
`jsosarbide mononitrate (D-Ghncitol, 1.4:3.6-dianhydro-, 5-nitrate CAS RN IGOSL-77-7),
`
`erythrity| tetranitrate (1,2,3,4-Butanetotrol, totranitrate, (ZR.3S }rel-CAS RN 7297-Z5-8},
`
`clonitrate(i2-Propanediol, S-chioro-, dinitrate (7C1, §C1, @CDB CAS RN 2612-33-19},
`
`dipyridamole Ethanol, 2,2',2',2'"-1{4,8-di-Lpiperidinyipyrimidof5,4-dipyrimidine-2,6-
`
`divbdiniirtic ltetrakis- CANS RN 38-32-32) nicorandil (CAS RN 65141-46-0 3-},
`
`pyridinocarboxamide (N-f2-(nitrooxyjethyl]-Nisoldipine3,$-Pyridinedicarboxylic acid, 1,4-
`
`dibydro-2 o-dimethyL-4-(Q-nitropheny)-, methyl 2-methylpropyl ester CAS RIN 63675-72-93,
`
`nifedipine3 4-Pyridinedicarboayhe acid, 14-dilrydro-2,6-dimethyl-4-(2-nitrophenyi}, dimethyl
`
`ester CAS RN 21829-25-4), perhexilince maleate (Piperidine, 2-(2,2-dicyciahexylethy)-, 27}-2-
`
`imitenedicate (1:1) CAS RN 6724-53-4), oxprenolol hydrochloride (2-Propanol, 1-[{4-
`
`methylethyDanmino[-3-[2-(2-propenyloxyphenoxy|-, hydrochloride CAS RN 6432-73-9),
`
`pentrinitrol (1,3-Propanedicl, 2,2-bis[{nitrooayymethyl-, mononitrate {ester} CAS RN 1607-17-
`) veraparnil (Benzencacctonitrile, a-[3-[{2-43,4-dimethoxyphenybethyl]- methylamine|orapyli-
`3, 4-cimethoxy-a-(1 -methyiethy)- CAS RN 32-53-and the like; angiotensin Hf receptor
`
`amMagonists such as, aprosartan, zolasartan, clinesarian, pratosartan, FIGS2SEK, RNH6270
`
`candesartan G H-Bensimidazole-7-carboxylic acid, 2-cthoxy-l-[[2'(TH-tetrazal-S-y TEL]
`
`biphenyi/4-ylfmethyl]- CAS RN 139481-59-7), candesartan cilexetil @4+/-}-1-
`
`fcyclohexyicarbonyloxyjothyl-2-ethoxy-l ~{P2-lH-tetrazal-5-y)biphenvi-4-yl|-lH-bensimidazaic
`
`carboxylate, CAS RN 145040-37-5, USATOALIO and LISS196444), eprosartan (3-[]-4-
`
`carboxvphenylmethyh}-2-n-butyl-pmidazel-S-yi}-(2-thienyvimeithy)) prepencic acid, UISSTRS351
`
`47
`
`10
`
`15
`
`20
`
`25
`
`30
`
`3421
`
`3421
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`
`and USS650650), irbesartan {2-n-butv1-3- [[2-(th-tetrazal-S5-y Dbiphenyi-4-yH methyl] 1 3-
`
`diazazspnro|44 inon-l-on-4-one, USS270317 and USS352783), losartan (2-N-buty!-4-chiora-S-
`
`hydroxymethyl-Li2(i_-tetrazelS-yibiphenyi-4-yl -methy imidazole, potassnim salt,
`
`USS138069, USSISS197 and USS1 2835S}, tasosartan (5,6-dihydro-2,4-dimethy!-8-[(2'-(H-
`
`ictrazol-S-yi}[Lr-bipbenvl]4-viimethyl-pyrido[23-dipyrimidin-7(6Hi-one, USS149699},
`
`telbmisartan (4-[(1 4-dimetby!-2*-propyl-(2,6'-bi-ll-benzimidazel-rvi}}-[ 1, 1 -biphenyl}-2-
`
`carboxyhe acid, CAS RN 144701-44-4, (83591762), milfausarian, abitesartan, valsartan
`
`nee (Novartis), (S)-N-valeryi-N-EP2'-CE-tetrazal-S-yl)bipheny!-4-ylpmethyvaline,
`
`55399578), EXP-3137 (2-N-botyl-4-chlore-L-](2HH-tetrazol-5-yDbiphenyi-4d-yh-
`
`methyllimidazole-S-carboxylic acid, LISST3RO69, LISSE33197 and USS1 28355}, 3-£2'-(tetrazal-
`
