NZ758464B2 - Prostacyclin compounds, compositions and methods of use thereof - Google Patents
Prostacyclin compounds, compositions and methods of use thereof Download PDFInfo
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- NZ758464B2 NZ758464B2 NZ758464A NZ75846414A NZ758464B2 NZ 758464 B2 NZ758464 B2 NZ 758464B2 NZ 758464 A NZ758464 A NZ 758464A NZ 75846414 A NZ75846414 A NZ 75846414A NZ 758464 B2 NZ758464 B2 NZ 758464B2
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- treprostinil
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- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Abstract
Prostacyclin compounds of Formula (III) and compositions comprising the same are provided herein. Specifically, prostacyclin compounds comprising treprostinil covalently linked to a linear C5-C18 alkyl are described. The linkage is via an amide bond. Methods for treating pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension are also provided. .g., pulmonary arterial hypertension) and portopulmonary hypertension are also provided.
Description
PROSTACYCLIN COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF CROSS NCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Application Serial Nos. 62/042,123, filed August 26, 2014; 62/028,758, filed July 24, 2014; 61/950,967, filed March 11, 2014; 61/910,703, filed December 2, 2013; 61/895,680, filed October 25, 2013; and is a divisional of New Zealand Patent Application No. , which is a national phase entry of International Patent Application No. , all of which are incorporated by reference in its ty for all purposes.
BACKGROUND OF THE INVENTION Pulmonary hypertension (PH) is terized by an abnormally high blood pressure in the lung ature. It is a progressive, lethal disease that leads to heart failure and can occur in the pulmonary artery, pulmonary vein, or pulmonary capillaries. Symptomatically patients experience shortness of breath, dizziness, fainting, and other symptoms, all of which are made worse by exertion. There are multiple causes, and can be of unknown origin, idiopathic, and can lead to hypertension in other systems, for example, portopulmonary hypertension in which patients have both portal and pulmonary hypertension.
Pulmonary hypertension has been classified into five groups by the World Health Organization (WHO). Group I is called pulmonary al hypertension (PAH), and includes PAH that has no known cause (idiopathic), inherited PAH (i.e., familial PAH or FPAH), PAH that is caused by drugs or , and PAH caused by conditions such as connective tissue diseases, HIV infection, liver disease, and ital heart disease. Group II pulmonary hypertension is characterized as pulmonary hypertension associated with left heart disease.
Group III pulmonary hypertension is characterized as PH associated with lung diseases, such as chronic ctive pulmonary disease and interstitial lung diseases, as well as PH associated with sleep-related breathing disorders (e.g., sleep apnea). Group IV PH is PH due to chronic thrombotic and/or embolic disease, e.g., PH caused by blood clots in the lungs or blood clotting disorders. Group V includes PH caused by other disorders or conditions, e.g., blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), metabolic disorders (e.g., thyroid disease, glycogen storage disease). ary arterial hypertension (PAH) afflicts approximately 0 people ly with approximately -40,000 of those patients in the United States. PAH patients experience constriction of ary es which leads to high pulmonary arterial pressures, tnalring it difficult for the heart to pump blood to the lungs. Patients suffer from shortness of breath and fatigue which often severely limits the y to perform physical acti yity. lllililSl The New York Heart Association (N‘r'l-lA) has categorized PAH patients into four functional classes, used to rate the severity of the disease. Class l PAH patients as categorized by the NYHA, do not have a limitation of physical activityg as ordinary physical activity does not cause undue dyspnoea or fiatigueg chest pain, or near syncope. 'l‘reatnient is not needed for class I PAH patients. Class ll PAH patients as categorized by the NYHA have a slight limitation. on physical activity. "l‘hese patients are comfortable at rest, but ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near e. Class 111 PAl-l patients as categorized by the NYE-EA have a marked limitation of physical activity.
Although comfortable at rest, class lll PAH patients experience undue dyspnoea or fatigue, chest pain or near syncope as a result of less than ordinary physical activity. Class lV PAH patients as categorized by the NYHA are unable to carry out any physical activity Without symptoms" Class l‘v’ PAl-l ts might experience dyspnoea and/or e at rest, and discomfort is increased by any physical ty. Signs of right heart failure are often sted by class 1V PAH patients. {sass} Patients with PAH are t‘eated with an endothelin or antagonist (ERA), pliosphodiesterase type 5 (PUB—5) inhibitor, a guanylate cyclase stimulator, a prostanoid (ago prostacyclin} or a combination thereof. ERAs include ahrisentan {Letairis®)9 sitaxentan, bosentan ('l'racleeniil), and macitentan (OpsurninE). FDR—5 inhibitors indicated for the treatment of PAH include sildenatil (Revatiodh), tadalafil {Adcirca®). Prostanoids ted for the treatment of PAH include iloprost, epoprosentol and treprostinil (Remodulintislfi Tyvasotis‘). The one approved guanylate cyclase stimulator is riociguat (Adempas®). Additionally, patients are often d with combinations of the aforementioned nds. {6967} Portopulmonary hypertension is defined by the tence of portal and ary hypertension, and is a serious complication of liver disease. "the diagnosis of portopulmonary hypertension is based on hemodynarnic criteria: (l) portal hypertension arid/or liver disease (clinical diagnosis~ascites/varicc'/splenothegaly), (2) mean pulmonary artery re '> 25 mrnllg at. rest, {3) pulmonary ar resistance > 24% dynes s/crns, (4) pulmonary artery occlusion pressure < lSi'nrnl-lg or transpulnionary gradient > 12 mmllg. PPlil is a serious EN.) complication of liver disease, and is t in 0.25 to 4% of patients suffering from cirrhosis.
Today, PPH is contor‘oid in 4—6% of those refizrred for a iiver transplant 330%} Despite there being treatments for PAS-i and i’RE-i, the current prostacyciin therapies are associated with severe toxicity and toierahiiity , as well as the requirement for ineerwehient dosing scheduies. The present invention overcomes addresses these factors by providing compounds and treatment schedules that provide for less toxicity, better toierabiiity and more convenient (lasing sehedutes.
SUMMARY OF THE INVENTIQN 32116991 in one aspect of the invention, a prostaeyciin compound of Formuia (1), or a pharmaceutically acceptabie salt, is provided: 2\R11H0 R3 Formula (I) wherein R1 is NH, 0 or S; R; is H, a iinear (:1ng3 aikyi, branched CyClg aiityi, Einear CngJg aikenyi, branched C3"C1g i, aryi; aryi—Cl—ng aikyi; an arnino acid, or a peptide; R3 is H, OH, ivzyi or enyh R is an optionaiiy substituted Einear or branched (114315 aikyi, or an optionaiiy tuted iinear or branched (77,—ng aikenyi; and n is an integer from G to 5, with the o that the prostacyclin compound is not treprostinii, {$019} in another aspect of the inventinn, a prostacyciin compound of a (11), or a pharniaeeutiealiy acceptable salt, is ed: Forrnuia (11) wherein R1 is NH, O or S; R; is a linear or branched (Ts—C13 aikyi, a iinear CQ"C]8 athenyt or a branched Cg—Cgs aikenyi, aryi, aryE—C 14C; 3 alkyi, an amino aeid or a peptide; and n is an integer from 0 to 5.
{Mill} in one embodiment, a compound of Formula (1} and/or (H) is provided, wherein one or more hydrogen atoms is substituted with a deuterium, l—‘ieeordingly, in one embodiment, the present invention relates to an isotopologue of Formula (l) and/or (ll), substituted with one or more deuterium atoms. The isotopologue of Formula (1) and/or (ll) may be used to tely determine the concentration of compounds of Formula (3} and/or (ii) in biological fluids and to determine metabolic patterns of compounds of Formula (l) and/or (ii) and its isotopolognes. The invention further provides compositions comprising these denterated isotopologues and methods of treating diseases and conditions, as set forth herein.
{W12} in one embodiment of the inventiom a compound of Formula (1) or (H), or a. pharmaceutically acceptable salt, is provided, wherein R; is N and n is l. in a further embodiment, R2 is a linear C3613 alleyl or a branched CyC t8 alkyL in a further embodiment, R2 is a linear (264312 alltyl or a branched icy-(:12 alkyl. {@013} Another embodiment of the ion provides a compound of Formula (l) or (ii), n R; is O and n is l. in another embodiment, a compound of Formula. (1) or (ii) is provided, wherein R1 is S and n is l. in yet another ment of the invention, a nd of Formula (1) or (ii) is provided, wherein R1 is N and n is O" {Mild-l r embodiment of the invention provides a. eyclin compound of Formula (l) or (ii), wherein R2 is a linear (354.718 allryl. in a iiirther embodiment, n is {3 or l. in even a further embodiment, R1 is N or O. in yet a further embodiment, R2 is a linear C6"C1fj allryl.
Yet r embodiment provides a cyelin compound of Formula (l) or (ii), wherein R; is N, R2 is a linear (jg-Cm alkyl, and n is l. in even a further embodiment, R3 is a linear C6, Cs Clo, C1301" C14 alkyl. iititllfii Another embodiment of the invention provides a cyelin compound, of li‘ormnla (i) or (H), or a pharmaceutically acceptable salt, wherein R2 is a branched, C's—Cm alhyl. in a. further embodiment, n is 0 or 1. in yet a further embodiment, R; is N or 0. in even a further ment, the branched alkyl is hexyl, oetylg decyl, l, tetradecyl, hexadecyl or octadecyl. {$6.16} in yet another embodiment, a prostacyclin compound of Formula til) or (ii), or a pharmaceutically acceptable salt, is ed, wherein R2 in a linear C5nC 18 alkenylu in a. further embodiment, it is 0 or i. in yet a, iiirther embodiment, R"; is N or Q. in even a further embodiment, the ed alkyl is hexyl, octyl, decylg dodecyl, tetradecyl, hexadeeyl or oetadeeyl. {fifilfl in yet r embodiment, a eyclin compound nf Formula (l) er (ll), or a pliarrnaceutieally acceptable salt, is provided.% wherein R; is a branched C5-C18 allienyl, in a further embodiment, n is O or 1. in yet a further embodiment, R; is N er 0. in yet a further ment, the branched l is. pentenyl, l, neptenyl, oetenyl, nonenyl, deeenyl, undecenyl, dodecenyl, tridecenylr tetradeeenyl, ecenyl, hexadeeenyl, beptadeeenyl or octadeeenyl. {09.18} in one embodiment, a prostacyelin compound of Formula (i) or (11),, or a pharmaceutically acceptable salt, is provided, wherein R3 is a branched chain allcyl that is either a symmetrical branched alliyl or an asymmetrical branched aikyi. In nne embodiment CIZR'R' ( ) is of Formula (1) or (ll), R] is 0 or N and R2 isml m2 or R' R' where ml and 1112 are independently an integer selected li'orn l to 9 and each ence ofR.’ is independently H, a linear or branched (TI—Cg alkyl, or a linear or branched C]-Cg alkenyl. When ml and/or m2 is an integer from 2—9, the ml/m2 at the end of the carbon chain is CH3, while the remaining fill/1112 groups are CH3. in a further embodiment, n is i) or l. in even a further all) embodiment, n is 1, R1 is 0, R2 is m1 m2 and the tollowing eoi'npound is provided; m 1 t:JK/o OH HO or a phannaeeutically acceptable salt thereofi in one embodiment, ml and m2 are both 4. in r embodiment, ml is 3 and 1112 is 4. in even a further embodiment, n is l. {6919} In one embodiment, a compound of Formula (1) or til) is provided, R; is O and R2 is V\jN\/\/. In yet another embodiment of Formula (ill or {ll}, R1 is O and R2 is {new} in one embodiment, a nd of a (l) or (H) is provided, R1 is N and R3 is VJ/V.In yet another embodiment of a (1) or (H), R1 is N and R2 is; {0921} In a further embodiment, n is l and the following compound is provided: HO (reterretl. to herein as 5~nonanyi—treprostinil or 589—1751} {thin} in one embodiment, the prostaeyelin compounds of the formulae provided herein having a. branched alleyl or branched alkenyl (eflg where R2 ofthe formulae provided herein i9 5—1’ionanyl, 3~heptyh 4—lieptyl, 4—oetyl, 3—oetyt, Z—oetyl, 2~diniethyid—1:>i'opyt, niethyl— i—bntyi, Z—ethyi—l ubutyl, 3—pentyl) at position R3 exhihit a slower conversion rate relative to a prostaeyelin compound having a ar alcohol chain at position R2, and have the further advantage of high solubility.
{M23} Yet another embodiment of the invention relates to a prostaeyelin compound of Formula (lit), or a phai‘n'laeeuticaily acceptable salt; R2\R1)K/O R60 Formula. (lll), wherein R1 and R2 are defined above, and R5 and R6 are ndently selected from H, ally substituted linear or branched (fl-(315 alkyl, optionally substituted linear or branched (Liz—(:15 aikenyl, {C====()il" optionally substituted linear or branched C1—C5 alkyl, or {C=Q)—optionaiiy tuted linear or branched C2~C15 aikenyi, with the proviso that the prostacyciin compound of Formuie (i i i) is not stinii.
{Mimi Another aspect of the invention relates to a prostacyciin composition comprising a cyciin compound of Formuia, (I), (it) or (iii). in one embodiment the prostecyciin composition comprises a prostacyciin compound of Formnie (IE), {it} or (iii) and a hydrophobic ve. in a, further embodiment the hydrophobic additive is a hydrocarbon, a terpene or a hydrophobic lipid. in another embodiment, the hydrophobic additive is choiesteryl e, ethyl stearate, ate, ate, paimityi paimitate, tocopheryi acetate, :1 monoglyeeride, a digiyceride, a trigiyceride like pain'iitate, myristate, dodecanoate, decanoate, octanoate or squaiane. in even a further embodiment, the. hydrophobic additive is soueiane. {9925} in another aspect of the invention, a composition comprising a prostaeyeiin compound of Formuia (1')," (it) or (Hi), and an amphipbiiic agent is provided. in one embodiment, the arnphiphiiie agent is a PEGyiated iipid, a surfactant or a, block copoiymer. in a, further embodiment, the prostacyclin composition comprises a prostacyciin compound of Formula (I), (H) or (iii), and e PEGyiated lipid. in a. further embodiment, the PEGyiated lipid comprises 00, PEGSGQ, ), PEGZGGO, GG, P5364000, or P53565009 in a further embodiment the lipid. component of the PEGyiated iipid comprises PEG covalently iinked to dimyristoyi phosphatidyiethanoiamine {BMFE}, dipeimitoyi phosphoetbanoiamine (DFPE), distearoyiphosphatidylethanolamine (DSPE), stoyigiyceroi giyceroi (DMG), diphosphatidyigiyceroi (DPG), disteraroyigiyceroi (DSG).
{Gold} in another embodiment of the invention, a composition sing a cyciin compound of Formula. (IL (11) or (111),, a hydrophobic additive and en emphiphiiie agent is provided. in one embodiment, the amphiphiiic agent is a PEGyiated iipid, a surfactant or a block copoiymer. In a further embodiment, the hydrophobic additive is squaiene. in a thither embodiment, a PEGyEated iipid is t in the composition and comprises 9333406? PEGSOO, P1381000, PEGZOOG, P2263000, PEG4090 or PEGfiGOG. {8927} In another aspect of the invention, a method for treating pulmonary hypertension (PH) is provided, The treatment methods include ent of group i (PAH), group ii, group iii, group 1V or group V I’H. In one embodiment, the. method for treating PH comprises treatment of pulmonary arteriai hypertension (PAH) in a patient in need ti'iereof. in one embodiment, the method for treating PAH ses administering to the patient in need of treatment, a 'prostacyclin compound. of Formula. (i), (H) or (ill), or a, phannaceutically acceptahle salt f, or a composition comprising a prostacyclin compound of Formula (i), (H) or (ill), or a. pharmaceatically acceptable salt thereof, in a thrther embodiment, the administration is subcutaneous, oral, nasal, intravenous or a pulmonary route of administration. in the case ofpulmonary administration, the compound of Formula (I), (ll) or (ill), or the composition comprising the prostacyclin compound of a (1), ill) or (ill) is administered to the patient Via a nehulizer, dry powder inhaler, or metered dose inhaler.
{W28} In another aspect of the invention, a method for treating portopuimonary hypertension (l’Pl-l) in a patient in need thereof is provided. in one ment, the method for treating PPH comprises administering to the patient in need of treatment, a prostacyclin compound of l?’orrnula (I), (ll) or (ill), or a pharmaceutically able salt thereof, or a composition comprising a prostacyclin nd of a (l), {ll} or (ill), or a pharmaceutically acceptable salt thereof... in a, thither embodiment, the administration is aneous, oral, nasal, intravenous or a pulmonary route of administration. in the case of pulmonary stration, the compound of Fomrula (I), (H) or (ill), or a pharmaceutically able salt thereof, or the composition comprising the cyciin nd of Formida (i), (ill) or (ill) is administered to the patient Via a. nebulizer, dry powder inhaler, or metered dose inhaler. {ililzgl in one embodiment of the invention, a method for treating PH, PAH or PPH in a patient in need thereof is ed, comprises administering to the lungs of the patient a prostacyclin compound. of Formula (l), (i!) or {ill}, or a pharmaceuticaliy acceptable salt thereof, Via. a metered dose inhaler comprising a. propellant. in a further embodiment, the propellant is a fluorocarbon. in one embodiment, the compound of Formula (l), ill} or (ill) or pharmaceuticalljyr acceptable salt thereof is administered Via a metered dose inhaler to the lungs of a patient in need of PH, PAl-l or PPH treatment, and administration occurs once, twice or three times daily. in embodiments where the compound of Formula (1), (ll) or (ill), or a composition comprising the eon’ipoand of Formula (l), (ll) or (iii), is administered orally, nasally, subcutaneously, intravenously or to the lungs- {e.g., Via nehulization, dry powder inhaler or d dose inhaler), administration to the patient is either once or twice daily. in one embodiment, the compound of Formula (1), (ill) or (ill), or a composition comprising the compound of Formula. (1), (ll) or (ill) is stered once daily to the patient in need of treatment, and administration is subcutaneous, intravenous, oral, nasal, or to the hints Via aerosolization usin t a nehulizer, dr I owder r or metered dose inhale 1 E3 9 {$030} in one embodiment, the patient d for Pi-l, PAH or PPS-i with the nds, compositions and methods described herein experiences a decreased number e effectts), or a reduction in severity of side effeett's), compared to the number of side etit‘er:t(s) or severity of side effect(s) experienced when the patient is administered treprostinil. in one embodiment, the side effect is the patient’s cough response, and the fifequency and/or severity is reduced, as compared to the ncy and/or ty of cough response enced by the patient when administered treprostinil.
{MESH in another embodiment, the prostaeyelin compound administered to a patient in need thereof Via a pulmonary route by the PH, PAH or i’E’lii treatment methods described herein provides a greater ary elimination hall‘llit‘e (tug) of the prostacyelin compound and/or its metabolite treprostinil, compared to the puimonary elimination half-life (tug) of treprostinil, when trcprostinil is administered. Via a pulmonary route ., by nebulization, dry powder inhaler, or a metered dose r) to the patient, {M32} in another embodiment, the prostacyclin compound administered to a patient in need thereof, Via the PH, PAH or PPH treatment methods described herein provides a greater systemic haitllife (ti/2) of the prostaeyclin compound and/or its lite treprostinii, compared to the systemic elimination half—life (tug) of treprostinil, when treprostinil is administered to the t. in a further ment, administration of the prostacyclin compound and treprostinil comprises subcutaneous or intravenous administration. {3&33} in another embodiment, the prostaeyelin compound administered to a patient in need of PH, PAH or PPl—i treatment provides a greater mean pulmonary Cm.dx and/or lower plasma Cum of stinil for the patient, compared to the respective pulmonary or plasma Cum of treprostinil, when treprostinii is administered to the patient. {(31334} In another embodiment, the eyelin compound administered to a patient in need of PH (6.5;, PAH) or PPH treatment provides a greater mean pulmonary or plasma area under the curve (A'UCTW) of the prostaeyciin compound and/or its metahoiite treprostinil, compared to the mean pulmonary or plasma area under the curve (AUCM) of treprostinil, when treprostinil is administered to the patient. in yet another embodiment, the prostacyciin compound administered to a patient in need thereof provides a greater pulmonary or plasma time to peak tration (tmax) of the prostacyelin compound and/or its metabolite treprostinii, compared to the puimonary or plasma time to peak concentration {tum} of treprostinii, when treprostinii is administered to the patient.
BRIEF BESCREPTIGN (H? THE FEGURES {9835i Figure LA is a graph showing the spontaneous hydrolysis of treprostinii compounds vs. time, (C3: propyi ester, C4: hutyl ester, C5: pentyi ester, C6: hexyi ester, C8: oetyi ester and C10: deeyi ester). {0936} Figure 18 is a graph showing esterase-niediateci ysis of the alkyi chains at various tirnepoints (15 min.., 30 min, 66 min) of treprostinii compounds dissoiveo in aqueous buffer, and treprosti nil compositions comprising iated iipids. {8037} Figure 2 is a graph of the average particle diameter for various treprostinii aikyi esters in torrnuiations comprising 'PEGyEated iipids as a function of aikyi ester chain length. The aikyi Chain is present at the carboxyiie acid moiety of treprostinii. PD is poiydispersity.