`5-vf-Le- biphen-4-ylimethyt-5,7-dimethyl-2-othvi-3H-imidazol4,5-binyridine, Vi2-cthyl-4-
`
`methyl-6-(5.6.7,8-tetrahyvdrotmnidazolLZ-alpyridin-2-yi]-benzimidazei-l-yip-methyl}-ir
`
`biphenyl]-2- carboxylic acid, 2-butvl-6-(i-methoxy-l-methylothy)}-2-[2"-HEH-tetrazal-5-
`
`yiibiphenyi-4-yimethyl] guinazolin-4(3H)-one, 3 - 2" -carboxybiphenyl-4-yDmethv!| -2-
`
`cyclopropyl-7-methyt- 3H-imidazoi4.s-b}pyridine, 2-buty!-4-chioro-L{(2’-tetrazol-5-
`
`yijbinhenyi4-ybmethylfimidazole-carboxylic acid, 2-butyl-4-chioro-1-|[?"-4{LH-tetrazol-S- yh [1
`
`* -binhenyi] -4-yvilmethvip 1 H-imidazolo-5 -carboxylic acid- 1 -(ethoxycarbonyl-oxyjethy!
`
`oster potassium salt, dipotassium 2-butyi-4-(mothylthio}-1-#[2-/[(propyiaminejcarbonyliamine b-
`
`sulfonyijit '-biphemyl-4-ylimethyi|-] H-imidazole-5 -carboxylate, methyi-2-[[4-buatyl-2-
`
`20
`
`methyl-6-oxo-5-[[2"-{lH-tetrazol-S-y)-[Li ‘-biphonvii-4-yilmethyl|-1-46H)}pyrinudimymethyi]-
`
`3-thiophencarboxylate, 5-[(3,5-dibuty1-1H-1.2.4-triaszol-L-yDmethyi]-2-12- (1 H-tetrazal-3
`
`yiphenyDpyridine, 6-buty!-2-(2-phenylethyi-3 [[2’-) H-tetrazol-3 -vDi 1,1 °- biphenyl}-4-
`
`rothylipyrimidin-4-(3H)}-one DL lysine salt, 4-methyl-?-n-propyl-S-[[2"-(1H- tetrazoi-5-
`
`yDbiphenyi-4-ylimethyl]-[ i 2,4} -triazolo{ | .5-cipyrimidin-2(3H)}-one, 2,7-diethyl-S- [[2"-
`
`tetrezolyjbiphenyl-4-ylimethyl]-S5H-pyrazolo[L5-b]fi24}iriazole potassiurn salt, 2-[2- natyhd.S-
`
`25
`
`dihydro-4-oxo-3-[2"-(TH-tetrazol S-yh-4-hiphenyimethyl]-3H-imidazol[4,5- clpyridine-S-
`
`yimethylbenzaic acid, ethy! ester, potasstum salt, 3-methoxy-2,6-dimethyl-4-
`
`GH-tetrazal-5-
`
`yI-LI -biphenyl-4-ylmethoxy lpyridinc, 2-cthoxy-]-[[2"-(S-oxn0-2,5-dihydro-1,2,4-oxadiazol-3
`
`yibrobonyi-4-yimetin!| ~ i H-benzimiudazole-T-carboxylic acid, | - PN-(2°-¢ | He tetrazal-3-
`
`30
`
`vibinheny1-4-yvE-methvl)-N-valerolylaminomethyheyvelopentance- | -carboxyvhe acid, 7- methyl-
`
`2n-propyi-3-[[2" HH-tetrazel-S-yUbipbeny1-4-yimethyi-3 A-imidazoal45-6 loyridine, 2- [5-[(2-
`
`48
`
`3422
`
`3422
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`
`ethy!-5?-dimethyL3 H-imidazal]4.4-b}pyridine-3-y]metityl]-2-quinolinyl|sediumbenzoate, 2-
`
`buty-6-chioro-4-hydroxymethyl-s ~rocthy3 ~[[2"-4 H-tetrazal-S -vbipheny|-4~-
`
`yilmethylipyridine, 2- f [[2-butyl- i - i{(4-carboxyphenvijmetiy?] -
`
`| H-rnidazal-5 -
`
`yilmethy aminotbenzoic acid tetrazol3-ybiphenyl-4-yljmethyiipyrimidin-6-one, 408)- f4-
`
`fcarboxymeihylphenoxy -N-[2¢R)-[4-(2-sulfobenzamidohmidazal 1 -yljoctanoyl]|-L-proline, i
`
`- (2,6-dirnethyipheny))-4-boty}-13-dibydro-3-[[6-[2-(1H-ietrazol-S-y phen yi}-3-
`
`pyridiny]fmethy ]]-2H-moidazol-2-one, 3 ,8-ethano-5 ,8-dimethyl-2-n-propybs .6,7,8-tetrahydro-
`
`1 - [2G-tetrazol-S-yDbiphenyl-4-yflimethyll-lH 4H 408a-tetrazacyclopenianaphihalene-9-
`
`one, 4-f-[24h 2 3,4-tetrazol-5-y biphen-4-ylhmethylamina[-3,6,7,8-tetrahydro-2-