{W38} Figures 3A, 3B and 3C are graphs of relative CAMP response of CHO~K1—F4 cells (2.5 x ":04 eeiis/weii) vs, time, in response to it) and {Figure 3A), 1 uM (Figure 33) or 0,} uM (Figure 3C) treprostihii and treprostinil alkyi ester compositions. (es: hexyi ester, C8: oetyi ester, {iii}: oeeyi ester). {$89} Figure 4 is a grapi'i of relative CAMP response of Ki~P4 eeiis (2.5 x ":04 cells/well) vs. time, in se to 5 uM treprostinil and treprostinii alkyi ester compositions. (on; hexyi ester, C8: ootyi ester, (Iii): tieeyi ester, €12: dodeeyi ester). {@040} Figure 5 is a graph of relative CAMP response of (ii-EiifiKi—Plt cells (25 x 104 cells/well) vs, time, in response to challenge with treprostinil and various treprostinii aikyi ester nds at 5 uM. {iiiicti} Figure 6 is graph ofreiative CAMP activity of (Ii-{G-is‘; 1~P4 cells (2.5 X 1()4 eeiis/weii) vs, time, in response to chaiienge with treprostinii and nebuiized and nonmehuiized treprostinil aikyi ester itions, as measured by a d (i-ioSensor assay. "(N)" indicates nehuiized compositions. {9942} Figure 7 is a graph of reiative CAM? response of CHO~K1~P4 cells (2.5 X 104 eel is/wei I) vs. free stini l, at various dosages and time points.
{M43} Figure 8 is a graph of relative CAMP response of CHOuKi—Pdi eeiis (2.5 X 'qu cells/well) VS. T554 ) treprostinii aikyi ester composition challenge, at various dosages and time points. {sass} Figure 9 is a graph of relative CAMP esporise of CHO—Kl—l’d cells (2.5 x M34 cells/well) vs. T568 (Cu—TR) treprostioil alkyl ester ition challenge at various s and time points.
{Midi} Figure l0 is a graph of relative CAMP response of CHO~Kl~P4 cells (2.5 X l04 cells/well) vs. T63l (CM—TR.) treprostiiiil alkyl ester eorripositiou challenge, at various dosages and time points.
{W46} Figure ll is a graph of relative CAMP response of CH0—Kldl4} cells (2.5 a it?’1 cells/well) vs. T623 (CW'I‘R) treprostioil alkyl ester composition challenge at various s and time points. {9347} Figure 12 is a graph of relative eAMP response of CHO~Kl—P4 cells (2.5 x 104 cells/well) vs. treprostinil ethyl ester (C2)) compound challenge? at various dosages and time points.
{MM-8} Figure l3 is a graph of relative CAMP response of CEO—Kle—l cells (2.5 a it?1 eells/well} vs" treprostioil ethyl ester {(212) eompormd challenge, at various dosages and time points. {llfiéllll Figure l4 is a graph of relative CAMP response of Cl>lO~Kl—P4 cells (235 X lil4 cells/well) vs" treprostiuil ethyl ester (Cg) compositions, at various dosages and time points {fififill Figure 15A is a graph of pulmonary al pressure (expressed as a percent of the starting hypoxia value) vs. thee, in, response to animal ehaileoge with phosphate bu‘fered saline (PBS), treprostiuilg arid prostacycliu compositions (T554 (Cg) and T668 ((312)). The target dose for stiuil and. prostaeyelin alkyl esters was 76.8 motile/kg; the achieved ted dose may be 5x lower than these target .
{MESH Figure 1513 is a dot plot g the ef‘eet of treprostiuil and C3, Cg, Cm,» and C" treprostinil alkyl ester compositions on PAP {expressed as a percent of the starting hypoxia value) in arr in viva acute hypoxia rat model of PAH. Doses were target values and actual aeliieved lung doses may e approximately 5x lower.
{M52} Figure 16 is a graph. of systemic arterial pressure {expressed as a percent of the starting hypoxia value) vs. time, in response to animal Challenge with l?’BS, stioila and stioil alkyl ester compositions (T554 (CTTR) and 11568 ((712312)) in an in vivo aeute hypoxia rat model of PAH. The vertical dotted line marks change in X-axis time increments" The target close for treprostinil and prostacyclin alkyl esters was 76.8 kg; the achieved depesited dose may he 5x lower than these target values: 3905M Figure 17 is a graph of in viva heart rate (expressed as a percent at the starting hypoxia. value) vs. time, in se to animal challenge with PBS, stinil and treprnstinil alkyl ester compositions ("37554 (Cg) and T1568 {€12}; in an in viva acute hypexi a rat model of PAH. The vertical dashed line marks- ehange in Xmaxis time increments. The target dose for treprestinil and prostacyclin allryl esters was 76.8 nptiole/ltg; the achieved ted dose maybe 5): lower than these target values. {9054} Figure 18, top paneh is a graph of relative cAl‘s/ll? response of CHG~K1 cells as a function of 5C9~TR anyl~treprostim‘l alkyl ester een'tposition) challenge, at s dosages and. time points. Figure l8" bottom panel, shews the ECSQ of 5C9—’l’l{ over timea calculated from the CAMP respcnse of CEO—Kl cells vs. 5C9~TR {9955} Figure 19, top panel, is a graph of relative cAh/l? response of Cl>lO~Kl cells vs. {314- TR (C14 treprostihil allqyl ester itien) challenge, at varieus desages and time points.
Figure l9, bottom, panel, shcws the ECSC of C14~TR ever time, calculated frern the (LAM? respense {if C HO—Kl cells vs. CMJFR.
{M56} Figure 2t), tep panel, is a graph of relative CAM? response (if GHQ—Kl cells vs. C16— TR (C16 treprostinil allay], ester composition) challenge, at varieus dosages and, time paints Figure 2t), hettom panel, shews the ECSQ of me'l'R ever time, calculated frmn the CAM? response of C llQ~K l cells vs. (Sm—TR, lllll57} Figure 2l are graphs of relative cAMP respense tot" (THO-Kl cells vs. time, in respense to challenge with Cing‘R, Cw’l‘R, CmJl'R, or Sunonanylu’l'R (:SCng'R) at ll) itva (top panel) or 5 nM (bottom panel). {@658} Figure 22 {top panel) is a graph of relative cAMP response of {THO—Kl cells vs. 75679 (C;4-TR 45 mol %, squalane 45 mol‘Vfi chol-PEGZK ll) %) treprnstinil alky ester eompesiticn challenge, at s desages and time peints. Figure 22 (bottom panel) shews the ECSG of T679 over time, calculated from the CAM? respense of CBS—Kl cells vs. 17679.
{M59} Figure 23 is a graph of ve CAMP respense 0f CEO—Kl cells vs time, in respense t0 challenge with treprnstinil, Trill (Chg-TR 40 mol %, sqttalane 4G mel "/5, chol—l’litiiml: ll) mel %, DOPC l0 mcl 0At), or T679 (CM—"FR 45 mel %, squalane 45 mol 9/5, clmlul?‘EGt2-: ll) mnl 0/6) at ll) lthl (tcp panel) or 5 uM (batten: panel}. {sens} Figure 2.4, top panei, is a graph of reiative CAMP response of {THO—iii ceiis vs. T647 (Cm—TR 9i} moi "/5, choi~PEG2ir iO moi %) treprostinii aiiryi ester composition chaiienge, at various dosages and time points. Figure. 24, bottom panei, shows the ECSG of T647 over time, eaicninted from the CAi‘v’iP responses oi’Ci-iO—Ki oeiis v. T647—TR. iiiiioii Figure 25 are graphs of reiative eAMP response of CEO-Ki eeiis vs. time, in response to chaiienge with treprostinii, T63i {CH—TR 40 moi %, squaiane 4i) moi %, choi- PEGZk 10 moi 9/0, DOPC it} moi ‘72)), or T647 (CM—TR 9i} moi %, choi—PEGZK ii) moi %) at iLiVi (top panei) or 5 iris/i (hottom panel). {@062} Figure 26, top panei, is a graph of reiative CAM? responses of CHG—Ki ceiis v. 757637 (C1 s—TR 40 moi "/6, squaiane 4O moi "72>, ohoi—PEGZR it} moi %, DOPC it) moi %) treprostinii aikyi ester lipid nanopartieie composition chaiienge, at various s and time points.
Figure 26, bottom panei, shows the ECSO of T637 over time, caicnieted from the GAR/ii) responses ofCi-iO—Ki ceiis v. —TR. fii Figure 27 are graphs of reiative CAMP response of CEO—Ki ceiis vs time, in response to chaiienge with treprostinii, T555 {Cori}? 40 moi %, souaiane 40 moi %, ehoi— i’EGZk ii) moi %, DOPC 10 moi %), T556 (Cw—TR 49 moi %, ne 40 moi %, choi— PEGZR ii} moi %, DOPC it) moi %), T568 (Cm—TR 4-0 moi %, squaiene 4i) moi %, choi— PEGZR ii} moi %, DQPC ii) moi 9-4;), T63i (CM-TR 4i) moi %, squaiane 40 moi "72;, choi" PEGZk ii) moi %, DOPC 10 moi 9/6), T623 (Cm—TR 4i} moi %, soneiane 4G moi %, choi— PEG’Zk ii} moi "72;, DQPC 10 moi "7a), or T637 (Cm-TR 4i} moi "/6, squainne 4i} moi "72:, Choi- PEGZR ii) moi "/33, DOPC iO moi %) at. ii) nM (top panel) or 5 nM (bottom pnnei).
{WM-i Figure 28 is a graph of the conversion rate (% of totai) over time (hours) for iinenr (CSTR) versus branched ethyi-i-propanyiii’i{, 3,3-dimethyi—i~hntanyi-TR, 2-ethyi—i— butanyi—TR, S—nonanyi-TR, or 3-pentnnyi—TR) prostaeyciin comoonnds.
{W65} Figure 29 is a graph showing the conversion of treprostinii eon'iponnds derivatized with various iinear aiiryi chains, relative to the conversion of the treprostinii compound, derivatized with an octyi moiety (R2 = C3). sion was measured at i hr after incubation with esterase. {@966} Figure 30 is a graph showing the sion of treprostinii compounds derivatizeri with s branched nihyi , relative to the conversion of the treprostinii compound derivatized with an octyi moiety (R3 Cg). Conversion was measured at i hr after tion with estersse" {11116571115:1110 31 15 11 5011011111110 01 the Ja0g01'—NY1;f 11050 only 0111001011—110w 111011 0110051110 5y5't0111 (CH "1001100109051 "7050110011., N3, www.0r151'050rg) 115011 101 0 24110111" pharmacoliihetics study. {111108} F1g110 321011.15 a, graph 01 11011105111111 1110011 plasma 101015 {mg/111i) 55 5 11111011011 01" 111110 {01' 11011105111111 and va.110115 1111101011 1100105111111 a131yl 051.01 11011005. F1g01'0 3'2, right, a g1aph 0f 11011105111111 b10001 plasma 1017015 (11g/1I11L) 05 0 11111011011 01111110 f0r 110p10511n11 and 1711110115 1111101011 1100105111111 alkyl 051.01 111100110 10101 .10.115. {1166.9} Figure 33 15 a graph 01’ 1100105111111 and 11011105111111 aikyi 05101 00110001151100 1.11 1110 lung 01101 dosing with 1101111112011 1100105111111 5011111011 01' 10111111151011 11011105111111 alliyl. 05101 51150011510115. lungs were 0011001011 at 6 5 01101 11051110 "11600105111111 11111511 051.01 00n0011110110n 15 1110501111011 215 11011105111111 0111111010111 011 0 111010 0050 {11157131171gu10 34,1019, 15 a graph 1.1111011105111111 010001 1111151115. 1017015 (110111141 115 a f11110110n 0f 1.11110 111 151.5 01101 11050—0111y 1111101511011 01 1101111112011 0013105111111 5.11131 051101: 10.111111111110115 Figure 34, 1110110111,, 15 11 graph of 11011105111111 and 11011105111111 alkyl 05101 1 111051110 10V015 {mg/011.) 55 5 1110011011 01111110 111 1015 211101 11050—01113; 10112112111011 01700011112011 11001105111111 51113/1 05101 10110111011005. 1} Figure 35, 10p 15 a graph 01" 110p10511111l 1110011 p1051’11a 1011015 (mg/111M 05 a, f11110110n of 1.11110 31101 110111111/511011 0111110110115 1011 00111121110115 of C5~TR 10101010110115 (11050 0111y 11051110) F1g01'03- :11 110110111 15 a graph of 110p105111111 and (15—TR 1110011 11155015 10V015 (11g/111L) 215 0 11111011011 01‘ 111110 after 11.010111125111011 0f v01ii0115 12011110111121.110115 01'" C 15—TR 10110111011005 (11050 011137 1115). {111172} F1g111‘0 36 15 a. graph of plasma 00000011011005 0f 110p105111111 11L) 111 1111111101011 (109,5 05 3. 11111011011 01’ 1111110, after 3.1110111151101100 0f 1100105111111 01‘ 1,110 T023 1111111 00111010 10111111101100 (Cm—TR 410 11101 %, 511110121110 40 11101 ‘34"), ch0luE’EG2k 10 11101 9/11, DGPC 11) 11101 9/0). 3} 0 37 1011. 15 a graph 01‘ 1100105111111 aikyi 05101 001110151011 10 1100105111111 05 11011 of 111110 for 1711110115 11011105111111 alkyl 051015 0111105011 10 rat lung 1155110 1101110g011at0.
Figum 3’7, 1117,1119 is a graph 01’C12~11'0131'05111111 c011v0151011 1.0 1100105111111 55 11111011011 01111110 111 101, dog and 11101111031 1.1111g 1155110 11010011011010. 41 191111110 '38 15 a graph 0f 1110011 pulmonary 01101101 111055010 (111F151?) 05 a f11110110n 01’ 111110 111 11115 11001011 with PBS 1100105111111 T568 (Cu—TR £11} 11101/14), 51111510110 40 111013-41 01101— PEGZk it) inoi %, DQPC it) moi 9/0) or T623 (Cm—TR 4G rnoi %, squaiane 40 mol 0/6, choi— PEGZK it} moi %, DOPC l0 inol 9/9). {@075} Figure 39 top, is a graph of mean systemic arteriai pressure (tnSAi’) as a function of time in rats treated with PBS, treprostinii, T568 or 11623. Figure 39, bottom, is a, graph of heart rate as a function of time in rats treated with PBS, treprostinii, T568 or T623. {($76} Figure 40 is a graph of treprostinii blood niasrna ieveis {rig/nil) as a on of time in rats after administration of free treprostinit, T568 or T623. {0677} Figure 41 is a graph. of trenrostinit blood inasma ieyeis (rig/mm as a function of time in rats after administration of composition T763 i {M78} The term "alkyi" as used herein refers to both a straight ehain aikyi, wherein aihyi chain length is indicated by a range of numbers, and, a branched alkyl, wherein a branching point in the chain exists, and the total number of carbons in the chain is indicated by a range of numbers. hi ary embodiments, " reters to an aihyi chain as defined, above containing 6, '7, 8, 9, it), 11, i2, 13, 14, 15,, '36 carbons (116., Cit—C15 aihyi).
{M79} The term "aikenyi" as used herein refers to a carbon chain containing one or more carbon—carlmn double bonds, {thigh} The term " as used herein refers to a eyeiic hydrocarbon, Where the ring is characterized by delocalized it electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated, by a range of numbers. in exemplary embodiments, "aryi" refers to a cyclic hydrocarbon as bed above ning 6, 7, 8, 9, or l0 ring atoms (126., {35—4310 aryl). Examples ot‘an aryi group e, but are not iiniited to, benzene, naphthalene, tetrahn, indeneh and indane. {0981} The term "aihoxy" as used herein refers to —0—(athyt), wherein "aihyi" is as defined above. 32116821 The term "substituted" in connection with a moiety as used herein refers to a thither substituent which is attached to the moiety at any acceptabie ioeation on the moiety" Unless otherwise indicated, moieties can. bond through a carbon, nitrogen, , suitor, or any other acceptable atom. {9383} The term "amino acid," refers to both natural (geneticaiiy encoded) and tnrai (non-genetically encoded) amino acids, and es thereof, ()f the twenty naturai amino . HzN—C—CozH acids, 19 have the general H where R . . . . . structure:_ is the amino acid Sidechain.
The ZG‘h amino acid, proiine, is aiso within the scope of the present invention, and, has»; the toiiowing Structure: "OHNH . Of the twenty natural amino acids, aii hat glycine is chiral, and both the D— and L amino acid iSomers, as weii as mixtures thereofi are amenable for use with the prostacyciin compounds; deacribed herein. it is also noted that an amino acid moiety is encompassed by the term "amino acid." For example, the amino acid es R R #0" R l H | H E—C-COZH g—N-C-COZH N \ g—N—c—Co—EI H H 4"" H encompassed , , , by the term "amino acid." meat} es of non—natural amino acids amenahie for use with the. present invention e fiaaianine (ii—Ala); 2,3—diantinopropionic acid {Dpr}; nipecotic acid {Nip}; pipecoiic acid (Pip); ornithine (Gin); oitruiline (Cit); t—butyiaianine (t—BuA); 2~thutyigiycine (thuG); yiisoieucine (Meiie); phenyigiycine {PhG}; cyciohexyiaianine {ChA}; norieucine {Nie}; naphthyiaiahine (Nat); 4~chiorophenyiaianine (Phe(4—Ci)); 2—fiuorophenyiaianine (Phe{2~F)); 3~fluorophen yiaianine (Phe(3—F)); 4—fluorophenyiaianine (Phe(_ 4~F)); peniciiiamine (Pen); 4—tetrahydroisoquinolirte—3—carhoxyiic acid (Tic); [3—2— thienyiaianine (Tin); methionine soifoxide (MSG); hornoarginine (hArg); N~acetyiiysine {Achys}; 2,4adianiinohutyric acid (Dim); 2,3—diaminobutyric acid, (Dab); p- arninophenyiaianine (Phe (pNHgfi; N—methyi vaiine (MeVai); ysteine (hCys), homophenyiaianine {hPhe); homoserine ; hydroxyproiine }; homoproiine (hi’ro); and the corresponding tiomer of each ofthe foregoing. Other eticaily encoded amino acid residues include 3~aminopropionic acid; 4~aminohutyric acid; isonipeeotic acid (11113:); aza-pipecoiic acid (azPip); azawproiine (azi’i'o'); o—aininoisohutyric acid (Aib); t:- aminohexanoic acid (Aha); 5~aminovaieric acid (Ava); N~iriethyigiyeiiie } {0085} A "peptide" is a polymer of amino acids (or moieties thereof} iinked by a peptide bond. Peptides for use with the present invention, comprise from about two to about fifteen amino acids, for example, two, tine", four, five, six, SeVen, eight, nine or ten amino acids (or moieties thereof). {asset The term "salt" or "salts" as used herein encompasses pharmaceutically acceptable salts comn'ionly used to form alkali metal salts of free acids and to form addition salts of tree 'bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
Suitable pl'iari'naceutically acceptable acid on salts may he prepared from an inorganic acid or from an organic acid, Exemplary pliannaceutical salts are oserl in Stahl, Fifi, Wermuth, CG, Eds. Handbook Qf‘Piiarinaceuticai Saks: Properties, Selection and Use; Verlag etica Chimica Acta/Wiley—Vtiil-l: , 2082, the contents of which are hereby incorporated by reference in their entirety. Specific non-limiting examples of inorganic acids afe hydrochloric, liydrobromic, hytlroiotlic, nitric, carbonic, sulfuric and phosphoric acid.