`
`tifyiqumnazoline, 2-(2-chlorobenzoy)imino-5-ethyi-3-[2"-h-tetrazole-3-yLbiphenyl-4-
`
`yOmethyl-13,4-thiadiazoline, 2-[5-ethyl-3-[2-(H-tetrazalo-5-ybbiphernyi-4-yilmethyl-1 3 4-
`
`thiarolinc-2-ylidenc jaminocarbonyl-l-cyclopentencarboxylic acid dipotassium salt, and 2-butyl-
`
`4-{NW-methyl-N-(3 -methyicrotonoybamino}- 1- [12° -{ 1 H-tetrazol-5 -vibiphenyl-4-
`
`ylimethy!]- 1 H- imidzole-5 -carboxylic acid 1-ethoxycarbonvioxyethy! oster, those disclosed in
`
`patent publications EP475206, EP497150, EPS39086, EP539713, BPS35463, EP535465,
`
`EP542659, EP497121, EPS35420, EP407342, EP4i 5886, EP424317, EP435k27, EP4AS3983.
`
`EP47S5898, EP490820, EPS528762, EP324377, EP323841, EP420237, EPS00297, EP426621,
`
`EP4s80004, EP429287, EP430709, RP434049 FP446062, EPSO5954, EPS524217, EPSLS197,
`
`EPSI4i98 EPSi4io5 EPSi4192 BP4S0566, EPAGSS72, EP485909, EPSO3162, EPS3305¢,
`
`EP467207 EP399731, EP300732, BP4i2848, EP4$3210, BP456442, EP470794, EP47G705,
`
`EP495626, BP495627, EP4904 14, PP490416, EP490415, EPSLL?9L, EPS16392, EPS20723,
`
`EP520724, EPS39066, EP438869, EPS03893, EPS30702, EP400835, EP400974, EP4010230,
`
`EP407102, BP411766, EP4G0332, PP41 2594, EP4io04s, EP4e0eS9, PP481G14, EPA9OS&7,
`
`EP467715, £P479479, EPSO62725, EPSO383¢, EPSOSO9S8, EPSOSTL] BPS13,979 EP507504,
`
`EPSiO812, EPS11767, EPSi2675, BP512676, EPSi287G, EPS17357, EP537937, EPS34706,
`
`EPS27534, EPS40356, EP461040, PP540039, EP465368, EP498723, RPAGR 722, EP49R721,
`
`EPS1S265, BPS03785, EPSOLRS? EPSI9R31, BPS32410, EP49R361, BP432737, EPSOAge
`
`ou
`
`EP508593, EPS08445 EP403149, BPP403158, EP42S? 11, RP427463, PPA37103, EP4ART448,
`
`PP48RS32, RPSO1 269, BRPSOOdO9, EPS40400, RPOQO5S28, EPOLZ&834, PPOZ8533, EP4L ESOT,
`
`EP425921, BP430300, EP434038, EP442473, EP443568, EPA4S8 11, EP4S9136, EP483683,
`
`EPS18033, BPS20425, EPS31876, EPS31874, EP392317, EP468470, EP470343, EP5023 14,
`
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`30
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`PCT/US2009/046287
`
`EP529253, EPS543263, EPS40209, BP449609, EP465323, RPS21768, EPA 5504, WO92/1 4468,
`
`WOSS/08 E71, WO9S/I8 169, WOST/G0277, WO9L/GO281, WOUL/T4367, WOURR067,
`
`WO97/00977, WO02/20542, WOOS/D4045, WOOS4046, WOO1/ES206, WO92/14714,
`
`WHS? /08600, WO928/1 6552, WOS2/03025, WO93/0201 &, WOS LOT 404, WOG22508,
`
`WO9Z/1 2853, WO9L/1 9697, WOST/1 1909, WOOTT2001, WOOT/T E999, WOST/1 5209,
`
`WOOL/TS4EIS, WOOR/2 0687, WOS2/20062, WO97/20661, WOSS/GLI77, WOSE/E4679,
`
`WOSE/7 36063, WOOZ/1 3564, WOOL/LT7L48, WOSLTBBSE, WOOL/TSTES, WOS2/02 257,
`
`W392 /04335, WOS2/05161, WOS2/G7852, WOSZ/1 5577, WOSS/03033, WOOL/E6S IS,
`
`WOS2/O06068, WO9Z/G25 FO WOS2RO278, WOO2 T0179, WOSZ/1 G16, WO9Z/1 G186,
`
`WOO2/BERE, WO92/1 0097, WOS2/10183, WO9Z/TOLKZ, WOS9Z/TOLE7, WOO2/1O184.