Appropriate organic acids include, without limitation, aliphatic, liphatic, aromatic, arylaliphatic, and heterocyclyl containing carhoxylic acids and ic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, e, pyruvic, aspartic, glutamic, henzoic, anthranilic, mesylic, stearic, salicylic, p—liydroxybenzoic, plienylacetic, mam‘lelic, embonic (pamoici), methanesulfonic, ethanesultonic, benzenesultonic, pantothenic, esultonic, 2nliytlroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3~liyrlroxyhutyric, galactaric or uronic acid. Suitable pharmaceutically acceptable salts of free acid~containing nds disclosed herein include, without limitation, metallic salts and organic salts, Exemplary metallic salts include, but are not limited to, appropriate allrali metal (group la) salts, alkaline earth metal (group lla) salts, and other physiological acceptable metals. Such salts can he made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Exemplary organic salts can he made from primary amines, secondary amines, tertiary amines antl quaternary ammonium salts, for example, trometliamine, cliethylamine, tetra—N—methylammoniurn, MN"- dibenzylethylenediamine, procaine, choline, diethanolamine, ethylenerliamine, meglumine {N—rnethylglucamine) and procaine. {9687l in one aspect, the t invention provides a prostacyclin compound, for example, a treprostinil derivative, or a composition comprising the saflrne that is effective when employed in a once-daily, twice—daily or three»times daily dosing regimen, for example, for the treatment onary arterial hypertension or portopulmonam hypertension in a patient in. need thereof. The prostacyclin compound ed herein, in. one otlintient, can, be administered less frequently than stinil, with equal or greater efficacy. Moreover, in one embodiment, the side effect profile of the contractions provided herein is less deleterious than the side effect profile resulting from stinil administration. These advantages, in one embodiment, allow for greater patient compliance. 'l‘reatrnent, in one embodiment, occurs through pulmonary administration of one of the compounds previded herein, for example Via a nebulizer, dry powder inhaler; or a metered dose inlialer. in some embodiments, a composition comprising one of the nds provided, herein is administered Via a nebulizer to a patient in need of PH treatment. in some embodiments a compound described. herein is suspended in a propellant and delivered to a patient Via a metered dose inhaler. {0088} in one aspect of the invention described , a prostacyclin, compound of Formula (I), or a pliannaeeutieally acceptable salt thereof, is ed: RARHLHO R3 a (1), wherein R1 is NH, O or S; R; is H, a linear 3 alkyl, branched C5413 jg alkyl, linear {jg—C13, alkenyl, branched {@ng alkenyl, aryl, ]—Clg allryl; an amino acid or a peptide; R3 is ii, (Ill-l, eptionally substituted linear or branched {314315 alkyoxy, (Ilsoptionally substituted. linear or branched (2?ng alkenyL O—{C=Q}—eptionally substituted linear or branched 15 alkyl, or O—(C:=O)—op'tionally substituted linear er branched €sz 15 alkenyl; R4 is an optionally substituted linear or branched (ill-{315 alkyl, or an optionally tuted linear or branched {72—ng alkenyl; and n is an r from t) to 5, with the previso that the prostaeyelin compound ofFoninula (1) is not treprostini l. {0989} In a r embodiment a prostacyclin compound of a (1) is provided wherein R3 is 01-1 and n is 0 or l. In even a further embodiment, R4 is an optienally substituted linear or branched €3ng allcyl. ln even a further ment, R1 is \H or Q. liltllllll in one embodiment, a, prostaeyclin compound of Formula (1) is provided, wherein R1 is Nil, 0‘ or S; R; is a linear (35"ng allcyl, branched {754313 alkyl, linear {lg-(:13 alkenyl, branched (Is—Cm alkenyl; R3 is H, OH or O—alkyl; R4 is an optionally substituted linear or branched {31th 5 alhylfi or an optionally substituted linear or branched £7ij 5 alkenyl; and n is an integer from 0 to 5.3 in even a turtber embodiment, R; is NH or G and R2 is a linear €9ng alkyl or a branched (Ts—C13 alkyl. l in one embodiment, R2 is aryl or aryl-Ct—Cm allryl; R3 is CH and n is l} or l. in even a tintber embodiment" R4 is an optionally substituted, linear or branched, {Tl—C; 5 alkyl. {($92} In one embodiment, the present invention provides a eyelin compound of Formula (I), wherein the nd is a. compound of one ot‘Formul-ae (la)a (lb), (10) or (Id), or a phannaeeutieally acceptable salt thereof: 0 o o R2\O)J\/o RASJK/o R2\NJl\/o H o R4 R4 R4 R4 R3 R3 R3 R3 Formula (la) a (lb) Formula (lo) Formula (id) Whereim R3 is H, a linear or branched (354313, allrylr linear C2618 allrenyl, or a. ed (134318 allrenyl; R3 is H, OH, optionally substituted linear or ed (El—€15 alkyoxy, 0—0ptionally substituted linear or branched (3243.55 alleenyl, -0(C==={))—optionally substituted linear or branched (114315 alkyl, or JO(C===())—optionally tuted linear or branched (jg-C15 allrenyl; R4 is 0R5 an optionally tuted linear or branched (El-(315 alkyl, or an optionally substituted. linear or branched Cg-Clg alkenyli where R5 is H5 optionally substituted linear or branched (314315 alkyl, optionally substituted linear or branched {lg—(315 allrenyl, (C=O)—optionally substituted linear or branched {314355 alleyl, or (C=G’)—optionally substituted linear or branched Cngg alkenylr in a further embodiment? R4 is 0R5 with the proviso that the compound is not treprostinil, , 118.? R2 and R5 cannot both be H. {@593} in one embodiment of Formula (Ia), a {Eb}, Formula (tie) and Formula {Mia R3 is a linear er branched Cs—Cig aikyi. in even a timber ernbedirnent, R; ism(M or CIIR'R' l/ \ R RI I‘fli and nu are each independently an integer seieeted fromA . , ‘ i to 9 and each , where occurrence of R’ is independently H? a Einear or branched €3ng aikyi, or a linear or branched C1-Cg aikenyi in even a fwurtherinbodirnent R2 ism m2 and mi and n12 are both 4° In another embodiment, R2 is "‘1 m2 and ml is 3 and 1112 is 4, or ml is 2 and 1:32 is 3. {@543} When mi and/or n12 i s an integer frern 24.3, the rn 1/an at the end of the carben chain is CH3, While the ing nil/mil groups are CH3. {9&5}Hn one embodiment oi Formuia (Ia), Formula (Eb) Formula (1e) and Formula (Ed) R) \l/V,W:\Q/V Or ASSV in a further embodiment, R3 is OH and R4 is 0R5 where R; is H, optionally substituted iinear or branched C1—C1:— ahtyi", optionally substituted iinear er branched Cz—C 15 aikenyh (C=O)-optionaiiy substituted linear or branched €5qu aikyi, or {C=O)uoptionaiiy substituted linear or ed 15 aikenyt. {(31396} In one embodiment of Formuiae (Ea), {Eb}, (5e) er (Ed), R; is H, R3 is {2333i and R4 is W 0 9R'R‘ - m1( )m2 CR’ 1 / \ OR5 and R5 is ' or R' R where m1 and m2 are each , , ndently an integer selected from i to 9 and each occurrence of R" is independently H, a linear or branched (3]ng alkyi, or a iinear or branched. {71435 aikenyi. When mi and/or n12 is an integer frern 2—9, the inl/rn2 at the end of the carbon ehain is CH3, while. the remaining Z grnuns are CH; {@097} in another embediment, a pi‘nstaeyelin nd of one 05 Formula (la), (lb), (icy) 0r (id) is previdetl wherein R3 is OH, as provided in one of Fni‘niulae (la) lib"), tie") or Gd"): 0 O O R2\OJJ\/O \/O R2\"Jl\/O R2/N\n/O R4 R4 R4 R4 HO HO HO HO Fonnula (la’) Fermaia (itb’) Fennula fie") annula (ld’) wherein, R2 is H, a linear er ed (jg-(:33 ethyl, or a linear or hranehefi (jg-{:18 allrenyl; and R4 is 6R5 an optionally substituted, linear or ed (SJ—€15 , alley}, or an nptienally Substituted linear er branched (124315 alkenyl, wherein R5 is H, eptienally substituted linear er branched C1—C15 alhyl, optionally substituted linear or branched Cngs allrenyl, {tiI===())—0pti0nally substituted linear er branched (314315 ethyl, or (C===())—nptinnally substituted linear er hranehed CR'-(:35 alkenyle with the proviso that R3 and R; are net both H.
In one ment 0f Fermula (la’), Formula (113’), Fonnula He") and Fen'riula (ld’), R4 is ‘ "‘1(item l/ and R3 | . <0 is gr R R r2 gr R515 or CIZR'R' I/ \ R RI where ml and n12 are each independently an integer selected tron:.. A .\ l. to 9 and each Qccunenee of R’ is independently H, a linear or branched CguCg alkyl, 01' a linear 0r branched C1-Cg alkenyl. In even a further ment, R3 is \/\jN\/\/ \i/5 5 {MEEPS} Yet another embodiment of the invention relates to a prostaeyetin nd 0f one of Formula (Ia’ ’), (11)"), (10") or Gd"), or a pharmaceutieaily acceptable Salt thereefi O 0 0R5 0R5 R3 R3 Formula (Ial 5") Formula {lb ’ ’) H 2 T 0R5 0R5 R3 R3 Formula (10" ’) Formula (Id’ ’) wherein, R2 is H, a linear or ed {IS—C18 alkyl, linear {jg-€13 alkenyl, branched {lg—C13 alkenyl, aryl, amrl—Cg—ij'g alkyl; an amino acid or a peptide; and R3 is H: OH, optionally substituted linear or branched C ij15 y, O—eptionally tuted linear or branched (7?ng alkertyl, O~{C===t0}meptianally substituted linear or branched {Tl—€15 alkyl, or O—(C=O)~optienally substituted linear er branched Cgucls alkenyl; R5 is El, optimally substituted linear or branched (31415 alkyl, eptinnally subatituted linear or branched Cz-C 15 alkenyl, {C=O)—eptionally substituted linear er branched C1—C15 alkyl, er (C====G)—0ptlenally substituted linear er branched C3—C5 all-genyl, with the previse that R3 and R5 are not 'beth H. In a r embediment, R3 is GH and R3 is S—nnnanyl, 4~heptylfl 4—oetyi, 3—oetyi, 2—diniethyini -propyi, 3,3—diniethyiwi—bntyi, 2—ethyi—i—bntyi, yifl pentyifl nexyi, neptyh oetyi, nonyi, decyi, i, dodeeyi, trideeyi, tetradeeyii pentadeeyh hexadeeyi, iieptadeeyi or oetadeeyi. in even a further embodiment, R3 is deeyi, nndeeyi, dodeeyi, trideeyi, tetradeeyi, pentadeeyi, hexadeeyi, beptadeeyi or eyi. in even a, further embodiment, R2 is a linear aiiqyi. {flfi9§} One embodiment of the present invention is directed to compounts of Formula (1c), (10") and tie"). in a r embodiment, R2 is a iinear C5~C 13 aikyi or a branched {Ts—C13, alkyl. In even a further embodiment, R2 is a linear {3.6qu aiiryi or a branched C6—C3 aikyi.
In yet a r embodiment, R2 is a linear C‘s-CM aikyii tag, a iinear C5 aikyL Cg aikyig Cm alkyl, C12 aiit'yl or C14 aikyi. {fifilflfl} in one ment, a compound of Formula fie") is provided wherein R3 is a iinear (Cs—{T18 aikyi; R3 is OH and R5 is H. in another embodiment, a compound of uia (10") is provided wherein R; is a linear (jg-(jig aikyi; R3 is (iii and R5 is Si. in yet embodiment a compound of Formula fie") is provided wherein R; is a linear €6ow aikyi; R3 is {Iii-ii and, R5 is H. in even another embodiment, a compound of Formnia Go") is provided wherein R2 is a linear ngCH aikyi; R3 is CH and R5 is OH. {sewn in one embodiment, a. nd of Formuia. (ie’ ’) is provided wherein R2 is a iinear (jg-{:13 aikyi; R3 is OH and Rg is H. in another embodiment, a compound of Eioi‘mnia tie") is provided wherein R2 is a branched (35—ng aikyi; R3 is 0H and R5 is H. in yet embodiment, a compound of Formula (10") is provided wherein R2 is a branched (154315 aikyi; R3 is 0H and R5 is H. in even another embodiment, a compound, of Forrnuia (10") is provided wherein R2 is a branched. {Cg-(234 aikyi; R3 is {)H and R5 is H. iiBZE in even a iiirther embodiment, a compound of Formnia (is), (ic’) and (:ie") is administered. to a patient in need ofPH treatment via a d dose r.
{W103} in yet another embodiment oi‘Forrnnia (131")? (1‘0"), Go") or (id"), IR; is OH, (FR'R' ( ) /CF§' R5 is H and R3 ism1 m2 or R' R' where rni and m2 are each independently an integer selected from i to 9. in even a finther embodiment, R2 is V\jN\/\/ {$3104} In yet another embodiment of Fennuia Ga"), (113"), (10’ ’) or Gd"), R3 is H, R; O (FR'R' ( ) "3' is OH, and R5 is m1 m2 . or R' R where mi and 1112 are each independently an integer ed frem 1 to 9 in even a furthei embodiment, R2 is V\j~\/\/, {99195} In ene embodiment, a. prostaeyelin enmponnd efFonnula (I), (la), (1b), (In) or (Ed) is previded Where R2 is a linear or branched (354313 aiky}. in a r embodiment, R2 is S—nonanvl, 4~heptanyL 4—eetanvl, nyL Zudimethyl—iiwpmpanyi, 3,3-d11’nethyi—141111311134, 2ethyi—i—butanyi2Lpentanyi, pentvi hexyl, hepwl, oetyi nenyi, deny}, undeey}, i, trideeyi , tetradeeyi, pentadeeyi, hexadecyl, heptadeeyl er oetadeeyi. {391%} In one embodiment, a prestacyelin compound of Formula {1), (la), (1b), (1c), (Ed), (Ia’), (1‘0"), (Ic’), (1111’), (121"), (1‘0"), Ge") er Gd") is provided Where R2 is a iinear or branched (Ts—C13 aikyi. In even a further embodiment, R2 is a Einear {Ts—€13 alkyl. In another W?)m2 E? ment, R; 15"" 01' R' R where m1 and 1112 are each independentiy an integer ed from 1 to 9 and each occurrence ef R’ is independently H, a linear or branched C101 alkyl (11 a linea1 01 bianehed ( 1—(s aiken'yi En eVen a fu1the1 embodnnent, R3 VVMLV, JNV, ALV: VWKN, {MIME In another embodiment, a prostacyciin compound of Formula (1)," (in); (1b), {1e} or (Id) is provided wherein R2 is a branched Cg—ng alkyi. in a, further embodiment, R2 is —nonanyl, 4—hepty1, 4~octyL 3-Day}, 2—dimethyi~inpl‘opyi, 3,3—din1ethyi~inbutyl, Z—ethylwlbutyl , 3~pentyL pentyl, hexy]., , ootyi, nonyi, deeyi, undecyie dodeey}., "widecyig tetradecyi, pentadecyl, hexadecyl, heptadecyi or octadecyi. {@0108} In one embodiment of the invention, the prostaeyclin nd of the nwel'ttion has the foilowing structure: n R1 is NH, (I) or S 399M393 For e, R1 is. O or N, and one ofthe foiiowing compounds anyl n‘eprostinil (alkyl esterfi 5Cg—TR} or S—nonanyi n‘eprostinii (amide linked; 5C9nTRnA) is provided: H5 or N: "J: ll} in one embodiment, a prostaeyelin nd of Formula (I), (la), (lb), (le) or all CER'R‘ 1 . . . l ) ./ (Ed) m1 m2 . is prowded wherein Rg 18 or R R where mi and m2 are each independently each an integer selected from i to 9 and each occurrence of R" is independently H, a linear or ed {:l-Cg alkyl, or a linear or branched {Tl—Cs alkenyi. {fifilil} When 1111 and/or m2 is. an integer from 219, the nil/1112 at the end of the carbon chain is CH3, while the remaining nil/r112 groups: are C337,, {061.12} In even another embodiment, a compound ei‘Fommla (i), (la), (To), (11;), (id), (121’), (lb’), (1113") (Id’), (253") , fie") or Gd") i5; provided and R3 is V\j~\/\/ {993.11% The eornpoui'ids provided herein can ii'iciude a, symmetrical branched alley} or (9%)", an asymmetrical branched alkyl as ihe R; moiety. For example, where R; is m1 mi and n12 can be the same integer and R2 is therefore a symmetrical branched ailryi. R3 is an assynietrieel branched aiiiyi when mi and ml are different } In another embodiment, a compound ofForniuia. (I), (121), (lb), (1e), (1d), (13’), (lb’), (lc’), (id’), (121"), {.E‘b"), (5.9") or Gd") is provided, 512 is; "‘1(3),, ml , is 2 and I112is 3 mi and 111?; are each independently 4-, 01 ml andrmm2a1e each independently 3 {W115} in another en’ibmiiment, the prostaeyeiin compound comprises an asymmetrical hranclied alkvl at the R; position sueh as for example Enliexanyl (3C5),.-1~ yl (203, 3-heptany1 (3C7), 2-octanyi (2C3), 3~ectanyl (3C3), or 4—oetanyi (4%). {991.16} In another embodiment. a. prostaeyciin compound of For‘ntinla (ii), (in), (1b), (is) or (id) is ed wherein Rz is a branched alkyl seieeted from ethyl—l—pentyi, 13.— , 4—octyl 5~nonanvl, -—ethylLbutyi, 2~propyl~i~peniyL l2—butyl—i ~eeiyl, 2—dirnethyl— l—propyl, and 3 ,3 -dimetby i —1 —butyl. i’} in another embodiment, a. prostaeyciin compound of Fermnia, (i), (is), (_1b} (in), (id), (ia’), (Ib’) (30’) or (id’) is provided, wherein", R2 is a iinear or branched C5~ng aikenyi. For example" in one ment, R3 is a linear C5—C3 i seieeted from pemenyi, hexenyL heptenyi, octenyig nonenyh deeenyi, undeeenyi, trideeenyh ietradeeenyi, peniadeeenyi, hexadeceny}, heptadecenyi or octadeeenyi. in a further embodiment, R3 is 01-1. in r embodiment, R2 is a branched {35-ng aikenyi selected from pentenyif, hexenyii, heptenyl, octenyi, nonenyl, i, undecenyi, n'idecenyi, tetradecenyi, pentadeeenyi, hexadeeenyL heptadeeenyi or oetadecenyi. In a further embodiment R3 is OH. {03118} In one embodiment, a, prostaoyciin nd of Formula (I), (la)? (1b), (10) or (id) is ed and R, is OH . in a furiher ment, R4 is {$011593 in one embodiment a pi'ostacyelin compound of Fennnia {i}, (is), (iii), (icy) or (Ed) is provided and R; a. linear ngC18 silky}? R3 is 0H and R4 is OH . in a. further embodiment, 312 is Ssnonanyi, yi, zit—octanyh 3~oetanyL ZedimetiiyE-l—propyi, 3,3wdimetiiyini"butyi, Z—ethyidmbutyL 3—pentyi, pentyla iiexyi, heptyifi oetyif, nonyL decyif, undeeyi, dedeeyi, trideeyl, tetradecyi, pentadecyi, hexadeeyi, iiepiadeeyi or oetadecyi.
{WEN in one ment, a prostacyclin compound of Fonnnia (i), (is), (iii), {Io} or (Ed) is provided and R2 hexyL dodeeyi, tetradeeyL hexadeeyif, 5—iionenyifi 4—heptanyi, 4~ oat-any}, Iiwoetanyi, 2—dimethyi~i -propyi, 3,3-dimethyiddintyi, Z—eih'yi-i -bntyi, 3—pentyi, R3 is OH and R4 is OH e In one embodiment, a prostacwiin componnd oi‘Fontnuia (1),, (In), {1b} (in) or (Id) is provided and R2: hexyi, Rs is OH and R4 is CH {M1221} In one embodiment, a, prostaeyelin compound of Formula (I), (in)? (1b), (is) or {id} is provided and R2 hexyi, R3 is 0H and R4 isiii/YW‘CH {@123} in another embodiment, 3’\ a prostaeyclin compound of Formula Ga"), {in 3-» He") or (id") is provided. and R2 sexy}, R3 is 0H R4 is H. In a tittther embodiment, the. compound is a compound of Formula Go"). In yet another ment, a pi‘ostaeyeiin compound of Formula Ga"), (1‘0"), fie") or (1rd") is provided and R; dodeeyi, tetradeeyi, pentadeeyi or hexadecyl, R3 is CH R4 is if}. in a finther embodiment, the compound is a compound of Formula (121,"). in even a further embodiment, the compound is present in a iipid nanoparticle formulation as described in more detaii beiow, {60.1214} In one embodiment, a prostacyciin compound of a (i), (Ia)g (1b), {is} or (Id), or pitannaeeuticaliy acceptable salt, is provided, and R2: heptyi, R3 is OH and, R4 is {@3125} In one embodiment, a prostaeyoiin compound ot‘Fonnuia (i), (la), (1b), (in) or (id), or pharmaceuticaliy aeoepta‘oie salt, is provided, and R2 oetyl, R3 is OH and R4 is } in one embodiment, a prostaeyelin compound of a (i), (is), (_ 1b), (is) or {id}, or phannaeentieaiiy acceptable salt, is provided, and R; nonyi, R3 is OH and R4 is {$01273 in another embodiment, a prostacyciin compound, of Formula (it), (in), (1b), (is) or (id), or phamiaceutieaiiy acceptable sait, is provided, and R3 decyi, R3 is OH and R4 is W.OH {W128} In yet another embodiment, a pi‘ostacyeiin compound of Formnia (I), {is}, {Eb}, (10) or (1(1), or phannaoeutiealiy able salt, is provided, and R2 undeeyi, R3 is CH and R; is OH } In even another embodiment, a ptostacyciin compound of Fotmuia (i), (is), (1‘0), (It?) or (id), or phzmnaeeutieaiiy acceptable sait, is ed, and R2 dodeeyi, R3 is UH and R4 isW.OH llltlliill} in one ment, a prostacyelin nd of a (l), (la), (lb), (le) or (let), or phennaeenticelly acceptable salt, is pint/low.a and R2 yl, Rg is CH and, R4 is {@131} In another embodiment, a prostaeyclin nd of Formula. (l), (la), (lb), (la), or (id), or pharmaceutically acceptable salt, is. provided, and R2, tetradecyl, Rs is OH and R4 is OH } In even another embodiment, a. pmstaeyciin compound of Feminist. (1), (la), (lb), (lo) or (Id), or pharinacenticallgv' acceptable sell, it; in'ovitled, and R2 pentadeeyl, R3 is on and n4 is OH {lltllflfil Another embodiment of the invention concerns a prostaeyelin compound of a (I), (la), (lb), (lo) or (Id), nor phannaeeuticelly acceptable salt, n R2 hexaoeeyl, R3 is Oil and, R4 is OH lilltll34i Yet another embodiment of the invention concerns a, prostacyclin compound of Fonnula, (i), (la), (lb), (lo) or (id), 3 or phannaoeutieally acceptable salt, wherein R2 lieptadecyl, R3 is OH and R4 is- OH {@135} Yet another embodiment of the invention ns a. prostaeyelin compound of Formula (l), (la), (lb), (lo) or (ld), or a pharniacentieally acceptable salt, wherein R2 octadecyl, R3 is 0H and R4 in OH {($136} in one embodiment, a, compound of Formula (3), (la), (lb), (lo) or (id), or a pl‘iarmaeeuticaliy acceptable salt, is provided, wherein one or more hydrogen atoms is subotitutetl with a, deuterium. Accordingly, in one embodiment, the present invention relates to an isotopologue of Formula (l), (Ea), (lb), (lo) or {to}, substituted, with one or more deuterium atoms. The isotopologue of Formula (1), (la), (lb), (lo) or (id) may he used to accurately determine the concentration of compounds of Formula (1), (la), (lb), (1c) or on) in biological fluids and to determine metabolic patterns of compounds of Formula (1), (la), (lb), (is) or (id) and its isotopoiogues. The invention further provides compositions comprising these ated isotopoiogues and methods of treating es and, conditions, as set {with herein. {@137} in another aspect of the invention, a, prostaeyeiin compound ofForniuia (H), or a pharrnaeeutieaiiy acceptable salt thereof, is provided: R2 \R1JLHn/o Formula (11), wherein R1 is NH; O or S; R3 is a linear or branched ij'CJg alkyi, a linear 03¢ng alikenyi or a branched {$33ng aikenyia aryi, l—Clg silky}, an amino acid or a pep’tide; and n is an integer from O to 5. {@138} in one ernhodnnenn a prostacyciin compound of Fonnuia (11)., or a pi’iai‘inaceutieaiiy aeeeptahie salt thereof", is provided, wherein R1 is NH, (I) or S; R3 is a iinear or branched 03»ng aikyie a linear C2"C'g aikenyi or a branched C3413 aikenyi; and n is an integer from i} to 5. in a fiirther embodiment, n is I and R1 is NH or 0‘ {@0393 in one ment, the present invention relates to the eyeiin compound ofFonnuia (11),, wherein the nd is a compound of formula (Ha), (11b), (He) or (Bid), or a pharmaceutieaiiy acceptabie saitthereof: o o R2\OJJ\/o RbskO Formula (Ha) Formula (1113) 0"" I H5 H6 Formula (110) a (11d) wherein R2 is a linear er branched {ls—{713 aikyi, a linear {jg-€13 alkenyl, or a branched (334318 alkenyl, aryl, aryLCrCIg aikyi, an amine acid er a peptide in a further embodiment, a nd of formula. (11a), (11b), (110) or (lid) is provided wherein R2 is a linear er branched (is—Cu; alkyl, a linear (fig-{313 allrenyi er a branched (lg-{313 alltenyl. 1n nne embodiment, a compound, of Formuia (11), (11a). (1113),, (He) or (11d) is prevideth wherein one er mere hydrogen aten'is is substituted with a deuterium, Aenerdingiyr in nne ernbedirnenL the present invention relates to an isntepningue of Fni'inula. (ill)a (11a), (11b), (:11c) or (11d), substituted with ene or rnere deuterium atoms. The isetnpeiegne of FQfi‘fluia (ll), (11a), (lib), (lie) er (11d) may be used to accurately determine the coneentratien 0f cemponnds of a (11), (11a)? (111)), (110) 0r (lid) in bielngicai fluids end te determine metabniie ns 01’ eempeunds of Ferrnula (ill), (11a), {lib}, {116) 01' (11(1) and, its nlegnes. The invention further prevides eempesitiens comprising these deuterated isotopelogues and methods ef treating diseases and ennditiens, as set forth herein. {11111411} in ene embodiment, the prestacyclin tive is a compound, of Formula (11C). in a further embodiment, R3 is a linear C5—C5; alkyi or a branched C5613 alkyi. For example, in ene inient, R2 is a linear (ifs—(:13 aileyi. in another inient 0f Ei‘ni‘ninla (110),, R2 is a. linear (76—er0 alkyl. 1n even a further einbedinient 0f Fni‘rnnla (11c), R2 is a hexyl, heptyi er eetyl. {(311141} Compounds efliormuia {113) and FOi’i'fl'ilifi {E id) are ed in, tables A and 8 below.