`
`WOSZMTOLBE, WOOZ/TOLSE WOS2ZDISS, WOO2/2065 1, WO83/O5722, WOF306824,
`
`WO93/93040, WOO?/PS2 1, WO98/22533, WOIZ/0008L, WO9Z/0S87 84, WOOS AMISI.
`
`WOS9Z/04343, WOO2/O408¢, USSI04877, USSLSTIGS, USS149699, USSISS340, US48 80804,
`
`USS138069, US49 16129, USSES3197, US5173494, USS13 79606, LISS 133126,
`
`185140037,
`
`983137902, US5157026, US5053329, USS132216, USSOS7S22, USSO66586, USSO89626,
`
`USS049565, USSOS7702, US5124335, USSIOZ RKO, LISSEDR327, LISS151435, USS262322
`
`USS187 159, US5198438, USS LG2288, USSO36048, USS 40036, USSOS7634, USS196537,
`
`USSITS3347, USS191086, US5190842, UISST77G97, LISS2 T2177, LISS2G8244, US520823
`
`S52 12195, US5130439, USS045540, USSO41 152. and USS2 10204, and pharmaceutically
`
`acceptable salts and esters thereof; a/G adrencreic blockers such as ripradilol, arotinolol,
`
`amosulalol, bretvliumtosylate (CAS RN: 61-75-6)}, dinvdroergtamine mesviate (such as
`
`ergotaman-3’, 6',18-trione,9,-10-dihyiro-12"-bydroxy-2'-methyl-5"-(phenylmethyl-13’
`
`rmoncmethancsuitonate, ¢g., DHE 45@Injection, Novartis), carvedilal (such as (2)-44(Carbazol-
`oeo-methoxyphenoxyjethyi] amino] -2-propanol, 2.2., Coreg®, SmithKfine
`
`echara), labetalol (such as S-[l-hydroxy-2-|(-methy|-3-phenylpropy)) arnimo}
`
`ethylisalicylamnide monohydrochioride, ¢¢., Norraodyne®, Schering}, bretvlium tosylate
`
`(Benzenemethanaminium, 2-bromo-N-cthy LN,N-dimethyt-, salt with 4-methytbensenesulfonic
`
`acid (1 1) CAS RN G1-75-6), pheniolamine mesylate (Phenol, 3-[[(4,5-dihydro-lH-imidarol-2-
`
`wimethy]l(4-methylphonyDarnino +. monomethanesuifonate (sait} CAS RIN GS-28-1},
`
`solypertine tartrate (SH-13-Dioxctol4.S-flindole, 7-[2-14-(2-methoxypheny)-l-
`
`tiperazinyUethyll-, (2R.3R}-2,3-dibydroxybuianedicate (1 11) CAS RN 55%1-43-5), zolertine
`
`50
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`
`nydrochlovide (Piperazine, Lphenyi4-[24PA-tetrazol-5-yDethy!l]-, monohydrochloride (RCL 9CD
`
`CAS RN 7241-94-3) and the likc: o adrenergic receptor blockers, such as alfuzasin (CAS RN:
`
`&1403-68-1}, terazosin, urapidil, prazosin (Minipress®), tamsulosin, bunarosim, trimaezosin,
`
`doxazosin, naftopidil, indoramin, WHP
`
`164,XENOIO,fenspiride hydrochloride Qvhich may be
`
`prepared as disclosed in LIS3399192) proroxan (CAS RN 33743-96-3), and lahbetalol
`
`hydrochioride and combinations thereof) o 2 agonists such as methyldopa, methyidepa HCL,
`
`lofexidine, Hamenidine, moxonidine, rilmenidine, guancbenz, and the like, aldosterone
`
`inbthbitors, and the like; renin inhibitors inchiding Aliskiren (SPPIOO): Novartis/Speadely;
`
`angionotetin-2-binding agents such as those disclosed in WOOG3/030833; aiti-angina agents sich
`
`as ranolazine Chydrochioride [-Piperazineacetamide, N-(2,6- dimethyiphenyl}-4-[2-hvdroxy-3-