'I‘ableA. Cam ennds eanrmnla 1.1a R2" linear C5—C3 alkyl ranehed (lg—C13 alkyl R2... linear Cg alkyl R2 branched C6 alkyl 112 linear (36C; 3 alkyl R2 branched €6ng alkyi R2 linear Cg alkyl R2 branched C7 alkyi R2 linear {37-ng alkyl R2, branched (37-ng alkyi R2 linear Cm alkyt R2 branched Cg alkyi .........................................................................................................................................................................................................................................................
Table Ac Cam eands (if Formula Ila R2, linear Cir-C18 allryl R2 branched (33»ng allry’l R2, linear C31 alkyl R; ed Cg alkyl : 5 : ----------------------------------------------------------------++ R3: linear C9313 allzyl l R branched (39—ng allryl R linear C39, alkyl R2 : branched C10 alkyl . l : ----------------------------------------------------------------+- -------------------------------------------------------------+---------------------------------------------------- ----------------------------------------------------------i R2 : linear C104:13 alkyl R3 : branched C10~C13 alkyl R3 : linear C13, alkyl R3 : branched C11 alkyi .
R2 : linear Cl 1-C13 alkyl R3 : branched C; 1~C13 alkyl R3 : linear CM alkyl R: : branched Cm, alkyl R; linear C1TC" alkyl R2 ed Gig-(:13 alkyl R3, linear C15 alkyl R; branched C13 alkyl "';ii'iib‘i3'§1"'iffiir£"Kelli;'Eiiiiiiiiliiiiiiiimiié""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""" R2 = linear C5—C1; 3 alkyl R2 = branched (3—018 alkyi R3 = linear {:6 alkyl R2 = ed Ce alkyl Rg linear (its—C13 alkyl R3 branched {764313 alkyl R3 linear C7 alkyl R; branehed C7 alkyl R; linear {Pp-Cm alliyl R3 2 branched {T’r'CES alley} R; 2 linear C3 allryl R3 branched Cg allryl R2 : linear CC} 9, alkyl R2 : branched (jg-C1 g alkyl Kg : linear Cm alkyl R; : branched Cm alkyl R2: linear Cv‘iqum allryl R2 : branched Cm—Clg alkyl R2 : linear C1 1 alkyl R2 : branched Cl 1 alkyl Ra: linear {Ts—C12 alkyl R2 ,7: branched C5—ng alkyl R2- linear C33 alkyl R; : branched C13 alkyl R2, linear {Ta-Cw allryl R2, branched Ce-Cre alliyl R2 linear C13 alkyl R; branched C13 alkyl ......................................................................................................................................................................................................................................................... {@3142} Yet anether embodiment of the ion relates to a prestaeyelin eenipeand 0f nnla {ill}, er a phannaeeurieally acceptable salt thereef: R2\R1J‘J\/O 0‘" R5 ReOI"! la Hi), wherein R1 and R2 are defined as previded for Formula. (I) and (ll), and R5 and, RS are independently selected frern l-l, ep‘iinnally Substituted linear er branched (SJ—CH alkyl, optienally substituted linear er branched C2—C5 allrenyl, (CFO)— eptinnally substituted linear or branched Cr61 5 alkyl, 01" (C:O}«013'tionally subalilaled linear or branched C2—C1 5 allienyl, with the proviso that the prostaeyclin compound of Formula (ill) is not treprostinil, {titlfldSl in one embodiment, the branched chain prostacyclin compounds provided herein exhibit both higher solubility and slower enzymatic conversion to treprostinil relative to a linear chain derivatized prostacyclin compound. ln one embodiment, an asynnnetrical branched chain prostacyclin compound is provided, wherein the asymmetrical branched, chain, prostacyclin compound is more stable than a corresponding synnnetrical branched chain prostacyclin compound. {96.14% in. one embodiment, the present invention provides prostacyclin compounds that contain a chiral moiety at one or more of the R2, R5; and/or R5 positions. For example, the moiety at position R3, in one embodiment, is a chiral moiety and comprises either the R , the S isomer, or a e thereof. An optical isomer at position R2, R5 and/or K; can also be classified with the D/l_, nomenclature. For example, where R2 is an amino acid or an amino acid moiety, the amino acid or amino acid moiety can be the Duisomer, L—isomer, or a mixture thereof. {lllllélii} in one embodiment, one or more of the R2, R5 and/or R6 moieties is the R isomer or S isomer. in another embodiment, one or more of the Rg, R5 and/or Rig moieties provided herein comprise a mixture of R and S moieties. The "R isomer" or "S ier" as used herein refers to an enantiomerieally pure isomer. An "enantiomerically pure isomer" has at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure R— or S— isomer or when using the DZL nomenclature, Du or L—isomer, A racemic compound is a compound having a mixture in equal s of both enantiorners. {@9146} In another aspect of the invention, the prostacyclin compound described herein is provided in a composition, for example, for delivery, to a. patient for the treatment of pulmonary hypertension (PH). Compositions can include the compound, a ceutically acceptable salt of the compound, or a combination f. in one embodiment, the Ell-l is pulmonary arterial hypertension (PAH). Pi‘ostacyclin compositions (so called "lipid rticle itions") and tbnnulations comprising a prostacyclin, a cationic nd, and a surfactant have been described in FCT publication no. WO mid/085813, the. disclosure of which is hereby incorporated by reference in its entirety for all es.
The compositions described in W0 20l4/tl‘858l3 are le for use with the prostacyclin derivative con'iponnds provided herein. ltltllcl’l} in one embodiment, the composition ses one of the prostacyclin compounds described herein, i..,e a. compound of Formula. {1), (la), (lh), (lo), (lo), (lad, (lh’), (lc’), (ld’), , , (lc"), lid"), (ll), (Ila), (llh), (lie) (lid), or (illl), and an amphiphilic agent. When ated together, in one embodiment, the prostacyclin nd and amphiphilic agent form micro- or nanoparticles. in one embodiment, the hilic agent is a. PEGylated lipid, a surfactant or a block copolymer, in another embodiment, the prostacyclin composition provided herein comprises two or more of the prostacyclin compounds described herein (eg a, compound of Formula ti), (la), (lb), (lo), (id), (la’), (lh’), (lc’), (lid’), (121"), (ll)"), tile"), Gd"), (ll), (Illa), {lib}, (lie) (Nd), or (ill), including ated compounds) and an amphiphilic agent (cg, l’EGylated lipid, a lipid, a surfactant or a block copolymer). in one embodiment, the cyclin ition eomprisnig the cyclin compound component and amphiphilic agent, when formulated together, comprise a plurality of nanoparticles. in a further embodiment, the mean diameter of the plurality of nanoparticles is from about 20 nm to about 7G0 nm, for example about St) 11111 to about 500 nm, about lOO nm to about 600 nm or about lOG rim to about 590 nm. When the hilic agent comprises a lipid, e.g., a PliGylated lipid such as Cliolesterolsl’lit’i or distearoylphosphatidylethanolamine—l’EG (USPS—PEG), the composition is described as comprising lipid nanoparticles, llllllcltl} in a further ment, the prostacyclin composition comprises a prostacyclin compound of Formula (I), (la), (lb), (1c), (ld), (la’), tlb"), (lc’), (ld’), Ga"), (lif’), tic"), are"), (ll), (lla), (llb), (lie) (lid), or (ill), and a l’EGylated lipid, as the plrilic agent. In a further embodiment, the {BEGylated lipid comprises PEGll-llil— PEGSGllll. For example, in one embodiment, the PEGylated lipid comprises PEG4GO, l’EGSGG, PEGlOOO, PEG2000, PEGEEOGQ, l’EGIltlllll, or PEGSGGQ. in a further embodiment the lipid component of the PEGylated lipid comprises cholesterol, dimyristoyl phosphatidylethanolamine (DMPE), itoyl phosphoetlianolamine (DE’PE), distearoylphospliatidylethanolamine (DSPE), dimyristoylglycerol glycerol (DMG), diphosphatidylglycerol (DPG) or disteraroylglycerol £33546). in even a further embodiment, the PEGylated lipid is cholesterol—P562006 or 3339313562899. {@149} Depending on its molecular weight (MW), PEG l3 also referred to in the art as polyethylene oxide (PEG) or polyoxyetliylene (PCB). The l’EGylated lipid can include a branched or unbranched PEG molecule, and is not limited by a. particular FEG MW. {0&150} For example, the PEGylated lipid, in one embodiment, comprises {:1 PEG: molecule having, a. molecular weight of 300 g/rnol, 400 g/moi, 500 g/mol, 1000 g/moi, i500 i, 2000 g/rnol, 2500 g/niol, 3000 , 3500 g/niol, 4000 g/mol, 4500 g/mol, 5000 g/mol, or "3,000 g/rnol. In one embodiment, the PEG has a MW of l000 g/mol or 2000 g/inol. {0%151} The lipid component of the PEGyEated lipid, can have a net—charge (eg cationic or anionic), or can be net—neutral. The lipids used, in the PEGylated lipid component of the present invention can he synthetic, serni~synthetic or natni'allyuoccnrring lipid, including a phospholipid, a sphingolipid, a giyeolipid, a cerarnide, at tocopheroi, a , a. fatty acid, or a glycoprotein such as albumin. in one embodiment, the lipid is a sterol. in a further ment, the sterol is cholesterol. In another embodiment, the lipid is a phospholipid. Phospholipids include, lint are not limited, to pliosphatidyleholine (PC), phosphatidylglycerol (PG), phosphetidylinositol {i’l}, atidylserine (PS), phosphatidylethanolamine (PE), and 'phosphatidie acid (PA). in one embodiment, the phospholi‘pid is an egg phospliolipid, a soya olipid or a hydrogenated egg and soya phosphohpid, in one embodiment, the PEGyleted lipid comprises a phosphoiipid. in a further embodiment, the phospholipid comprises ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of glycerol that e choline, glycerol, inositoi, serine, ethanolamine, as well as the corresponding phosnhatidic acids. The chains on these fatty acids can he saturated or rated, and the phospholipid can he made up of fatty acids of different chain lengths and different degrees of unsaturation. in particular, in one embodiment, the PEGylated lipid of the prostacyclin composition ed herein ses roylphosphoethanolamine (BSE’E), dipalmitoylpliosphatidylehoiine (DPPC), dioleoylphosphatidylcholine (DOPC) istoyl phosphatidylethanolamine (DMPEL dipalmitoyinhosphoethanolamine (DPPE), disteamylphospl‘iatidylethanolamine (ESPEL dimyristoylglycerol (DR/l6), nhatidylglycerol (DPG) or disteraroylglyeerol (DSG). {00152} Other examples of lipids for use in the compositions comprising PEGyleted lipids disclosed herein include diniyristoylphosphatidylcholine (Dh/lPC), dimyristoyiphosphatidylglyceroi (DMPG), dipalmitoylphosphatidylglyceroi (DPPGL di stearoylphosph atidyleho l ine (DSPC), di stearoylnhosphatidy l glycerol (DSPG} dioleylphosphatidylethanolainine (DOPE), and mixed pliosphoiipids such as paimitoylstearoylphosphatidy[choline (PSPC) and palmitoylstearoylphosphatidyiglycerol (PSPG), tiiaeylglyceroi, diaeylglyeerol, cei'amide, sphingosine, sphingomyelin and single aeyiated phosphoiipids such as mono-oieoyl—phosphatidyieti'ianolamine (it/301333), in another embodiment lipid portion of the PEGyEated lipid comprises an ammonium salt of a fatty acid, a phospholipid, a. glyoetide, a. phospholipid and giyoeride, a stei'ol (tag, cholesterol), phospliatidyiglyeeroi (PG), phosphatidie aeid (PA), a phosphotidyleholine (PC), a phosphatidylinositol (Pl), a phosphatidyiserine (PS), or a ation thereof. The fatty acid, in one embodiment, comprises fatty acids of carbon chain lengths of .12 to 26 carbon atoms that are either saturated or unsaturated. Some specific examples include: myristylamine, palmitylamine, iaurylamine and stearyiamine, diiauroyi ethylphosphooholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipahnitoyi ethylphosphoehoiine (DPEP) and distearoyl ethylphosphoeholine (DSEP), N—(Z,3—di—(9(Z)~oetadeeenyloxy)~prop—l—yl— \,N,N—trimethylammonium de (DOTMA) and l ,2-bis(oleoyloxy)—3 — (trimethylaimnoniomropane (DOTAP). Examples of steiols for use in the compositions ed herein include terol and ergosterol. ples of PCES, PAS, Pia, PCS and l-"Ss for use in the compositions ed herein include EMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPL DPPl, DSPI, DMPS, DPPS and DSPS, SSE’C, DPPG, DMPC, DGPC, egg PC and soya PC. {@153} in one embodiment, the PEGylated lipid is eliolesteroleEGZGGQ, ESPE— PEGE one or DSCE—ldEGlefltl. {fifilfid} in another embodiment, the prostacyelin composition provided herein comprises a prostaeyelin nd of Fon’iinla (I), (ta), (1b), (lo), (id), (121’), (ib’), (Ie’), (ld’), Ga"), Uh"), Us"), (501"), (it), (Eta), (lib), (lie) (lid), or (iii), and, a hydrophobic additive. in a inrther embodiment, the composition comprises an hilie agent, eg, a.
PEGyl-ated iipid, as described above.
{WEISS} In yet another embodiment, two or more of the cyclin compounds described herein (eg, a compound ot‘meul-a {E}, {1a), (1b), (10), (Id), (ia’), (113’), (10"), (Id’), (121"), (lb"), Ge"), Cid"), (ll), (Ila), (lib), (lie) (ild), or (33D) an amphiphiiie agent (rag, PEGyiated lipid, a. lipid, a surfactant or a block eopoiyrner) and a hydrophobic additive are provided in a composition.
{MISS} In one ment, the prostaeyolin eompoeition comprises a prostaeyolin compound of a (I), (la), (lb), (lo), (Id), (ia’), (lb’), (ie’), (id’), Ga"), ab"), tie"), Gd"), (El), (Ha), (llb), (lie) (lid), 01' (ll!) and a iylated lipid. in another embodiment, the prostacyciin composition comprises a. prostacyciin compound of Formula ti), (Ea), (1b), (1c), (id), (ia’), , He"), Gd"), Ga"), , tie"), Gd"), (11), (Ha), (lib), (Ho) (Hd), or (iii) and a surfactant. in yet another embodiment, the prostacyciin composition comprises a prostacyciin nd of Formuia (i), (Ea), (1b), (to), (id), (ia’), (113’), (ic’), (id’), ("in"), flit"), tic"), (501"), (31), (Ha), (Bib), (tic) (Hd), or {iii}, a hydrophobic additive and an amphiphilic agent. In a further embodiment, the amphiphiiie agent is a surfactant, a ted iipid or a ‘biock copoiymer. in even a titrther embodiment, the aniphiphiiic agent is a PEGyiated lipid.
{W157} In one embodiment, the prostacyciin compound is present in the composition at 5 moi'i’da 99 moi%. in a further ment, the pi‘ostaoyciin compound is present in the composition at 4Q niol% m 95 1110191). In a further ment, the prostacyciin compound is present in the composition at 40 moi% 6t) nioi‘E/s. in one embodiment, the prostacyciin compound is present in the composition at about 40 moi‘h’; or about 45 moi%. {@158} The amphiphiiic agent, eg, a PEGyiated iipid, when present in the composition, in one embodiment, is present at it} fllfliii/o 30 rnoi%, for exampie, it) moi% 2t) moi% or 15 15110in — 25 1110192.». In even a further embodiment, the PEGyiated iipid is present in the composition at about it) moi% or 2Q moi%.
{MEWS The hydrophobic additive, when present in the composition, in one embodiment, is present in the composition at 25 molt?" — 5% 1110196, for example, 30 moi% — 5t} mow/é, 3:3 inflifi/E‘: 45 mol%. in even a thither embodiment, the hydrophobic additive is present in the eomposition at about 4t} mow?) or about 4.5 moi%. {anion The prostacyolin composition, in one embodiment, eomprises a nd of ES’ormuia (I), (la), (1h), (1c), (1d), (321’), (ih’), (10‘), (id’), Ga"), tit‘b"), tic"), Set"), {it}, (ita), (iib), (He) (11(1), or (III), or a. pharmaceutieaiiy acceptabie sait thereof, as described herein, an atnphiiphiiic agent and a hydrophobic ve. In one embodiment, the hydrophobic additive tag, an additive that is at ieast partially hydrophobic) is a arbon, a terpene compound or a hydrophobic lipid (tag, toeopheroi, tocopheroi acetate, , steroi ester, alkyl ester, Vitamin A e, a triglyceride, a phosphotipid). in one embodiment, the composition comprises a prostacyciin compound, for exampie, a nd tnuia (i) or (it), an amphiphiiic agent, and a hydrocarbon. The hydrocarbon can be aromatic, an aikane, , cycioalkane or an aikyne. In one embodiment, the hydrocarbon is an aikane (tie, a saturated, arbon). in another embodiment, the hydrocarbon is a (jig-{:50 hydrocarbon, In a, further embodiment, the hydrocarbon is a C15, C520, C35, C30, C35, C40, C45 or C50 arbon. in yet another en'ibodiment, the hobic additive is a {$154725 hydrocarbon, C15~C35 hydrocarbon, C15-C45 hydrocarbon, €154ng hydrocarbon, {Sm—C25 hydrocarbon, €37,5— ng hydrocarbon, ng—ng hydrocarbon, (335-sz hydrocarbon, Cam—€45 i’iydi‘ooerboo or a C45— {259 hydrocarbon. {@161} In one embodiment, a composition comprising a pi'oetaeyetin compound, an, amphiphilic agent and a. terpene compound (eg, the hobic additive) is: provided. The composition, in a further embodiment, comprises a ted iipid as the hiiic agent.
However, as noted above, bioek mers as welt as surfactants can be used as the amphiphiiic ent of the composition. The terpeoe compound (hydrophobic additive}, in one embodiment, is a hydrocarbon (6.5g. isopreiie, sooatemeor squaiene). In another ment, the tet‘pene compound is a itemitei‘peoe ((353333), monotetpetie (tint-{15), sesquitetpene (CHEM), ditetpene (Consz) (6g, eafestoi, kahweot, cembrene, eoe), seoterteipene (Clo-140), triterpene (Cotes), oesouatetpeoe {C35}{56), tett‘aterpeoe (C4DE5554), polytetpene (6.53., a polyisopi‘eoe with "11715 double bonds) or e oorisoptenoid (6.5., 3—oxo—o— ioooi, 7,8«dihydtoionone derivatives). The tet’pene compound, in another dittteot, is; selected from one of the compounds provided in Table t, beiow. to one embodiment, the hydrophobic ve is squatane. .................................................................................................................................................................................................1 Tobie i. Terpene hydrophobic additives amenabie for me to the eompogitions of the present invention.