`
`i2-mothoxyphonoxy propyl, difrverochlioride CAS RIN 9S5635- 56-6), botaxolol hydrochloride
`
`2-Propancol, |-[4-f2 teyclopronvimethoxyjethyl[ohenoxy|-3-[0- methylethy famine |-,
`
`hydrochloride CAS RIN 63659-19-8), butoprozine hydrochloride (Methanone, {4-
`
`i3idibutylaminejpropoxylohenvil f2-ctayl-3-indolizinyli-, monohydrochiaride CAS RN 62134-
`
`34-3}, cinepazet maleatel-Piperazincacetic acid, 4-H-oxo-3-(3,4.5- trimethoxypheny))-2-
`
`proponyll-, ethyl ester, (27}-2-butencdioate (7 11} CAS RIN56679-07-7), tosifen
`
`(Benzenesulfonamide, 4-mothyi-N-[[Pd8}-l-methyL-2-phenviethy! jamine}carbonyi}- CAS RN
`
`32295-1884), verapamilbyydrochloride (Benzenecacetomtrile, -£3-[F2-(3_4-
`
`dimethoxypheny letivylfmethylaminolpropy!{-3 .4-dimethoxy-a-f 1 -methyicthyl-,
`
`monohydrochioride CAS KN 152-114), moisidemine (1,2,3-Oxadiazalium, 3-
`
`ifethoxycarbonyamino|-3-(4-morpholinyl). immer salt CAS RN 25717-860-0), and ranclazine
`
`hydrochloride (1 -Pipcrazincacctamide, N-{2.6-dimothylphenyl}.-[2-hydroxy-3-(2-moth-
`
`oxyphenoxyjoropvil-, dibydrochioride CAS RN 93635-36-6); tosifen (Benzenosulfonamide, 4
`
`methyl-M-[ PRS}-l-methyl-2-phenylethyljaminolcarbonyl]- CAS RIN 3225-184), adrenergic
`
`stimulants such as guanfacine hydrochioride (such as N-srnidine-2-(2,6-dichlorapheny)
`
`aceturnide hydrochloride, ¢.u., Tenex® Tablets avalable froma Robins}; methyidopa-
`
`hydrochlorethiazide (such as leva-3“-aihydroxypheny)-2-methylalanine} combinedwith
`
`Hydrochlorothiavide (such as 6-chiore-3,4-dibvdre-2F -124-benvothiadiazine-7- sulfonamide
`
`10
`
`15
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`20
`
`25
`
`Li-dioxide, e.g., the combination as, «g., Aidorii® Lablets available fram Merck}, methyidopa-
`
`chicrothiazide (such as 6-chloro-2H-I, »A-bonvothiadiavine-7-oulfonamide 1 i-dioxide and
`
`30
`
`methyidona as described above, 2.z., Aldoctor®, Merek}, clonidine hydrochloride (such as 2-
`
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`(2.4-dichlorophenylamina}-2-imidazoline hydrochloride and chlorthalidone (such as 2-chlora-5S-
`
`O-bydrosxy-3-ox0-Lisoindolinyl) benzencsulfonamidc), 4g., Combinres®), Bochringer
`
`Ingelheim}, clonidine hydrochloride (such as 2-(2 6-dichlorophernylamino)-2-imidazolins
`
`hydrochloride, ag., Catapres®, Boehringer Ingelheim), clonidine (H-Imidazol-2-amine, N-(2,0-
`
`dichlorophenyvl)4,5-dibydro-CAS RN 4205-90-7}, Hyzaar (Merck: a combination of losartan and
`
`hydrochiorothiazide), Ca-Diovan (Novartis; a combination of valsartan and hydrochlorothiazide,
`
`Lotrel (Novartis; a combination of benazepril and amlodipine) and Cacuet (Pfizer, a combination
`
`of amlodipine and atorvastatin}, and those agents disclosed in 11520030069221.