Name Formula Isoptene Lin'ionene humulene famasene \ \ \ Table 1. Terperie hydrophobic ves amenable for use in the compositions of the present invention.
Name a squelene Squa l an6 WWW {90162} As provided above, the composition provided hereina in one embodiment, comprises a prostecyclin compound and one or more E’EGyla‘red lipids. In a furrlier ei'nbodlinenn the eompoeitioo comprises a hydrophobic additive, as described above. In one embodiment, the composition provided herein comprises a eyelln compound of one of Formula (1)15 (1a,), (1b)., (lo) (Id), flax"), (Ib’), (le’), (ld’l, fie"), ab"), Ge"), Gd"), (II), (He), (lib), (lie) {lid}, or (Ill), a hydrophobic additive and a PEGylared lipid. In a further embodiment the hydrophobic additive comprises a. hydrocarbon eg a. terperie compound. {$3163} in one embodiment, the trepi‘ostinil derivative composition ed herein includes the components provided in le C, below.
Table C. Re regenerative Tre rostlnilCom ns‘ Composition Trerostioil eom-oond l—lvdro leer) Amphlphilie Additlona . re additive ll Wagent E liggifi Formula (II) where R1 is O, . . \ x "la-3e. 1e("ii Li REC 'letedW li .idp n/a R2 18 linear (26"(—=i6 Formula (ll) where R1 is O, Toipene PEGyle’ted, lipid, DOPC Ry. is linear (7'ow Formula (ll) where R, is O, Squalene‘ (,hol‘ 3 I " . _ l. :2l<: n a/ .12 is linear (jg-(:35 Formula (H) where R] is 0, Squaleoe osreeeozk R2 is linear C63", Ema Formula (11) where R1 is o. Hlerperae Fl. {xylel d lipid.m 7‘ . , ‘ ‘ ‘ v' E .
R2 is linear 16. . '3 'e g rs a/ Formula (ll) where R1 i3 0, .
.Teipene 0 j ~.
, PEGyle‘ted lipid,,. A. DDPC1 Ry. is linear {:ow ......................................................................................................................................................................................................................................
Table (3. Re raserirarivo "Fro rostlaniICom ositions. _ ., .. H‘r lob rtion 'Frew'ostiiiilcomound w Wmin him. l. lmAdmtmna.. ll: Wfigifllt E hail": Fm???" (11) \thim R1 is 0" Squalane Chol~PEG2k ri/a R2 is linear (mg—(.45 Formula (ll) Where R1 is O’ . i , . . Squilane, 2" > DrPi—FS F P {312'k a r1 a R2 is linear CW0") Formula (jar) where R, is 0, R2 is linear (Tim—(315 Formula (H) where R; is O, Terperre Pilil’jylared lipid R2 is linear C; 24:15, Formula (H) where R1 is O, Squalane Ch"1 ) 'j ..1 "bk‘4‘) R2 is linear (3:24:16 Formula (ll) where R1 is 0, Squ llama," 2" > DSPF g—H172k R2 is linear C12~Cis Formula (ill) Where R] is 0, R2 is ed (354316 Formula (H) where R] is 0, PEGylam lipid R2 is branched €643]6 Formula (H) where R1 is O, (hOl‘1 3 *3 ‘1") 7 ..E EASIER R2 18 bTflHChfiil(_15—(:15 ula (ll) where R1 is O, DSPE PEQJg‘u. "‘7, R3 is branched {Te—Cu; Formula (ll) where R] is N, R2 is linear (76-1335 Formula (11) where R] is N, PEGyla‘led lipid R? is linear (ls-Cris Formula (II) where R1 is N, ‘ ' ( hoif LPE ‘Qk(1 R2 is linear (Lg—Cm Formula (lljfiwlrere R1 is N, DSPE—PEGZR R1 18 linear L‘s-C36 Formula (ll) where R1 is N, R2 is linear C5~C§0 Formula (II) where R; is N, PEGylated lipid DOFC Rg is linear (3647,50 Forrmila (H) where R1 is N, fixqualaria {.hol l lfiuk3 3 V) , 11%/ R2 is linear C613") Formula (H) e R] 15 N’ Squalarie DSPE—FEGZR rv’a Rg is linear C's—(rm tilll The present invention also provides methods for treating a patient in need thereof, with one of the prostacyclin compounds or compositions described herein. it is understood that re e to a prostacyelin compound in a treatment method includes the use of a pharmaceutically acceptable salt of the nd. Similarly, administration of a prostacyclin composition comprising a prostacyclin compound includes the use of a pharntiaceutically acceptable salt in the composition. {($165} in one aspect, a method for treating pulmonary ension (Pl-l) is provided.
The method comprises, in one embodiment, administration of a compound, pharmaceutically acceptable salt thereof, or composition. provided herein to a patient in need thereof.
Administration, in. one embodiment, is pulmonary administration and can be, for example, with a. d dose inhaler (MDl), dry powder inhaled (OH), or a nehulizer. The World Health Organization (Wl-lO) has classified PH into live groups Wl-lO Group E Pl—l es pulmonary arterial hypertension (PAH), idiopathic pulmonary al hypertension (lPAH), familial pulmonary arterial ension (Fl’Al—l}, and pulmonary arterial hypertension associated with other diseases . For e, pulmonary arterial hypertension associated witl'r en vascular disease (rag, scleroderma), ital shunts between, the ic and pulmonary circulation, portal hypertension and/or HlV infection are included in group l Pit. The methods provided herein, in one ment, are ed to treat a WHO Group l PH patient in need thereof, for example a PAH patient, an ll’AH patient, a Fl’AH patient or an APAH patient. WHO Group ll PH includes pulmonary hypertension associated with left heart disease, e.g.. atrial or ventricular disease, or valvular disease (eg, rnitral is). The methods provided herein, in one embodiment, are provided to treat a WHO Group ll patient in need thereof. WHO group ill pulmonary hypertension is characterized as pulmonary hypertension associated with lung diseases, 8.3;, chronic obstructive pulmonary disease (COPD), interstitial. lung disease OLD), and/or hypoxemia, The methods provided herein, in one embodiment, are provided to treat a WHO Group lll patient in need thereof.
Wit-10 Group 1‘] pulmonary hypertension is pulmonary hypertension. due to chronic thrombotic and/or em‘bolic disease. Group lV Pl-l is also referred to as chronic thromboemholic pulmonary hypertension. Group lV PH patients experience blocked or ed blood vessels due to blood clots. The methods ed herein, in one embodiment, are provided to treat a WHO Group lV patient in need thereof. WHO categorizes Group V PH as the "miscellaneous" category, and includes Pll caused by blood disorders (6.3:, polycythemia vera, essential thrombocythemia), systemic disorders (eg, dosis, vasculitis) and/or metabolic disorders (eg. thyroid disease, glycogen storage disease). The methods provided herein, in one embodiment, are provided to treat a WHO Group V patient in need thereof. {tidied} The methods provided herein can be used to treat a WHO Group i (17.9., pulmonary arterial. hypertension or PAH), Group ii, Group ili, Group 1V or Group V PH patient. In. one embodiment ofthe method for treating Pi-i, a method of ng pulmonary arteriai hypertension (PAH) is provided. in another embodiment, a method for ng chronic thromboembolic ary hypertension patient is provided, in one embodiment, the method for treating Piri tag, PAi-l) comprises administering an effective amount or" one of the compounds described herein via a pulmonary (inhalation, egg, via an MDi or nehuiizer or dry powder inhaler), a subcutaneous, oral, nasal or an intravenous route of administration, to a patient in need thereof. in one embodiment, administration is via inhalation via an MEI or nebuliaer, in one en'ibodinient, where compound delivery is via a nebuliaer, the compound is provided to the patient as a composition, for example, as a. lipid nanoparticle composition, as described, above. {titlidfl in another aspect of the invention, a method for treating portopulmonary ension (PPR) is provided. in one embodiment, the method ses administering an el’i‘ective amount of one of the compounds described herein (or a pharmaceutically acceptable salt f), via a pulmonary (inhalation), a subcutaneous, oral, nasal or an intravenous route of administration, to a patient in need thereof. In one embodiment, administration is via inhalation via an MDE or nebulizer. in one embodiment, where compound delivery is via a nebniizer, the compound is ed to the patient as a. composition, for exampie, as a lipid nanoparticie composition, as described above. {@168} Methods for administering treprostinii and analogs f for treatment of pulmonary ension have been described in US. Patent Nos. 5,153,222; 6,521,212; 7,544,713 and US. Patent Application Publication No. 2i§i€l¢iii§76083, the disclosure of each are incorporated by reference in their ties for aii es. {(913169} The method for treating a t. for PM (age, PAH) or PPH comprises, in one embodiment, administering to a patient in need thereof, one ofthe prostacyciin compounds or compositions provided , for e, a compound of Formula (1), (la), (1b), (lo), (id), (13’), {513’}, (563’): (if): (1%"), (139"), {10"}, {51’1"}, iii}, {"303 (115)» (110) (Ed), 01' (fill), a ceutically acceptable salt thereof, or a. composition comprising a compound of Formula (i), (la), (1b), (1c), (id), (ia’), (ib’), (10’), (id’), Ga"), ("lb"), , tilt"), (ll), (ila), (lib), (llc) (lid), or (ill), or a pharmaceutically acceptable salt thereof. in one embodiment, the method for treating PH (tag, PAi’i) or PPi-i comprises administering to a patient in need thereof, one of the prostacyclin compounds or compositions provided herein, for example, a nd of Formula (1), (la), (Eh), (lo), (ld), (ia’), (133’), (ic’), (id’), Ga"), ab"), Go"), (ld’l), (II), (Ha), (lib), (tic) (Bid), or (ill), or a composition comprising a compound of Formula. (I), (la), (1h), (1c), (id), (Ia’), (113’), Go"), (id’), Ga"), (ib"), Ge"), Gd"), (11), (Ha), (lib), (11c) (11d), or (iii), or a composition. comprising a denterated compound of Formula (It), (la), (lb), (1c), (id), (ia’), (ib’), (ic’), (id’), (12%"), (133"), tic"), add"), (ll), (Ha), (lib), (llc) (lid), or (ill). Routes of administration to the patient include pulmonary (inhalation), subcutaneous, oral, nasal and intravenous. in one embodiment, administration of a compound of Formula (I), (la), (Eb), (lo), (Id), (ia’), , (ic’), (id’), Ga"), Hid"), Clo"), (ld’l), (ll), (ila), (11b), (lie) (ltd), or (ill), or a pharmaceuticaliy acceptable salt thereof, is via inhalation via. an M91 or nebulizer. in one embodiment, where nd delivery is via a nebuiizer, the compound is provided to the t as a composition, for example, as a lipid nanoparticle composition, as described above. {@173} in one embodiment, the method for treating PH, PAH or FPH comprises administering to a patient in need thereof, an effective amount of the prostacyclin compound or prostacyclin composition described herein. In a thither embodiment, the compound, or a pharmaceutically acceptable salt of the compound, is administered, to the patient via a pulmonary ation), a subcutaneous, oral, nasal or an intravenous route of administration. in a. thither embodiment, stration is via inhalation and the prostacyclin compound or composition is administered with a nehulizer, dry powder inhaler, or MDl, in even a further ment the prostacyclin composition or ition comprises a prostacyciin compound of Formula (I), (la), (jib), (to), (Ed), (ia’), , ('ic’), (id’), (ia’i’), rib"), (ic’i’), (ld’l), (11), (Ha), (11h), (11c) (iid), or (ill), or a deuterated n thereof or a pharmaceuticaily acceptable salt of the compound {flfil’ii} In one embodiment, administration of an effective amount of a prostacyciin compound or composition of the present ion for the treatment of PH, FAH or PFH via inhalation, oral, nasal, subcutaneous or intravenous administration results in a decreased number of side effects, or a reduced severity of one or more side effects (also referred to herein as "adverse eventS"), compared to the stration of an effective amount of treprostinil, when an effective amount of treprostinil is administered via inhalation, oral, nasal, subcutaneous, or intravenous administration. For exan'iple, in one embodiment, a Pit, PAH or PPH t experiences a reduced severity and/or frequency in cough or a reduced cough response when administered a prostacylin compound, or composition of the invention via inhalation (rag, nehulization, dry powder inhaler, or via a metered dose inhaler), compared to the severity and/or treatiency of cough or cough response elicited by tion stration of treprostinil to the patient. {60.172} In another ment, oral, nasal, intravenous, sultcutaneous or inhalation administration of an effective amount of the prostacyclin compound or composition of the invention, compared to oral, nasal, subcutaneous, enous or inhalation administration of stinil, results in a reduced severity of one or more of the following adverse , or a decreased occurrence of one or more of the following adverse events: headache, throat irritation/pliaiyngolaryngeal pain, nausea, flushing and/or syncope. {@173} in another embodiment, oral, nasal, intravenous, subcutaneous or inhalation administration of an effective amount of the prostacyclin compound or ition of the invention, for the treatment of PH, PAH or PPH, compared to oral, nasal, subcutaneous, intravenous or inhalation stration of treprostinil, results in a d severity of a systemic adverse events, or a decreased occurrence of a systemic adverse event. {@1774} t wishing to be bound by theory, it is believed that the improved e event profile ct" the prostacylin compounds and compositions of the invention exhibited patients, as ed to treprostinil, results in improved ance of the ts. {@175} in one embodiment, the prostacyclin compounds and compositions of the t invention are administered on a less frequent hasis, as compared to currently approved. therapies for PH, PAH (cg, Tywasotih, Remodulintttl) or PPH, while still achieving a suhstantially equivalent or better therapeutic response, Routes of administration to the patient include pulmonary (inhalation), subcutaneous, oral, nasal and intravenous. The therapeutic se of the patient, in one embodiment, is a reduction in. the pulmonary vascular resistance index (PVRI) from pretreatment value, a reduction in mean pulmonary artery pressure from pretreatment value, an increase in the hypoxernia score from pretreatment value, a decrease in the oxygenation index from pretreatment values, improved right heart fimction, as compared to pretreatment or improved exercise capacity (ago, as measured by the six—minute wailr test) compared to pretreatment. The therapeutic response, in one embodiment, is an improvement of at least lG%, at least 2il%, at least 30%, at least 49% or at least 50%, as ed to pretreatment values. ln another embodiment, the therapeutic response is an improvement of about 16% to about "ISO/ii, about 10% to about 623%, about ; to about 50%, about 10% to about 49%, about "3% to about 30%, about 13% to about 20%, about 26% to about 70%, about 28% to about (it???) or about lb'il/is to about 59%, as com rared to iretreatment levels.i {09.176} Without wishing to be bound by theory, the less ffeqnent administration. oftbe compounds and compositions of the invention allows for improved patient compliance, as compared to the compliance of patients being stered a. different PH, PAH or FFH treatment tag, treprostinil ‘l‘yvasotiIRD, Remodulin-(RD). {llfil'77} in one embodiment, a composition or compound of the present invention is administered Via a metered dose inhaler (MDl) to a patient in need of PH, PAH or PPH treatment. The composition or compound, in one embodiment, is delivered via a Mill by the use of a propellant, for example, a chlorowtluorocarbon (CFC) or a carbon. in one embodiment, Where delivery is via an MDl, the nd is not formulated as a lipid, nanoparticle composition, and instead, is suspended or dissolved directly in a propellant solution. The patient, in one embodiment, is administered the prostacyclin compound or composition of the invention once daily, twice daily or three times daily. in one e ent, the administration is with food. in one embodiment, each administration comprises l to 5. doses } from an Milli, for example l dose (1 puff), 2 dose (2 , 3 doses (3 , 4 doses {4 putts) or 5 doses (5 . The MDE, in one embodiment, is small and transportable. by the patient. {@1783 In another embodiment, the cyclin compound or prostacyclin composition is administered via a nebulizer to a patient in need of PH, PAH or PPH treatment. The administration occurs in one embodiment, once daily, twice daily, three times daily or once every other day. {09179} In. one embodiment, a composition. or compound ot‘ the present invention is administered via a dry powder inhaler (DPI) to a patient in need of PH, PAH or PPH treatment. The patient, in one embodiment, is administered the prostacyclin compound or composition of the invention once daily, twice daily or three times daily. in one embodiment, the administration is with food. in one embodiment, each stration comprises 1 to 5 doses (paths) from a DPl, for example 1 dose (l pull), 2 dose (2 putts), 3 doses (3 puffs), 4 .5}. U: doses (4 puffi‘} or 5 doses (5 puffs). The BM, in one embodiment, is srnaii and transportable by the patient.
{MEWS in another embodiment, the prostaeyeiin compound, administered to a patient in need thereof Via a. pulmonary route by the PH, PAH or PAH treatment methods described herein provides a greater pulmonary elimination haitdife (ti/2‘) of the prostaeyeiin compound or its treprostinii metabolite, compared to the puimonary eiimination ife {tn/3:) of treprostinil, when tieprostinil is administered via a puimonary route (rag, by nehniiaation, dry powder inhaler, or a metered dose inhaier) to the t in need of PH, FAH or PPH treatment. {($181} In another embodiment, the prostaeyciin nd administered to a t in need thereof, via the PH, PAH or PPH treatment methods described herein provides a greater systemic half—life (tug) of the prostaeyeiin compound or its treprostinii metabolite, compared, to the systemic elimination trait—fife (tn) of treprostinii, when treprostinii is administered to the patient. in a fiirther embodiment, administration of the prostaeyeiin compound and sti nil ses orai, nasai, subcutaneous or intravenous administration, {@182} in another embodiment, the prostacyciin compound administered to a patient in need of PH, PAH or PPH treatment es a greater mean pulmonary Cum and/or lower piasma CHM of treprostinil for the patient, compared to the respective puimonary or piasrna Cum oftreprostinii, when treprostinii is administered to the patient. in a further embodiment, administration of the prostacyeiin nd and treprostinii comprises intravenous administration. {@183} in another embodiment, the eyciin compound administered to a patient in need of PH, PAH or PPH treatment provides a greater mean puimonary or piasma area under the curve (AUCM) of the prostaeyeiin compound or its trepr‘ostinit metabolite, compared to the mean pulmonary or piasma area under the curve 9"]ng of treprostinii, when treprostinii is administered to the patient. in yet another embodiment, the prostaeyciin compound administered to a t in need thereof provides a greate pulmonary or piasrna time to peak concentration (tmx) of stinii, compared to the puimonary or piasrna time to peak concentration. (tmax) of treprostinii, when treprostinii is administered to the t, {$3184} in another aspect of the ion, a method of treating a disease, disorder or condition other than PH, PAH or E’P’H is provided. US. Patent No. 5,i53,222, incorporated by nce herein in its entirety, describes use of stinii for treatment of pulmonary hypertension. ’l‘reprostinil is ed for the intravenous as well as subcutaneous route, the latter avoiding potential septic events associated with continuous intravenous catheters, US Patent Nos. 6,52l,2l2 and 6,756,033, each incorporated by re ~erence herein in their entireties, describe administration of treprostinil by inhalation for treatment of pulmonary hypertension, peripheral ar disease and other diseases and conditions. US. Patent No. 6,803,386, incorporated by reference herein in its entirety, discloses administration of treprostinil for treating cancer such lung, liver, brain, pancreatic, kidney, prostate, breast, colon and heath eck cancer. US. Patent Application Publication No. EGGS/Glofillll, incorporated by reference herein in its entirety, discloses treprostinil treatment of iseheinic lesions. U .S. Patent No. 7,199,157, incorporated by reference herein, in its entirety, discloses that treprostinil treatment improves kidney functions. US. Patent No. 7,879,909, incorporated by re "erence herein in its entirety, discloses treprostinil treatment of neuropathic foot ulcers. US. Patent Application ation No. 2G08/028G98ti, incorporated by reference herein in its ty, discloses treprostinil ent of ary fibrosis, interstitial lung e with treprostinil and asthma. US. Patent No. 6,854,486, incorporated by reference herein in its ty, discloses treatment of peripheral vascular disease with treprostinil. US patent application publication no. 20G9/(Hl36465, orated by reference herein in its entirety, discloses combination ies sing treprostinil. US, Patent Application Publication No. EMS/0200449 discloses delivery of treprostinil using a metered dose inhaler.
US Patent Nos. 7,417,070, 7,384,978 and 7,544,7l3 as well as US, Patent Application Publication Nos. 2607/0078095, 2095/0282901', and 2008/0249l67, each incorporated by reference herein in their entireties, describe oral formulations of treprostinil and other prostacyelin s as well as their use for treatment of a variety of conditions. US Patent Application Publication No. 20l27‘0094367, incorporated by reference herein, ses the use of orally administered treprostinil for ent ot‘ Raynand’s phenomenon, ic sclerosis and digital ischernic lesions. Each of the inclinations recited above can be treated with the compounds and corn positions ed herein, Routes of adntiinistfation to a patient in need of treatment include pulmonary (inhaiation), subcutaneous, oral, nasal and intravenous. {80185} Additionally, the following references are incorporated by nce in their entireties for all purposes for practicing the embodiments of the present invention: J. Org.