`
`10
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`15
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`25
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`30
`
`Agents for the Treatment ofRespiratory Disorders
`
`‘The GCRA poptides described herein can be used in combination therapy with one or
`
`more of the following agents useful in the treatment of respiratory and ather disorders inchiding
`
`but not limited to: ( 1} S-agonists including but not limited to: albuterol (PRO VENTIL® .§
`
`ALBUT AMOI® | VENTOLIN®}), bambuterol, bitoteral, cleniuterol, fenoterol, formaoterol,
`
`isoetharine (BRONKOSOL®, BRONEKOMETER®), metaproterenol (ALUPENT®,
`
`METAPRELG@), pirbuterol MAXAIRG®), reproteral, rimiterol, salmeterol, terbutaline
`
`(BRETHAIRE®, BRETHINE®, BRICANYL®), adrenalin, isoproterencsl (ISUPREL®),
`
`epinephrine bitartrate (PRIMATENE®) cphcdrine, orciprenlinc, fenoteral and isoetharme; (2)
`
`steroids, including but not limited to beclomethasone, beclomethasone dipropionate,
`
`betamethasone, budesonide, bunedoside. butixocort,. dexamethasone, flunisolide. fluoceartin,
`
`fluticasone, hydrocortisone, methyvi prednisone, mometasone, predonisclone. predonisone,
`
`tipredane, tixocortal, triamcinolone, and triamcinolone acctonide; (3) B2-agonist-corticosteroid
`
`combinations f¢.e., salmeterol-thiticasone (AD V AIR), formoterol-budesonid (S
`
`YMBICORT@)] ; (4) leukotriene D4 receptor antagonists/leuketricne antagonists/LTD4
`
`antagonists (L¢., ary compcund that is capable of blocking, inhibiting, reducing or otherwise
`
`interrupting the interaction between leukotrienes and the Cys LTT receptor) inchiding but not
`
`limited to: zafhrukast, moniclikast, montcinkast sodium (SINGULAIR ®), pranhuikast, iralikast,
`
`pobilukast, SKB-106,203 and compounds described as having LTD4antagonizing activity
`
`described in US. Patent No, 3,565,473; (53 5 ~lpoxygenase inhibitors and/or leukotricne
`
`biosyothesis inhibttors [e.g.. zllcuten and BAY 1005 (CA registry 128253-31-G}]; (6) histamine
`
`Hi reeeptor antagonisis/antihistamines (.c., army compound that is capable of blocking, inhibiting,
`
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`
`reducing or otherwise interrupting the interaction between histarnine and its receptor} including
`
`but not lirotted to: astemizolc, acrivastine, antazolinc, azatadinc, azclastine, astamizolc,
`
`bromopheniramine, bromopheniramine maleate, carbinoxamine, carchastine, cetirizine,
`
`chlorpheniramine, chloropheniramine maleate, cimetidine clemastine, cyclizing, cyproheptadine,
`
`descarbocthox vioratadine, dexchlorpheniramine, dimethindene, diphenhydramine,
`
`diphenvipyraline, doxylamine sucemate, doxylarnine, cbastine, efletirizine, epmastine,
`
`famotidine, fexofenadine, hydroxyzine, inydroxyzine, ketotifen, levocabastine, levocetirizine,
`
`levocetivizing, loratadine, meclizine, mepyramine, mequitazine, mothdilazine, mianserin,
`
`mizolastine, noberastine, norasternizole, noraziemizole, phenimdarmine, pheriramine, picumast,
`
`promethazine, pynlamine, pyrilarmine, ranitidine, termelastine, terfenadme, trimeprazine,
`
`tripclenamuns, and triprolidime; (7) an anticholinergic inchiding but not limited to: atropine,
`
`
`benztropine, biperiden, fhutropium, hyoscyamiine (2.e. Levsin®: Leviid®: Levsin/SL®,
`