Chem. 2004, 69, 18904902, Drug of the Future, 299i, 26(4), 364—374, US. Patent Nos. ,l53,222, 6,854,486, 6,521,212, 6,756,633, 6,803,386, and 7,l99,157, US. Patent Application Publication Nos. 2005/0165} ll, EGGS/6282.963, 2%08/0200449, 2008/3280986, 2909/0G36465 and. 2Gl2/00l0159. {$01853 in one embodiment, a method is provided, for treating a patient in need thereof for congestive heart failure, peripheral vascular disease, asthma, severe intermittent clandication, suppression, erative es, cg, cancer such as lung, liver, brain, pancreatic, kidney, prostate, breast, colon and head—neck cancer, ischemic lesions, athic foot ulcers, and pulmonary fibrosis, kidney function and/or interstitial lung disease. In one embodiment, the method comprises administering aneffeetive amount of one of the prostaeyclin compounds or compositions provided herein, for e, a compound of Formula (I), (la), (lb), (lie), (Id), (Ia’), (lh’), (lc’), {ld’}, , (RV), (10"), Old"), (ll), (ll-a"), (llh), (llc) (lld), or (III), or a deuterated version thereof, or a composition sing a nd of Formula (I), (la), (in), (lo), {'ld), (la’), no), (le’), (ld’), (la’l), ("lb"), (lc’l’), (Ida’), (ll), (Ila), (lib), (Ilc) (lid), or {lll}, or a composition comprising a deuterated compound of Formula (I), (la), (lb), (lo), (id), (la’), (In), (Ic’), (ld’), Ga"), (RV), Go"), Gd"), (ll), (Ila), (lib), (llc) (Ild), or (Ill) to the patient. Administration, in one ment, is via inhalation (eg, with a nebnlizer or d dose inhaler), subcutaneous, oral, nasal or intravenous. in some embodiments, the pharmaceutical formulation may comprise one or more active ingredients in addition to treprostinil nionohydrate, {llllld’ll in one embodiment, a method is provided tor treating and/or ting interstitial lung e (gag, pulmonary fibrosis) or asthma, or a condition associated with interstitial lung disease or asthma. in a patient in need of such treatment. in a further embodiment, the method ses administering to the patient an effective amount of one of the prostacyclin compounds or itions provided herein, for example, a compound of Formula (I), (la), (lb), (3c), (Id), (la), (in), ('lc’), {id}, Ga"), (Ib"), (Ic’i’), (ld’i’), (ll), (ll-a), (llh), (llc) (lid), or (III), or a deuterated version thereof, or a composition comprising a compound of Formula (I), (la), (to), (lo), (Id), Ga"), (133’), (Id), (ld’), Ga"), ab"), tile"), Gd"), (ll), (Ila), (lib), (IIc) (lid), or (Ill), or a composition comprising a denterated compound of Formula (I), (la), (In), (to), (id), (la’), {In}, (lc’), (ld’), Ga"), fin"), Clo"), Gd"), (ll), (Ila), (lIb), (llc) (lId), or (III). ’l'he composition or compound, in one embodiment, is delivered via a MDI by the use of a propellant, for example, a chloron fluorocarbon (CFC) or a fluorocarbon, The patient, in one ment, is administered the prostacyclin compound or composition of the invention once daily, twice daily or three times daily. in one embodiment, the administration is with food. in one embodiment, each administration ses i to 5 doses (puffs) from an MDi, for e i dose (l puff}, 2 dose (2 putts), 3 doses (3 puffs), 4 doses (4 puffs) or 5 doses (5 pulls). The l‘viiitl, in one embodiment, is small and transportable liy the patient. in another embodiment, administration is oral, nasal, subcutaneous or intravenous. in another embodiment, oral, nasal, enous, subcutaneous or inhalation administration of the effective amount of the prostaejyrclin compound or ition of the invention, for the treatment of interstitial lung disease (e.g., pulmonary fibrosis) or asthma, or a condition associated with interstitial lung disease or asthma, compared to oral, nasal, subcutaneous, intravenous or tion administration of treprostinil, results in a d severity ot‘ a systemic adverse events, or a. decreased occurrence of a systemic adverse event.
{MISS} in one embodiment, a method for ng an ischemic disease or condition, such as scleroderma, including ic sclerosis, or Raynaud’s Phenomenon in a patient in need of such treatment is provided. in a further embodiment, the method comprises stering an effective amount of one of the prostacyciin compounds or compositions provided herein, for example, a compound of Formula (i), (la), (lb), (ic), (id), (la’), (lb’), (lc’), (id’), Ga"), (ib"), ac"), Gd"), (ii), (iia), (lib), (iic) (lid), or (iii), or a deutera‘ted version thereof, or a composition comprising a compound of a (i), (la), (ib), (to), (id), (ia’), (ib’), (lc’), (id’), (ia"), (ib"), Ge"), Gd"), (ll), (Ha), (lib), (lie) (lid), or (ill), or a composition comprising a deuterated compound of Formula (1), (la), (Eb), (ic), (id), (:ia’), (lb’), (id), (id’), fiat"), (ib"), (ic"), Gd"), (ll), (ila), (lib), (ilc) (lid), or (iii), to the patient.
Administration, in one embodiment, is via inhalation (egg with a nebulizer or d dose inhaler), oral, nasal subcutaneous or intravenous administration. in another embodiment, oral, nasal, intravenous, subcutaneous or inhalation adn'iinisti‘ation of an et‘tective amount of the prostacyclin compound or composition of the invention, for the treatment of ischemie disease or conditimi, such as scleroderma, including systemic sclerosis, or Raynaud’s Phenomenon, compared to oral, nasal, subcutaneous, intravenous or inhalation administration of treprostinii, results in a d severity ot~ a systemic e events, or a sed occurrence of a systemic adverse event. {flfi189} The prostacyclin compounds or compositions provided herein, for example, a compound of Formula (1), (la), (iii), (lo), (Id), (ia’), {ib’}, (ic’), (id’), Ga"), (ib"), tie"), (ld’l’), (ii), (iia), (iih), (lie) (lid), or (ill), or a ated n thereof, or a composition comprising a compound of Formula (i), (la), (lb), tie), (id), (ia’), (ib’), (ic’), (id’), Ga"), (illi’l), tic"), (ld’l), (ii), (iia'), (lib), (lie) (lid), or (iii), or a composition comprising a deuterated compound of Formula (l), (la), (lb), (file), (id), (lat), (lhl), (lc’i), (ld’), Ga"), filo"), tic"), Gd"), (ll), (Ha), (lib), (llc) (lid), or (ill), in one embodiment, are used for treating, a patient for a digital ischemic lesion, such as a l ulcer or a necrotic lesion, or for ameliorating a syn'ipton'i or lunctional deficit and/or ng the number of symptoms and/or functional deficit(s} associated with a digital iscliemic lesion. The term "digital isehemic lesion" refers to a. lesion on a digit, z‘..,e a toe or a finger, of a suhiect, such as a human being. in one embodiment, the digital. ischemic lesion may be caused lay or associated with an ic e or condition, such as seleroderma, including systemic sclerosis, or d’s enon. The symptom that may be ameliorated and/or reduced may be, for example, a pain ated with a digital ischemic ulcer and/or scleroderma. in some embodiments, administering a prostacyelin compound or composition provided herein, upon administration to a patient in need of treatment, provides amelioration or reduction of one or more functional deficits associated with a digital ischemic lesion. For example, in one ment, the prostacyclin nd or composition provided herein ameliorates or reduces a hand function deficit, 116., provides an improvement in the hand function of the treated patient. stration, in one embodiment, is Via inhalation (eg, with a nehulizer or metered dose inhaler), oral, nasal, subcutaneous or intravenous administration. in r embodiment, oral, nasal ii'itravenous, subcutaneous or inhalation administration of an effective amount of the prostacyclin compound or composition of the invention, for the treatment of digital isehemie lesions, compared to oral, nasal, subcutaneous, intravenous or inhalation administration of treprostinil, results in a reduced severity of a systemic adverse events, or a decreased occurrence of a systemic adverse event. {llllllllll in one embodiment, a method for improving kidney fimction or treating symptoms associated with kidney malfunction or failure in a patient in need thereof is provided. in a. further embodiment, the method. comprises administering to a subject in need thereof an ive amount of a prostacyclin compound, or composition provided herein, for example, a. compound of a (1), (la), (lb), (in), (Ed), (la‘), (lh’), tie"), (id), Ga"), filo"), tile"), (ld’l), (ll), (Ila), (llh), (llc) (lld), or (Ill), or a deuterated version thereof, or a ition comprising a compound of Formula {1), (la), (lb), (lo), (ld), (la’), (lh’), (lc’), (Id), (121"), (1‘0"), ac"), Gd"), (ll), (lla), (lib), (lie) (lid), or (ill), or a composition comprising a deuterated nd of a (l), (la), (lb), (lo), (id), (l’a’), (lb‘), (le’), (ld‘), (la-1"), , Ge"), Gd"), (ll), (lla), (lib), (llc) (lid), or (ill), to the patient. Specific symptoms associated with reduced kidney functions include, for example, abnormally low urination, increased blood levels of creatinine and urea nitrogen, protein leakage in urine and/or pain. Administration, in one embodiment, is via. inhalation (rag, with a nebnlizer or metered dose inhaler), oral, nasal, subcutaneous or enous administration. in r embodiment, oral, nasal, intravenous, subcutaneous or inhalation adn'iinistration of an effective amount of the prostacyclin compound or composition of the invention, for improvement of kidney functions or amelioration of symptoms associated with kidney malfunction or failure, compared to oral, nasal, intravenous, subcutaneous or inhalation administration oftreprostinil, results in a reduced severity of a ic adverse events, or a sed ence of a systemic adverse event, {(36191} in one embodiment, a method of treating a cardiovascular e ing congestive heart failure comprises is provided. The method, in one embodiment, comprises administering to a patient in need thereof, a prostacyelin compound or composition provided herein, for example, a compound of Formula (i), (la), (lb), (lc), (l ), (la’), (lh’), (lei), (idl), (ii-t"), (lb"), tic"), Gd"), (ll), (Ila), (lib), (lie) (lid), or (ill), or a deuterated version thereof, or a composition sing a compound of Formula (i), (la), (lb), (lc), (id), (la’), (lh’), (id), (id’), (la"), (lh’l), tic"), Gd"), (ll), (Ila), (lib), (lie) (lid), or (ill), or a composition comprising, a deuterated compound of Formula (5), (la), (lh), (lo), (id), (Ea’), (lb’), (lc’), (ld’), Ga"), lib"), (lcl’), Cid"), (ll), (Ha), (lib), (lie) (lid), or (ill). Administration, in one embodiment, is via inhalation tag, with a nehulizer or metered dose inhaler), subcutaneous, oral, nasal or intravenous administration. {llllllfll in one embodiment, a method for treating a peripheral vascular e, including> peripheral arterial occlusive disease and, intermittent ciaudieation is ed. in one embodiment, the method comprises administering to a. t in need thereof a cyclin compound or composition provided herein, for example, a compound, of Formula (I), (la), (lb), (lo), (Id), (la’), (lb’), (lc’), {ld’}, Ga"), (lb"), Ge"), Gd"), (ll), (lla), (Illa), (llc) (lld), or (Ill), or a deuterated version thereof, or a composition comprising a nd of Formula (1), (la), (lb), (lo), (id), (la’), (lbl), {lc’), (id), (121"), (lb"), (lc’l), (ld7’), (ll), (lla), (lib), (lie) (lld), or (ill), or a composition sing a denterated compound of Formula (1), (la), (lb), (lc), (id), (33,), {lb’}, (lc’), (ld’), Ga"), (15"), tic"), (ld"), (ll), (Ila), (11h), (llc) (lid), or (Ill), in addition to the prostacyclin compounds and compositions provided herein, other phannacologieaily active substances may be present in the formulations of the t invention which are known to be useful for treating eral vascular disease. For example, the compounds of the invention may be present in combination with trental, a substance known to increase red blood cell deformability. stration, in one embodiment, is via inhalation (eg, with a nebulizer or metered dose inhaler), subcutaneous, oral, nasal or enous administration. {@193} in one embodiment, a method for treating and/or preventing neuropathic diabetic foot ulcer is provided. in one embodiment, the method comprises administering to a patient in need thereof, a cyclin compound or composition provided herein, for example, a compound of a (i), (Ea), (lb), (Sc), (id), {ia’}, (ib’), (lc’), (id’), Ga"), Gib"), (Ic"), (Id’"), (11), (Ha), (lib), tile) (lid), or (iii), or a deuterated version thereof, or a composition comprising a compound of Formula (1), (la), (1b), (In), (Id), (ia’), (lb) (1c"), (ld’), tile"), , (10"), Gd"), (ll), (Ha), (lib), (tic) (Sid), or (ill), or a composition comprising a deuterated compound of Formula (1), (la), (its), (1c), (id), (121’), (lb’), (ic’), tld’), Ga"), (1%)"), (10"), Cid"), (it), (Ha), (lib), (tic) (iid), or (ill). Administration, in one embodiment, is via inhalation (eg, with a nebulizer or metered dose r), subcutaneous, oral, nasal or intravenous administration. in addition to the prostacyclin nds and compositions ed herein, other pharmacologically active Substances may be present in the torinulations of the present invention which are known to be usetui for treating and/or preventing foot ulcers in patients with diabetic neuropatliy. For example, the compounds of the invention may be present in combination with analgesics to treat pain, dressing changes, vasodilator medications, and topical or oral antibiotics. {tittfid} in one embodiment, administration of an effective amount of a prostacyclin nd or composition of the t invention for the treatment of the various diseases and indications described throughout, by inhalation, subcutaneous, oral, nasal or intravenous administration, results in a decreased number of side effects, or a d severity of one or more side effects (also referred to herein as "adverse "), compared to the administration of an effective amount of treprostinil, when an effective amount of treprostinil is administered by inhalation, subcutaneous, oral, nasal or intravenous adntiinistfation. For example, in one embodiment, a patient treated by the methods provided herein experiences a reduced severity and/or trequency in cough or a reduced cough response wheiti administered a prostaeylin compound or ition of the invention via inhalation {ego nehulization, dry powder inhaler, or via a metered dose inhaler), compared to the severity and/or frequency of cough or cough se ed by inhalation administration of treprostinil to the patient. titltiiiififi in another embodiment, the prostacyelin compound administered to a patient in need of treatment provides a greater mean pulmonary Cmax and/or lower plasma Cm,u of stinil for the patient, compared to the respective pulmonary or plasma Cmax of treprostinii, when treprostinii is administered to the patient. in a furthe embodiment, administration of the prostacyclin compound and treprostinil comprises intravenous admini stration. {@196} in r embodiment, the prostacyclin compound administered to a patient in need of ent provides a r mean puimonary or plasma area under the curve (AUCm) of the prostacyelin compound or its treprostinii metabolite, compared to the ntiean pulmonary or plasma area under the curve {AUCGHET} of treprostinih when treprostinil is administered to the patient. in yet another embodiment the cyciin compound administered to a patient in need thereof provides a greater pulmonary or plasma time to peak concentration (tmax) of treprostinil, compared to the pulmonary or plasma time to peak concentration (tm‘n) of treprostinii, when treprostinil is administered to the patient. litltllg'i’i in one embodiment, a prostacyclin compound or composition provided herein, for example, a. compound of Formula {1), (la), (lb), (lo), (id), (ia’), (ib’), Ge"), (id’), Ga"), tilt"), tic"), flirt"), (ll), (Ha), filth), (tic) (lid), or (ill), or a deuterated version thereof, or a composition comprising a compound of Formula. (i), (la), (lb), tic)? (id), (ia’), (ih’), (ic’), (ld’), Ga"), flit"), tic"), Gd"), (ill), (lla), (lib), (lie) (lid), or (ill), or a deuterated version thereof, is administered in comhination with one or more additional active agents. in some embodiments, such one or more additional active agents can be also administered together with a prostacyclin compound or composition provided herein using a metered dose r. in one embodiment, such one or more additional active agents can he administered tely, 226., prior to, or subsequent to, the prostacyclin compound, or ition provided. herein. ular additional active agents that can be administered in combination with treprostinil may depend. on a particular disease or condition for treatment or prevention of which treprostinil is administer d in some cases, the additional active agent can he a cardiovascular agent. such as a cox~2 inhibitor, a rho idnase inhibitor, a calcium. l blocker, a phosphodiesterase inhibitor, an endotheiiai antagonist, or an antiplatelet agent.
} As provided above the prostacyciin nds and compositions of the present invention can. he delivered to a patient in need thereot’via an oral, nasal, pulmonary, enous or subcutaneous route. With respect to the pulmonary route, the prostacyciin compounds and compositions) of the present invention may he used in any dosage sing device adapted for such administration. The device, in one embodiment, is constructed to ain optimum metering accuracy and compatibility of its constructive elements, such as U: [N container, valve and actuator with the formulation and could be based on a mechanical pump system, eg, that of a metered—dose nehulizer, dry powder inhaler, solt mist inhaler, or a nehulizer. For example, pulmonary delivery devices include a jet nebulizer, electronic nehulizer, a. soft rni st inhaler, and a capsule—based dry powder inhaler. illllllllll Suitable propellants, 623;, for MDl delivery, may be selected among such gases as fluorocarbons, chlorotluorocarhons (CFCs), hydrocarbons, uoroalltane propellants (43.53., l€lIFA—134a and EPA—227), en and dinitrogen oxide or mixtures thereof. {90200} The inhalation delivery device can he a nehulizer, dry powder inhaler, or a metered dose inhaler (Mill), or any other suitable inhalation delivery device known to one of ry skill in the art. The device can contain and he used to deliver a single dose of the cyclin composition or the device can contain and he used to deliver ~doses of the composition of the present invention. lilllllllll A nebulizer type inhalation delivery device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension, For example, the prostaeyclin compound or composition can be suspended in saline and loaded into the inhalation delivery device. In generating the nehulized spray of the compositions for inhalation, the nehulizer delivery device may be driven ultrasonically, by compressed air, by other gases, electronically or mechanically (cg, vibrating mesh or aperture plate). r Vibrating mesh zers generate tine particle, low velocity l, and nelnilize eutic solutions and suspensions at a faster rate than con rentional jet or ultrasonic nebulizers. ingly, the duration of treatment can be shortened with a Vibrating rnesh ze ", as compared to a jet or ultrasonic zer. Vihrating rnesh nehulizers amenahle for use with the methods described herein include tl' e Philips Respironics l—Neh®, the Grnron MicroAir, the Nektar Aeronehifi), and the Pari eFlow® } The nebulizer may be portable and hand held in design, and may be equipped with a self contained electrical unit. The nehulizer device may comprise a nozzle that has two coincident outlet channels of defined aperture size through which the liquid formulation can be accelerated, This results in impaction ot‘ the two s and atomization of the formulation. The neh‘ulizer may use a mechanical actuator to force the liquid formulation through a. inultiorifice nozzle of d aperture sizets} to produce an aerosol of the ation for inhalation. in the design of single dose nebulizers, blister pachs containing single doses of the formulation maybe employed. lillllfilliii in the present. ion the nebulizer may be employed to ensure the sizing of particles is optimal for positioning of the particle within, for example, the pulmonary membrane. lilithld} Upon nebulization, the nebulized composition (also referred to as "aerosolized composition") is in the form of aerosolized particles. The aerosolized composition can be characterized by the le size of the aerosol, for example, by measuring the "mass median aerodynamic diameter" or "fine particle fraction" associated with the aerosolized composition. "Mass median aerodynamic diameter" or "MM AD" is ized ing the aerodynamic tion of aqua aerosol droplets and is determined by impactor measurementsa 63;, the Anderson Cascade lmpactor (AC1) or the Next Generation impaetor (NGI). The gas flow rate, in one embodiment, is 28 Liter per minute tier the ACl and l5 liter per minute for the NGl. {$3285} "Geometric standard deviation" or "(l-SD" is a measure of the spread of an aerodynamic particle size distribution. Low GSDs characterize a narrow droplet size distribution (_homogeneously sized. droplets), which is advantageous for targeting aerosol to the respiratory system. The average droplet size of the nebulized composition provided herein, in one embodiment is less than 5 nm or about l um to about 5 um, and has a GSD in a range of l .0 to 2.2, or about H) to about. 2.2, or l5 to 2.2, or about 1.5 to about 2.2. {some} "Fine particle fraction" or "FPF," as used herein, refers to the on of the aerosol having a particle size less than 5 um in diameter, as measured by cascade impaction.
FPS?" is usually expressed as a percentage. {thigh}?! In one embodiment, the mass median aerodynamic er (Mb/EASE: of the nebulized. composition is about 1. am to about 5 pm, or about l. um to about 4 am, or about l. um to about 3 pm or about l um to about 2 um, as measured by the Anderson Cascade lrnpactor (AC1) or Next Generation lmpaetor (N61). in another embodiment, the MMAD of the ne'bulized composition is about 5 um or less, about 4 urn or less, about 3 urn or less, about 32 um or less, or about 1 pm or less, as measured by cascade impaction, for example, by the ACI or NGl. {@298} hi one ment, the M MAE) of the aerosol of the ceutical composition is less than about 4.9 urn, less than about 4.5 urn, less than about 4.3 umF less than about 4.2 U: U: um, less than about 4.1 pm, less than about 4.0 pm or less than about 3.5 um, as measured by cascade impaction. {002093 in one embodiment, the MMAD of the aerosol of the pharmaceutical ition is about 1.0 pm to about 5.0 um, about 2.0 pm to about 4.5 um, about 2.5 pm to about 4.0 pm, about 3.0 pm to about 4.0 pm or about 3.5 not to about 4.5 pm, as measured by cascade impaction (6.32, by the ACI or NGI). {00210} In one embodiment, the EFF of the aerosoiized composition is greater than or equal to about 50%, as measured by the AC1 or NGE, greater than or etpial to about 60%, as measured by the AC1 or 'NGl or greater than or equal to about 70%, as measured by the ACE or NGI. in. another embodiment, the FPF of the aerosolized composition is about 50% to about 809/6, or about 50% to about 70% or about 50% to about 60%, as ed by the NGI or AC1.
{MERE in one embodiment, a metered dose inhalator (Milli) is employed as the inhalation delivery device for the compositions of the present invention. in a further embodiment, the prostacyclin compound is suspended in a propellant tag" hydroflourocarbon) prior to loading into the Mild. The basic structure of the MDI comprises a metering valve, an actuator and a container. A propellant is used to rge the formulation from the device. The composition may consist of particles of a defined size suspended in the pressurized propellantts) liquid, or the composition can be in a solution or suspension of pressurized liquid propellant(s). 'l‘he propellants used are primarily atmospheric ly hydroflourocarbons (HFCS) such as l31-‘i-a and 227. The device of the inhalation system may r a single dose via, eg a r pack, or it may be nlulti dose in . The rized metered dose inhalator of the inhalation system can be breath actuated to deliver an accurate dose of the lipid—containing formulation. To insure accuracy of dosing, the delivery of the ation may be programmed via a microprocessor to occur at a certain point in the inhalation cycle. The MD} may be portable and hand held. {002.12} in one embodiment, a dry powder inhaler {D131} is employed as the inhalation delivery device for the compositions of the present invention. in one embodiment, the Bid generates particles having an MMAD of from about 1 urn to about ll) pm, or about 1, um to about 9 pm, or about 1 urn to about 8 um, or about 1 urn to about 7 um, or about l urn to about 6 pm, or about 1 gun to about 5 urn, or about 1 um to about 4 pm. or about l um to about 3 urn, or about l urn to about '2 pm in er, as measured by the M31 or AC1. in another embodiment, the DPI tes a particles having an MMAD of from about l not to about ll} urn, or about 2 urn to about ll) um, or about 3 urn to about ll) um, or about 4 not to about ll) out. or about 5 urn to about ll) um, or about 6 urn to about ll) urn, or about 7 not to about l0 urn, or about 8 urn to about ll) um, or about 9 urn to about ll) urn, as measured by the NGE or ACE. {@213} In one embodiment. the MMAD of the particles generated by the DPl is about 1 urn or less, about 9 um or less, about 8. um or less. about 7 um or less, e um or less, 5 urn or less, about 4 out or less. about 3 am or less, about 2 urn or less, or about l are or less, as measured by the NGI or AC1. {($214} ln one embodiment. the MMAD of the les generated by the DH is less than about 9.9 urn, less than about 9.5 urn, less than about 9.3 urn, less than about 9.2 urn. less than about 9.l urn, less than about 9.0 um, less than about 8.5 urn, less than about 8.3 urn, less than about 8.2 urn, less than about 8.,l um, less than about 8.0 urn, less than about 7.5 um, less than about 7.3 urn, less than about 7.2 urn, less than about "Ll urn. less than about 7.0 urn, less than about 6.5 urn, less than about 6.3 um, less than about 6.2 urn, less than about 6.1 urn, less than about 6.0 urn, less than about 5.5 urn, less than about 5.3 urn, less than about 5.2 urn, less than about 5.l not, less than about 5.0 urn, less than about 4.5 urn, less than about 4.3 urn, less than about 4.2 urn, less than about All um, less than about 4.0 um or less than about 3.5 urn, as ed by the NGl or ACl. llEllZlil} in one embodiment. the MMAD of the particles generated by the Dl’l is about ll) urn to about lull um. about 2.0 our to about 9.5 am, about 2.5 urn to about 9.0 urn, about 3.0 urn to about 9.6 urn, about 3.5 um to about 8.5 um or about 4.0 urn to about 8.0 urn. tilltllloi In one embodiment, the Fl’l" of the prostaeyclin particulate composition generated. by the DPI is greater than or equal to about 48%, as measured by the ACI or NGI, greater than or equal. to about 5094;, as measured by the ACE or NEE-l, greater than or equal to about 60%, as measured by the ACl or NGIE, or greater than or equal to about 79%, as measured by the ACE or NGl iln. another embodiment, the FF}? ol’ the aerosollzecl composition is about 49% to about 70%, or about 5 % to about 7 % or about 40% to about 60%, as measured, by the N'Gl or AC}.
EXAMPIES l7} The present invention is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments deseribed above, are illustrative and are not to be construed as restricting the scope of the invention in any way.
Exam in l _ S ‘nthesis of tire rostinil alk ‘l esters {Mimi 'l‘reprostinil compounds derivatized with alkyl groups at the car‘hoxylic acid moiety were ed. Specifically, treprostinil was t erivatized at the carboxylic acid, moiety with Cg, C3, C4, {35, C5, Cg, Cw, Cu, (315., and (fig alleyl chains (lie, R2 in Formula (A), below, is C2, C3, C4, C5, C5, C3, C39, C17,, Cu, or Cig alliyl) to make treprostinil alliyl esters of s ester chain s. 'l'reprostinil can be synthesized, for example, lay the methods disclosed in US. Patent Nos. 6,765,l l7 and 8,497,393. Synthesis of prostaglandin derivatives is described in US. Patent No. 4,668,814. The disclosures of US Patent Nos. 6,765,117; 8,497,393 and 4,668,814 are each incorporated by reference in their entireties for all purposes.
R2\OJK/o i OH HO Formula (A) {@219} Scheme 1: illllZlel Treprostinil esterification was catalyzed by strongly acidic resin Amberlyst® l5 (Rohrn and Haas). ’l‘i‘epi‘ostinil acid was dissolved in anhydrous ex’alcohol at a concentration l0 mg/rnL (typically 4 mL). Alcohol (Rx—OH} added was appropriate to make corresponding chain. length at the R2 group. By way of e, for the (32 (ethyl ester} nd, the alcohol was ethanol. The molar amount of alcohol in the solvent was ten times the molar amount oftrepros'tinil, {(313221} Treprostinil in dioxanefalcohol solution was added to washed and dry Aniberlyst resin. Per each 40 mg treprostinil, l g resin in a glass Vial was added. The mixture was placed on a shaker and incubated ovemigltt at 40 "’13. Next, the liquid portion was taken out of the vial, washed twice with 3 tnL e. All recovered solvent was then collected.
The solvent was dried by nitrogen stream until the evaporation stopped, The remaining treprostinil alkyl ester and nonvolatile alcohol (if long chain alcohol used) was dissolved in 2 mL hexane/ethyl acetate lzl, and cleaned by liquid—liquid tien vs equal volume of phosphate batten and Ellen water. Next, the erganie layer was separated and, dried, by eii stream and further in vacuum. If a long chain alcehol used, an additional puritieatien step was required to te l by liquid elu‘on'iategraphy. ACE CN 5 am, Ultra-inert HPLC Column, lllllx2l «2 mm was used, with mobile phase of hexane/propanel 983%. {09222} Scheme 2: {9622M To a solution of (l R2R,3aS,9aS)-{E2,3,3aft,9,9a~ltexahydre—2—hy‘droxy-l- [(3S)—3—hydroxyoctyll—lH~benzlf§inden~5-yl}oxy}aeetic acid {treprostinil} {78.1 mg, 200 umeles') dissolved in l,4—dioxarle (2.0 ml...) was added Amberlyst® l5 resin. (2.0 g) and aleehol Rg—OH (2.0 mmoles, 10 equivalents). 'l‘lie reaction mixture was heated ta 4% °C and d, to shake at appreximately 100 rpm for "38496 heurs, Solvent was d and the resin was washed with acetonitrile (MeCN) (3 x 3 ml). The 1,4—dioxane and MeifilN extracts were eembiiied and dried using a gentle stream of warmed N2 gas and gentle lieat tu yield a thick waxy solid. The crude material was dissolved in 20% "Prifi-l/l-lexanes and submitted to preparatory HPLC purification. Solvent was removed Eleni the purified material using a gentle stream of warn'ied N2 gas and gentle lieat te yield an off—white waxy solid, The pure material was suspended in ethyl lactate for storage and was submitted t0 ical HPLC fer concentration detern'iinatien, {@224} By way of example, the follewing eempounds of Formula (A) were synthesized by the method of scheme 2.
R2 greup Cempeuad = abhreviatien R2 gmup Campmmd abhreviatim -------------- ‘ y 5mm R2 (50;) \/\/\/%‘L(€29) 2:35.}?--------------------------------------------4C, "a (S)—2C9~'I'R E R":MA ((Sly-ch) : \/\/\/\/""’ ('R3—2C941‘R R («Tm-26:9) Ci‘JTR k \/\/\/\/R"((38) "a (Eng—7m R NVY ((8)2ng E}"""""""" /\/\/\/mmflfgm R1 ((111)—2ng 6:IVER R2,W(( <) (4—3 R R2: W11 (C1) R) M ((1) R1 \/'711' (03 CrTR {09225} A general diagram for sis 01" the cthyi ester of trcpmstinfl is shown in Scheme 1, beiow. The aimhol can be modified "based on the desired aikyi ester chain, length (ag Cs—Cm alkyl esters of seven or Odd. chain length, straight chain 01' branched).
+ Ho—R2 81311-31116 1: Esterification Mechanism for aikyi ester-"17RConwmmds Exam 1:: 2 30111211130113 and esterase-mediated 1911113 of 11311113111111 .2111: '1 931613 {119226} Spontaneous and/"01* estcmse—mcdiatcd hydmlysis was measured. far the pmstacyciin alkyl ester compesitiems provided in Tabia 2. (ix 1111111321163 the aikyi chain 11 at position R2 011116 00111130112116 ofFormula (A)e ed above» T211119 2. Campsnents (1f pmstacyciin allay! ester mmpasitians iiyémphishi Hydroyhehi PEGyizate Campfisii‘i a: PEGJipid 301% c d (m Adfiiéive "101% n101‘5/ép Additive lipid mom/o Squalanc C110i~ Squalane 1311.821: C1101" T507 C6-TR Squeda P138211 0~ C1101- 1R 8111121121116 P1331 31111111110 .
Squalzme Cwe C1101- TRSquaIa11<.PEG-21< C1101- T623 1R nc P1X‘J‘K C ($11017 1Y3)3 8R— "11111 1.11110 PEG'ZR 4-0 40 1 Q 0 {tillZZ’i’} Additionally, spontaneous hydrolysis was measured for 200 old of treprostinil compounds derivatized at the carhoxylic acid. group with, either a C3, C4, C5, C5, C8 or Cm alkyl group in 26% ethanol at 40 DC at six time points (0 hr, 1 hr, 2 hr, 4 illi, 6 hr, 24 hr). {@228} Each sample was prepared as a 290 uM solution in 26% ethanol. At each time point, an aliquot was removed for lime-C analysis to resolve remaining reactants (Cg, C4, C5, Cg, Cg, Cw) or their ation product (treprostinil). tier each , hydrolysis was calculated from the measured. reactant and product peak areas: % hydrolysis (product peak (reactant peak area product peak area)*‘ ltlll}.
WGZZQE The results ot‘ the time course experiment are provided at Figure lA. The results indicate that hydrolysis rate is correlated with the length of the allryl ester moiety, {@239} se ed hydrolysis of treprostinil compounds and itions was measured for compounds derivatized at the ylic acid group with C2, C4, C6, Cs and C10 all The results of this study are provided below in Table 2A and Figure 37. Specifically, Figure 37 left, shows that conversion to treprostinil depends on aikyi chain length. in this experimenh treprostinil alkyl esters were incubated for 4 hours at a final concentration tit/300 nM in l mL of tissue homogenate prepared in water and nonnaiiaed to it) mg/rnL of protein. {(313233} Figure 37 right, shows conversion of {Egg-TR to treprostinil ntage) in the presence of rat, dog or monkey lung tissue homogenate. CHER was incubated for 4 hours at a final concentration ot‘ 200 anl in 1 ml, of tissue homogenate prepared in water and normalized to l() mg/mL of protein. Both Figure 37 experiments (left and right graphs) were performed in duplicate and the lines represent nonlinear exponential regression assuming 1 phase decay.
Table 2A,. Rate et‘treprostini} allay} ester conversion in the presence efrai, deg or monkey lung tissue heinogenate.
Rate of trepmstinii . alkyl ester conversion E (anL/h * g of pretein) Menkey Exam ie 3 m Particle size ehameterizatien 0f tre reefinii eem mittens {93234} The eonqfirositiens in Table 3 were Subject to le size eharaetei‘ization.. Cx indicates the alkyl chain length at en R2 0f Ferniuia (A), previded above.
Tame 3. Cmnpesfitiens subject to partiele size characterization PEGyiate (3‘0me firm Pugh" mm: Hydeepheb ogeobic ' Gym n ".3, .‘i. moi% Addmf'e 1mm mol% a Additive input} E moi?» ; E ' mei‘Z/o g Che‘i- T554132 Cz—TR PEGZk 10 T499 (C3) CTTR S e PEGZk O C‘hai— T500 (C4) (gm 13mm; 0 'TSGHCi) (ii—TR n T601636) C6--TR. m Cho‘i- T555 '08) Cg—TR PEG21< 10 "$690) ..L.C.::.q:T-.1$......................................$92.33...................i ...........................L9............i ‘ ‘ Choi— ‘ 1508((313) (Em—TR S ualane E’Et'flk 10 .............§.‘.19.§.3.§I}E...... 11337me CWTR S ualane PEGZ 1t) {tBfiZSS} All particle Size measurements were perfem‘zed using a Wyatt 'fE‘echneieg-y MebiusTM Zeta Potential/ Particle Sizing Instrument in Quasi~eie5tie light scattering (QELS) mede. Cempesitien aliquots were diluted d in preufiitered (0.02 Bum pore fitter) nin‘epure of deionized H20. Light scattering data was eeiiected and. convened inte particle size and size distribution using Dynamics® v. 7.2.4 instrument software. Reported average particle size diameter is hased on the cumulants model, which mathematically tits particle diffusion constants mined lay the raw scattering intensities of particles in a suspension} to obtain the particle size mean and a distribution of particle sizes around the mean diameter. {@236} it was found that the particle size (average particle diameter) of treprostinil compositions increases in size in compositions comprising C2—C5 alltyl, ester derivatized treprostinil, and decreases in size in compositions comprising (la—Cu alkyl ester derivatized treprostinil. 'l‘liese results are provided in Figure 2. The largest average particle diameter was found for itions comprising treprostinil pentyl ester (ties, stinil derivatized with a (:35 alkyl ester) (:le6 run). Compositions sing stinil ethyl ester had an average le diameter of All nm. It should he recognized that through manipulation of processing parameters the same compositions could he produced with different mean diameters and size butions. Manipulations of composition in ation with manipulation of processing parameters could also he performed to produce particles of various sizes. {@237} Under the conditions utilized here it was also found that longer chain ti'red treprostinil compounds tormed more uniforn'i particles than compounds having shorter alkyl ester . Particle uniformity was determined using the software—calculated polydispersity ("AFDl Polydispersity is defined as the standard deviation of the particle size distribution from the mean particle size value. %l’D normalizes the polydispersity to the mean diameter by dividing by the mean size and multiplying by lilil. These parameters indicate whether a particle suspension has one or more size populations of particles {monomodal versus multimodal). it also gives insight into the width of particle size distribution (or degree particle uniformity) around the mean for the respective particle populations. {09238} ich polydispersity parameter represents a monodisperse population of les if 9-65.31) \ l5. A calculated %l’l) 2‘: 57% represents a pt‘ilydisperse population of les. For instanceSe the %PD data plotted in Figure 2 yields information about the uniformity of particle size populations trorn the treprostinil, compounds . {lg-TR =treprostinil), (Sm—TR, Gig—TR, and CHER alkyl esters yielded near nionodisperse particles with %PD at or around l5. CTTR, C6~TR, , and C13~TR all-ryl esters yielded particles that have 9/:53l’D slightly above the l5, suggesting that there is one population of particles. l-lowever. these particles possessed a wider distribution of particles sizes around the mean particle size when compared to Cgu’l'R, C1(;~'l'l'{, 'R, and C1 4—TR. Cg—TR, C4— TR, and, Cg—TR shewed much greater than 15 %PD and some > 5 . These values indicate that there are multiple populations of particles that possess wide particle size distributinns.
Esamle 4 Measurement of evelic adennsine manohos gt hate ‘cAMP’ levels in CHE}— K‘l, cells in res cnse to ire rcstinil com ositions {llll239} A cell based Chinese hamster Kl (Cl-lil-Kl) assay based on the GlcSenschM cAMP assay (Promega) was used to characterize the effect of treprostinil alltyl ester compounds on cAfMP levels. {9624" cAQMP is a second messenger involved in signal transduction of G~protein coupled ors (GPCRS) acting through Ga~s and Goal proteins. Because the stinil or is a GPCR, the assay provides an tion of whether the respective prostacyclin compound (or metabolite thereol) binds its receptor and activates the GPCR cell signaling cascade, Willa/ill The GloSensorTM assay harnesses a genetically modified term of firefly lucii‘erasc into which a cAMP—binding protein moiety has been inserted. Upon binding of CA MP, a conformational change is induced leading to increased light eutput. {llllzclfil The EPZ pi‘ostahoid receptor was cc—transl‘ected with the GlcSensorTM d, (Promega) into CEO—Kl cells as fellows. CHO—Kl cells were harvested when the tnoncloayer was at 5049094; confluence. First, cells were washed with 5 nil. PBS" ’l‘wo mL of pre~warmed (37 CC) 0.95% n—EDTA (Life Technologies, Cat "ll: 253G0054) was added, and cells were dislodged by tapping the flash on the side. Next, it) rnL of antibiotic free growth media (Life Tech: Cat #: 31765092) containing 19% fetal bovine serum (PBS; Hyclone, Cat #: l7l .03) was added, and cells were centrii‘hged at 250 x g for 5 minutes at room temperature. The media was aspirated, and the cell pellet was resuspended in ll) mL of growth media. Cell number was determined using a hemacytorneter, Each well of a culture d 96 well. flat hottom plate (:Ccstar, Cat #: 3917:) was seeded. with l X 104 cells per 100 nL antibiotic-free growth media. The cells were ted overnight at 37 DC and % CO; in a water-jacketed incubator.
} Per small scale transfections of up to 20 wellsa the pGLcSensor—ZZF cAMP plasmid (Promega, Cat #: E23fil) (2 pg): {EPZ} (l0 rig) (Origene, Cat t. SClEhSSS) : pGEM~ BZfii-t) (ll) ng) (Promega, Cat #: PZZH) ratio was diluted to a final concentration of l2.t’i ng/nL (total plasmid) in 0pti~MEM l reducedusernm medium (Life Technologies Cat #2 l985062). Next, 6 ul; of FuGENE HID transfection reagent (Promega, Cat #: E23 l i) was added to ltill ills of diluted plasmid and mixed carefully by gentle pipetting, The complex was ted at room temperature for l) to 10 s, and then 8 llL of the complex was added per well ol‘a 96 well white assay plate (Costar, Cat it: 3917) and gently mixed without disturbing the cell monolayer, The plates were incubated for 29—24 hours at 37 "C and 5% C02 in a water—jacketed incubator. Following incubation, cells were treated and analyzed. {09244} For larger scale transfections, the athrementioned steps were scaled up accordingly, and cells were frozen following the last inculiation. in order to prepare frozen transfected CEO-Kl cells, the media was aspirated from culture flasks and cells were rinsed with 5 ml, PBS. As above, 2 ml, of rare-warmed (3‘? 0C) (3.05% trypsindZD'l‘z-‘r (Life eclinologies, Cat #: 25300054) was added, and cells were dislodged by tapping the flash on the side. Next, it) mL of antibiotic free growth media {Lille ’l‘echnologies, Cat #: 35l765ll92) containing l 0% FBS (Hyclone, Cat #: Sl-l3tlll7l .83} was added, and cells were centrifuged at % x g for 5 minutes at room temperature. Cell number was determined using a hemacytometer. The media was aspirated, and the cell pellet was resuspended in freezing media (Millipore, eat #: S—OOZél—T) at 2.5 x l85 cells!" Vial. Translected cells were incubated overnight at —8tl 0C before er to liquid nitrogen for long term e. The frozen stocks were then thawed one day prior to use for , and cells were seeded at 25 x l04 cells per well in lllll uL ot‘antibioticwfi'ee complete media (E712 (Life ’l‘echnologies, Cat # : 3 "65092) +10%FBS (Hyclone, Cat #1 SH3007l.G3)). Following an overnight incubation at 37 0C and % (it); in a water—jacketed incubator, the cells were ready for use in CAMP response assays.
{Wit/£53 in preparation for cAl‘s/ll? measurement, the cells were lirated with the sor cAMP reagent prior to treatment. For equilibration, the medium was carefully removed from the individual well. Next, lGO all of equilibration medium (6%v/V of Glosensor Reagent stock solution (Promega, Cat it: E29llfi l0% PBS (Hyclone, Cat #2 Sl~l3007lfl3> and 88% C02 independent medium {Lite Technologies, Cat #: l.8l}45988)) was added per well of the 96-well plate, and added to the side of each well. "l‘he plate was then iizicuhated for 2 hours at room temperature A first ore—read measurement was taken using a late reader (MicroLunrat Plus}. Plates- were ted for an additional l0 minutes at room temperature, followed by a second pre~read measurement {99246} g solutions of free treprostinil and treprostinil all-ryl ester compounds were prepared at 10X concentration so that the final concentration was lX once added to the cells. Following treatment, each plate was read every 5 s for the duration of the assay using a niicroplate reader (MieroLumat Plus). 111 erder to determine the feld change in CAMP relative tn the central, the transfeetien ncy was first determined by dividing the second pre—reacl measurement by the average of the corresponding ere—read measurements. Next, the normalized ve light units (RLUS) of the s were determined by dividing the plate read measurement by the transfectien etlleiency. The feld change in CAMP relative to the l was then determined by dividing the nemralizeel RLU of the samples by the ized RQLU of the control.