`Anaspaz®, Levsinex timecans®, Nueva}, titrophum, ipratropium, ipratropium bromide,
`
`methscopolamine, oxybutinin, rispenzepine, scopolamine, and tlotropium: (8) an anti-tussive
`
`including but not limited to: dextromethorphan, codeine, and hydromorphonc; (9) a decongestant
`
`inciuding but not limited to: pseudoephedrine and phenylpropanciamine, (10) an expectorant
`
`including but not lomited to: guafenesin, suaicolsulfate, terpm, ammonimm chloride, glycerol
`
`guatoglate, and iodinated glyceral; (11) a bronchodilator inchiding but nat Limited to:
`
`theophylline and aminophylline: (12) an anti-inflaramatory incliding but not limitedto:
`
`tluribiprofen, diclophenac, indormethacin, ketoprofen, S-ketroprophon, tenoxicam:; (13) a PDE
`
`inhosphodiesierase) inhibitor meliding but not limited ta those disclosed herein: (14) a
`
`recombinant humanized monoclonal antibody [e.g xolair (aiso called omalizumab), rhuMab, and
`
`talizumab]; (15) a humanized hing surfactant including recombinant forms of surfactant proteins
`
`SP-B, SP-C or SP-B [e.g. SURFAKIN i, formerly known as dsc-104 (Discovery Laboratorics}],
`
`(16) agents that inhibit optthelial sodium channels (ANeC} such as amiloride and related
`
`compounds: (17) antimicrobial agents used to treat pulmonary infections such as acyclovir,
`
`amikacin, amoxicilin, doxyoycline, trimethoprin sulfamethoxazale, amphotericin B,
`
`azithromycin, clanithronryom, roxtthromycin, clarithromycin, cophalosporins( ccftoxitin,
`
`cetmetazole cite}, crprofloxacin, ethambutol, gentimycin, ganciclovir, unipenem, isoniazid,
`
`iraconazole, penicillin, ribavirin, rifampin, rifabutin.amantadine. rmmantidine, streptomycin,
`
`tobranrycin, and vancomycin; (13) agents that activate chloride secretion through Cat+
`
`53
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`25
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`PCT/US2009/046287
`
`dependent chloride channels (such as purinergic receptor (P2Y(2} agonists); (19) agents that
`
`dccrcasc sputum viscosity, such as buman rccombinant DNase 1, (Pulmozyme®): (203)
`
`nonsteroidal anti-inflammatory agents (acemetacin, acetamimophen, acetyl sahevlic acid,
`
`alolofenasc, alminoprofen, apazone, aspirin, benoxaprofen, bezpiperylon, buclosic acid,
`
`earprofen, clidanac, diclofenac, diclofenac, diflunisal, diflusinal, ctodolac, fenbufen, fenbufen,
`
`fonclofonac, fenciozic acid, fenoprofen, fentiazac, feprazone, flifenamic acid, fhifenisal,
`
`flofenisal, flaprofen, furbiprofen, flarbiprofen, furofenac, ibufenac, ibuprofen, indomethacin,
`
`indomethacin, mdoprofen, isoxepac, isoxicam, ketoprofen, ketoprofen, ketorolac, meclofenarmic
`
`acid, meclofenamic acid, mefenamic acid, mefenamic acid, miroprofen, mofebutazane,
`
`10
`
`naburnetone ORaprozin, naproxen, naproxen, miflumic acid . oxaprozin, oxpmac,
`
`oxvpheniuilazone, phenacetin, phenylbutazone, phenylbutazone, piroxicam, piroxicam,
`
`pirproten, pranoprofen, sudoxicam, tenoxican, sulfasalazine, sulindac, sulindac, suprofen,
`
`tlaprofenic acid, tlopinac, tioxaprofen, tolfenamic acid, tolmetin, tolmetin, zidlometacin,
`
`zomepirac, and zomepirech; and (21} acrosolized antioxidant therapeutics such as S-
`
`15
`
`Nitrosoghatathione,
`
`Anti-obesity agenis
`
`The GCRA peptuics deseribed herein can be used in combination therapy with an anti-
`
`obesity agent. Suitable such agents include, bat are not muted te: | HS HSD-D¢)i-beta hydroxy
`
`steroid dehydrogenase type 1} inhibitors, such as BY TP 3498, BVT 2733, 3-(l-edamantyl}-4-
`
`ethyl-S-ethyvithio} 4H-L2.4-triezole, 3-(-adamantyl}-5-(3,4,5- trimethoxyphenyl)-4-methyi-4h-
`
`12 4-triazale, 3- adamantanyl-4.5,6.7,8,9,10,11,12,3a- decaby dro-1,2,4-triazolo[4,3-alft
`
`ilannulenc, and those compounds disclosed in WOOL/O0091, WOO L/90090, WOO 1/00092 and
`
`WO02/072084; SHT antagonists such as those in WO03/037871, WOO03/037887, and the like;
`
`SHTie modulators such as carbidopa, benserazide and these disclosed in US620764%,
`
`WO0S/02 1439, and the like; SHT2e (serotonin receptor 2c) agonists, such as BYT9S33,
`
`DPCAR72 145, Hh264, PNU 22394, WAYV161503, R-1065, SB 243213 (Glaxo Smith Kline) and
`
`YM348 and those disclosed in US3914250, WOGG/770 LO, WOG2/36596, WO02/48 124,
`
`WOOZ4G169, WOOL/S6548, WO02/44152, WO02/S1 844, WOO2/40456, and WO0240457;
`
`SHT6 receptor modulators, such as those in WOO3/030001, WO03/035961, WOG3839547, and
`
`the like; acyl-esirogens, such as oleayl-estrone, disclosed in del Mar-Grasa, M. ot al, Obesity
`
`20
`
`25
`
`30
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`54
`
`3428
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`WO 2009/149278
`
`PCT/US2009/046287
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`Research, $:202-9 (20013 and Tapanese Parent Application No. IP 20002456190; anorectic
`
`WOOO/L E749, WOOL/S32638, WOO01/62746, WOOL /62747, and WO03/015769, CB I
`
`bicyclic conrpounds such as 1426 (Aventis) and 1954 (Aventis) andthe compounds disclosed in
`eed-i receptor} antagonist/inverse agonists such as rimonabant (Acomplia; Sanofi}, SR-
`
`47778 (Sanofi, SR-141716 (Sanof), BAY 65-2520 (Bayer), and SLY 319 (Solvay}, and those
`
`disclosedin patent publications US4973587, USSOI3R37, USSORET22, LISSEL2ZR20, LISS29O2 736,
`
`LIS5532237, USSe24941, US6028084, US6509367, US6500367, WI8G/33 158, WO97/29079,
`
`WOOR/S 1227, WOOR/33 765, WOS8/3 7061, WOSS/41419, WOS8/43635, WOOR/43636,
`
`WOSS/02499, WO0D/1 0967, WOOO/TD9G6S, WOOLBO120, WOOT/SESGS, WOGIL/G4632,
`
`WOO 464633, WOGL/64634, WOG1/70706, WOGL/G6336, WOG2/076949, WOOSANI6007,
`
`WOOS/G078 87, WODS/0Z20217, WOOS26647, WOO03/O26648, WOO3/02 7069, WOG3/027678,
`
`WOO0S/9271 14, WOO3/037332, WOO3/040107, WO0S/G86940, WOO8 484943 and EP6SS8S46:
`
`CCK-A (cholecystokinin-Al agonists, such as AR-R PS849, GL IS1771 (GSK), IMY-1SO, A-
`
`Ti378, A-71623 and SR146131 (Sanofi), and those deseribed in LIS35739106: CNTR (Cillary
`
`neurotrophic factors}, such as GI- 181771 (Glaxo-SmithKline}, SRE 46131 Sanofi Syntheiabo},
`
`putebindide, PD 170,292, and PD 149164 (Pfizer), CNTF derivatives, such as Axokine®)
`
`{Regeneron}, and those disclosed in WO94/09134, WOOk/22128, and WO99/43213, dipentidyi
`neptidase PV COP-TV) inhibitors, such as isoleucine thiazolidide, valine pyrratidide, NVP-
`
`DPP728, LAV237, P93/01, P3298, TSL 225 Uryptophyl-12,3,4-tctrahydroisoquinoline-3-
`
`carboxviic acid; disclosed by Yamada ot al, Bioorg. & Med. Chem. Lott, & (1998) 1537-1540},
`
`TMOC-2A/2B/20, CD26 inhibtors, FE 909011, P9A1O/K364,. VIP G177, SDZ 274-444, 2-
`
`oyanorpyirralidides and 4-cyanopyrrolidides as disclosed by Ashworth ot al, Bicorg. & Med.
`
`Chem, Lett., Vol. 6,No. 22, pp 1163-1166 and 2745-27448 (1996) and the compounds disclosed
`
`patent publications. W