"Validation of CAMP assa * usin'r free tre ii'estinil {00247} The CAMP assay was validated using free treprostinil. ’l'represtinil (l0 nix/l, l 01%,, 0.1 , 0.01 itMg 0.001 itM, 0.0001 11M, 0.00001 shit and 0000001 ,ulvl) was added tn equilibrated CEO-Kl cells, and the cells were then ted fer 30 minutes. Luminescence "/35 111611 111608 1311’ij at 11301111 lefi‘lpfifilllll‘ti‘.
Ellie/lestertreme0511.11.99:ansitters {002483 CEO—Kl cells co-transfeeted with the £02 recepter and GleSenserTM plasmid were challenged with free treprostinil (l0 ul‘vflg 1 itlvlf, 0.1 {sh/1,, 0.01 trivia 0.001 tilt/15., 0.0001 hM, 0.00001 lil‘vl, 0.000001 MM) and treprostinil alltyl ester eenipeunds, ire, compounds having either a C6, Cg 0r C10 straight chain alleyl group at the R2 en of the cernpeund of Fnrnuila (A), shewn ahnvei {002493 The fellowing concentrations of cempounds were measured: 10 $11M, 1 11M, 01 ills/le 001 lthl, 0.001 0M, 0.0001 till/L 0.00001 0M, 0.000001 ulvl. CAMP levels were then measured every 5 inimites ever a time ennrse at S hears. s trern the three highest cencentrations are provided at Figure 3A (ll) "uh/l), Figure 3B (1 11M) and Figure BC {0.1 uM). The components of the treprestinil compositions set ferth in Figures 3A, 313 and 3C are shown in Table 4 below. {00250} cAMP levels in response to the treprestinil deeyl ester (CWTR) (l0 itlvl) were equivalent to free treprestinil and the levels were sustained fer at least 6 hours. The sustained CAMP level was not ted in response to free treprestinil. {00251} CHO~K1 eells ce~transtbcted with the E132 or and GlnSenserTM plasmid were challenged with free treprestinil (5 11M) and treprestinil een‘ipesitiens having either a treprestinil derivatized at the R2 position at" the above eenipeund with a C2,", Cs", C3,", C10, Or {112 straight chain group (5 lthl). The components of the treprestinil eernpesitiens are inmitied111 iabieS w. CAMP ieveis were that measmed every 5 minutes eve1 a time course 0178 heurs. {1102523 Results of these experiments using the 5 11M dese are provided, at Figure 4 and Figure 5 CAMP response to the C; and C10 trepmstinii aikyi esters (5 11M) was greater than er equivalent to the response induced by free treprostinii (Figure 4). The CAMP Eeveis in tespense to the C; and C 10 stinii alkyi ester compounds were sustained icantly Hunger "1111111 t‘ree treprestinil and the C6, Cg, and Cl; stinii derivatives.
Table 4. 'I'retsrestinil alkyl ester campusitions shown in Figm‘e 3. -., .. \ r1' ChOL (ox—ER 7-1‘4.)‘imoautade " ‘ ‘ ‘ Squaiam tempesfimn , , § 121(th Max 1AM? 31,111rs )r: PEG-20W (Cit—TR) 11101941 1110194} 11111117; 1110191; 1555 (es—1'11) 15561125111) itien (CXJE‘R) 'Ceneentmtitin Trepmstinii T554 (CZ—TR) (5 11M) 16111 (11611113 (5 11M) '1'555 (Cs—TR) (5 11M} '1‘556 ‘R) (5 11M) T568 (Cm—TR) (5 11M) Tie rostinil com 3011.1'1ds {(111253} The cell based (CHO~K1) CAM? assay was also used 113 terize the effect of unt‘ortnuiated treprostt‘nii compounds (Lei, cempounds without a hydrephehie additive and/or an amphiphilie agent such as a PEEGyiated iipid) en 12AM 1’ ieveis. {110254} CHO—Kl eelis contransfeeted with the EP2 reeepter anti GieSenserl‘M plasmid were Challenged with free treprostinii {5 11M) and treprestinit derivatives having either at Cz, C3, (‘4, C5, C6, Cg, Cm, er Cl; straight chain 11111311 estCi' moiety (5 11M). CAMP ieveis were then measured every 5 minutes over a, time eeurse of 8 11111113. 1'18 {@255} s of these experiments are provided at Figure 5. (If; and C10 treprostinil alltyl esters induced. CAMP response levels equivalent to free treprostinil. The C12 derivatized stinil compound was found to induce the smallest CAMP response.
Nebulized Tre rostinil Ester Com, ositions {@255} The cell based l) cAMF assay described above was also used to terize the effect of nebulization of various treprostinil compositions on cAMl’ levels. {@9257} CHOle cells coutransf’ected with the EFL? or and filoSensorFM plasmid were challenged with ll} nM free treprostinil (control or ne‘oulized} and it) uM treprostinil compositions comprising a compound derivatized with either a Cg, Cg, (his or €12 straight chain alkyl group at position R; of the nd of Formula (A; provided above (control or zed).
{M358} The compositions tested in this experiment are provided in Table 6 below (_results in Figure 6). CAMP levels were then measured every 5 minutes over a time course of 8‘ hours {562.5% Ne'hulizer Aerone‘b Pro (Aerogen) was used to ne'hulize treprostinil derivative compositions Desired volume of the formulation (usually 3 ml.) ‘y as loaded to the mesh head of the nelmlizer. The head was connected directly to the glass iinpinger with air- tight seal. zation was carried out using factory settings until the entire sample was ne‘bulized. After nehulization was complete, the head was disconnected; impinger capped and centrifiigved 5 min at 60G X g to settle the aerosol inside the impinges The procedure provided nearly ll)0% yield in collecting the nebulized sample. {@9250} As shown in Figure 6, nehulization of the derivatized treprostinil compositions did not have a deleterious effect on cAMP response levels, or duration of the response.
Table 6. stinil Alley! Ester Compositions: Effect of globalization Chol- CK—TR P3362009 Squslene fiQPC Max cAMP level ('5 M - (ix-TR_- inol% mol% tnol% s Fold » Tree:0Stiflil ~15 ‘ ‘ T554 (eerie 3' - 33 r555 (csxrn) = z . i . ~13 ' ‘ T556 (Cw—TR) '[568 ~ {Tn—'I‘R 'F‘ N13 . p C0111 5311an Of tie 1021111111 com minds and com ositiens c0111 Tisin ' the same {11112611 The ha11'niaximal effective concentratiens (EC50) 0f the varieus trepmstinfl eempeunds were detennined using the results 110111 the CAM? assays. T313113 7 {bebw} izes the Eng data for CAMP response in CBC—1Q ee11s for the. feflowing emnpnsitim’is and compounds: T554 '1'R.4G 11101 11A), squa1ane 40 moi ‘95, Choi—PEGZk 18 me}, %, 1301,)(3 10 11101 "711), T612 (Cy—TR 10 11101 "A, DMPE—P1K 91) 11101 %) 175111 (C51R 401110 °-o squalane 41} 1110190, C11011719'{12k 21111101 °A») T601 (Cg-1R 190, squalane 40 m01°/ 10 11101 We), , C110113131521< 11311191921 DOPC TT555 (Cg~TR 40 11101 53/0, squa1ane 40 moi ‘70, C~1101PEG21: 1811101 % DQPC 11) 111011115), 1556 (Cm—111 40 11101°A), squamne 40 11101"A), C11011315621 11’} 11101 9/11, DQPC 10 11101 9:53), T568 (Cm—TR 40 11101 0/1), 13115341} 1110190, PEG2k 11} 11101 %, DOPC 11} 11101 %), 1621 (C12ER 11) 1110191), DPPE-PZK 90 11101 *3/11), T623 (CWTR 411 11101/otsquzflane 411 11101/%C1101PEGZk 11} 190 1 DOPC 10 111111 %,)1 ’1‘622 (Cm;ER 10 11101 %, DPPE132K 9011101" ,1, anTR (1911 11101 ‘14»)? Cg—TR (1110 meE (1/5).» C12~TR (100 1110194)) and {Tree ti'epi'esti'nfl.
A subset 01‘" the dose Tespense CUWSS fer se1eeted trepmstinfi eempeunds and eernpesitiens are previded in Figures 7—141. With free treprostinfl the peteney decree withincreasing incubatimi time (supporting an immediate respense}, whiEe 2111 the various treprestiniE campesitiens exhibit an sing potency with ineubatien time (suggestive 01' a dehy— i'eiease profile).
Table 7. ECSG values for trepmstinii comnesitiipns. .0151 16.0111 37.0151 3TR) '"1'5'51'11‘1-111) "fame 7. EC50 113111135 for H'repmsrinil iiions. deinpfs EC" (11M) errn ° 43 227 1 MS 1 & (eonsdarn) -- .- 1:11" 3.39 (consiran .- (COHSPJU .- T61C ) "'102C1C;ER)" Cons-rain: A11EC 50 V211L1 *For szarnpies T612 (CZ-TR); T622 (Cm-TR), because of toxicity at higher concentrations, rhese values were excluded from the es in order to generate an Ean refine.
Exam 1e 5 — Determination (11' the effeet of ire 1113111111 eemroends 1111 ee11 reiiferetien {1111262} In order 10 determine any efeet ef stinii compounds on eelE proliferaEion, {Ce11 barnCd assavs using 131in1111 eeds and rat a1veo1are$311.81 (1111831111 cede) were perferrned.
CHO~K1 Ce11s {111121131 CHO—Kl oel1s were harvested when the cell ayer was 941 confluent {uee passage 4~1 1). Media was aspirated out of the flask, and eeils were rinsed, with 2 rnL of F12 rnedia. Next, 1 mi- of ere—warmed (37 °C) 0.25% trypsin—EDTA (Life ’i‘eehnoiogies, Catifi: 54) was added, and ceiEs were disiedged from the flask by tapping it on the side. Complete growth media (F12 (Life Teehno1ogies, Cat 11‘: 31765092) "1-1119617133 (Hydene, Cat #2 81131111371113) 1X rep (Life Teehnrfiogies, eat # 1514(1— 122) was then added at a veiuine of 10 mL. Cells were centrifuged at 250 X g fer 5 minutes at roern temperature, and the media was aspirated. The eeii pefie't was resuspended in 1.1) 1111.. eompiete growth media. Ce11 number was determined using a hemaeytoineter. Cede were then seeded at 2000 ceils per we11 0f 21. 1 plate in 101} 111- of te grew/11:1 media.
The piate was incubated overnight at 37 "C and 5A) (I{)3111 a waterjacketed inennbator {11112641} The next day, 81) 11L of fresh cernpiete media was added te each welh and, CEO—K1 ee113 were chafienged with 1111101111111 eempeund and eempesitien 1rea1111ents.T11e working solutions were prepared at 111x cencentratien, and foiiewing 2 foid seriai ddutiens, 211 grit aliquots were added per we11te arrive at a finai 1X concentration. Feflowing a. 48 hour incubatien at 37 0C and 5% C02 in a water—jacketed incubator, the ll’ll’llbllflly effect on cell prelit‘era‘tien was determined. Plates were analyzed using 20 till et‘ Prestc Blue reagent (Li 'e ’l‘echnelcgies, cat #: A8262) per well. The reagent was mixed, and plates were incubated for l lrcnr at. 37 "C and 5% CO; in a water—jacketed incubatcr. Plates were read using either a Cytcliluer Series 4600 {PerSeptive BieSysterns) or Synergy Nee rnicreplate reader (Bin'l‘ek) with emission it: 590 run and excitation a: 56G nni. The percent inhibition was determined using the following formula: % inhibition 1009/43 (treated samples/control X 300%).
NR8383 cells {@9265} Rat ar NRSSES cells were harvested when the monclayer was 50~ 90% confluent (use passage 5~l l). Because the NR8383: cells include bath adherent and non— adherent cells, media was transferred to a 50 mL Falcon tulle. "l‘c clitain the cells remaining in the flask, 2 HIL efplain media was added, and the remaining cells were scraped cut of the 75 crn?’ flaslt with a cell r and added to the St) trill tulle. Cells were centrifiiged at 200 X g for 5 minutes at room ature, and the media was aspirated. The cell pellet was ended in ll) mL complete growth media (F12 (Life ’l‘ecl‘anelegies, Cat #: Ill'765til92} +l5% PBS heat inactivated ne, Cat #: SHSGGHQB) + le’en—Strep (Life Technclegies, cat #: l54l0 — l22)). Cell number was determined using a liemacytenieter.
Cells were then seeded at 4000 cells per well cf a 96wwell plate in 100 tiL ct complete growth media. The plate was incubated overnight at 37 0C and 5% (302 in a wate jacketed incubator. llllllliitil The next day, 8t) still of fresh complete media was added to each well, and the NR8383 cells were challenged with treprestinil cernpcund treatments. Fellcwing a 72 lieur incuhatien at 37 0C and 5% C02 in a water—jacketed incubator, the inliibitcry effieet on cell preliferatien was detennined. Measurements and calculaticns were made as described aheve for the Kl cells.
Effect of tre rostinil alk fl ester corn ,oslticns on CHIS—Kl cell eratien {69267} CHO—Kl cells were challenged with compositions cenrprising treprostinil alkyl ester derivatives: T554 (Ch-TR 40 m0! "/6, squalane 40 incl ‘34}, lilil2k ll} l‘fiGl ‘34), DOPE? ll) incl 9'6), T543 (anTR 40 incl % Teen Acet 4G l‘l’lGl "/23, Chel~PE€32l< ll} rnel 9/0), T555 (Cg—TR 4t) l %, squalane 46) incl %, Chnl-PEGEk ll) nicl %, "C l0 rnel 9/5), T556 (C10"TR 4-0 1’110l %, squalane 4-0 incl %, CholmPEGer l0 rnol 9/6, DOPC ll) niel 0/3)), T568 (Cm—TR 40 mol %, squalane 40 mol 9/6, ll‘EG’Zl; l0 rnol % DQPC ll) inol0/o}., T623 {Cw—TR 40 mol 9/1}, sqnalane 40 mol 9/1), Chol—PEGZk l0 inol *3/09 DOPC ll} incl %)9 at concentrations ranging from 0.55 iiM to l25 iii‘v’l. Following a 48 hour incubation period, the tory effect of the treprostinil tive con'ipogitions on cell prolileration was determined. {@263} Table 8 below summarizes the effect of the above treprostinil compositions on CEO—Kl cell. proliterations. At the highest concentration of lot) iiM, only T543 TR") and T623 (Cm—".ETR) exhibited a Significant inhibitory effect on cell proliferation.
Table 8. Effect of Tre rostinil Com ns on cell rolil‘eratlon.
‘ Cil20~l§il Cells NR8383 (Selle i< 100 iii/i 0.78 nix/i) (3 ion tilt/Cl are ail/n Detectable cell proliferation W7"3-»4-7 lab.3 or:1R) : . inhibition only at concentration I> tilt/l concentration 2511M No detectable cell proliferation Deteetable cell proliferation r554 (Cg—TR) inhibition inhibition at 70 iiM ' able cell proliferation T5 5 5 (Cg—TR) lino tletectalile cell proliferation inhibition only at concentration > inhibition 50 iil‘vl Delectable cell eration No ‘ileteetable cell proliferation T5 5 {i (CitinTR) inhibition only at concentration >— inhibition Sil phi Detectable cell proliferation '1558 No detectable cell proliferation inhibition only at concentration > {Cm—TR) inhibition lGG iiM Detectahle cell proliferation Detectable cell proliferation T623 (CWTR) inhibition only at 100 iilvl inhibition only at 160 tin/l tration eoi'ieentration Effect of tre ii‘ostinil com ositions- on NR8383 cell rolifei‘ation {@9269} Rat alveolar NR8383 cells were challenged with the same treprostinil derivative itions: lifiGZ’l’ltE l543 (Cg—ER 40 mol ‘34), loco Ace ill} tool"A», Chol-l’EGZk 20 mol "3%), TT554 {C~—TR 40 mol 0/0, squalane ~10 inol %i, Ger ll) inol % DGFC l0 niol At), TT555 (CgTR 40 rnol "/0, sqiialane 40 mo} % Chol~PEGZl~t ll) i'nol *3/9, DOPC l0 tool 0/5), T556 (Cw-TR 40 mol 9/05 squalane 40 mol %, Cliolull‘EGZi: it) rno % DQPC ll) inol 903, T568 (Cu—TR 40 mol 9/0" equalane 4011710}, %, Cliol—PEGZk l0 moi *3/05 DQPC l0 inoll‘3/o) and T623 (Cm—TR 40 mol %, squalane 40 mol 9/5, Cliolull‘EG’Zli: l0 niol %, DOPE, ll) mol 9/0)," at the same concentrations (0.55 nM to l25 tilt/l} as the CEO—Kl cells above Following a 72 hour incubation period", the inhibitory effect of the treprostinil derivative compositions on cell 'prolileration was determined. {llllZ‘H} Table 8 above summarizes the el‘i‘ect ofthe above treprostinil compositions on NRSSSE» cell proliferation. At the highest dose of lilil nix/i, all of the treprostinil derivative compositions demonstrated. some inhibition of cell proliferation, and T543 (C5—TR.) exhibited the st inhibitory efflect.
Effect of tre rostinil alk ,-1 ester con1,oiinds on cell ,reliferation {992721} In order to determine any effect of treprostinil derivative nds (unlbrmulated) on cell proliferation, the cell based assays described above, using Kl cells and rat alveolar cells (NR8383 cells) were performed.
CHOnKl cell n‘olil‘eration assav {99273} {THO-Kl cells were challenged with treprostinil alkyl esters, 11a, TR compounds of Formula (A), having the following R3 groups: C29 C3, C45,, C5, Cm C89 C10 or C" straight chain alkyl, at dosages ranging from Bligh" hM to 25 tilt/l ing a 48 hour incubation period, the inhibitory effect on, cell proliferation was ined. {@274} Table 9 below summarizes the effect of the above treprostinil alkyl esters on Cl-lflsKl and NRSESLS cell proliferation. At the highest concentration, only the treprostinil octyl ester compound showed inhibition ofccll proliferation.
Table .9. Effect ot‘trearnstinil alkvl esters on cell ratlcn . Samples (EEG—Kl Cells NR8383 Cells l ,----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------4 : (0.195 nM 25 lib/l) (alas are 25 an) CTTR. No able cell inhibition No alfie cell inhibition C3—TR No detectable cell. inhibition No detectable cell inhibition.
(Li-TR. No detectable cell tion No detectable cell inhibition (jg-TR No detectable cell tion cé—rn No detectable cell inhibition (jg-TR Delectable cell inhibition at 25 nh’i Some detectable cell i inhibition {Sig—TR No detectable cell inhibition No detectable cell inhibition C13~TR No detectable cell inhibition No detectable cell inhibition, NRSS‘S?» cell roliferation assa , l9®275§ Rat alveolar NR8383 cells were challenged with treprostinil eornponndn derivatizetl at the R2 position of Formula (A) with a C2, C3, C4, C5," C5, C89, C10 or C1; straight chain alliyl moiety at. concentrations ranging from (It. l95 old to 2.5 iiM. Following a 72 hour incubation period, the tory effect on cell proliferation was determined. {09275} e l 1 above summarizes. the effect of the above treprostinil alkyl esters on NRSBS- cell proliferation. Similer to the lelol-‘Kl cell assay? only the treprostinil octyl ester showed some inhibition of cell proliteratioh at the highest concentration ’l‘re n‘ostinil derivative corn .ositions effect on cell ,i‘oliferation, } In order to ine the effect of treprostinil derivative compositions on cell eration, cell based assays using Cl-lO-Kl cells; and rat alveolar cells (NRSISSLS cells) were performed.
Effect of trearostinil 00111. ositions on CHO cell roliteretion {99278} Cl-lO~l§l cells were challenged with treprostinil tive compositions: T596 (Cg—'l‘R 45 mol %, DSG—l’2K 55 mol %), 'l'597 (Cg—’ll‘R 45 mol 9/253, DSG—PZK 55 mol %)i T598 (anTR 45 mol 9/6, DSG—PZK 55 mol (3/0)? T599 (CWTR 45 rnol%e DSG—PZK 55 mol 9'6}, and T600 (Cgifll 45 mol %, DSG—l’2K 55 mol 9/5), T612 (Cgfl‘ll l0 inol %, DMPEE- Plli 9G inol 9/2)), T6l3 (Cg-TR l0 niol ‘34; DMPE—PlK 99 mol (3/0)? at concentrations ranging from 0.23 nM to 29 lilvl. Following a 72 hour incubation period, the inhibitory effect on cell proliferation was determined. Following a 148 hour incubation ? the inhibitory effect on cell proliferation was determined. lilil279} 'llahle 10 below summarizes the effect of the treprostinil compositions on CHO—Kl cell eration None of the compositions tested, exhihitetl at significant inhibitory effect on Cil-lO-liil cell proliferation.
Table 10. Effect of treirostinil comtositiohs on cell trollferai‘lon, CHGKE Cells NR8383 Cells Sample concentration (29 33M 9.23 pl") (‘29 girl {3.23; 31M) Some detectable cell proliferation No detectable cell proliteration r595 (CZ) inhibition only at concentration > inhibition No detectable cell proliferation Some detectable cell proliferation inhibition inhibition at 70oM Table til. Effect of tre rostinil eoiriosltions on cell 3 rolll'eratiorh coon}. Cells nnsges Cells Some detectable cell proliferation No detectable cell proliferation T598 (Cg; tion only at concentration > inhibition SOUlVl Some detectz cell proliferation r.£599 (on. t No ctahle "ell‘" lii‘nlilei‘ttion‘ . . ES inhibition at 7: l4.5ul\zl ’ inhibition concentration Some detectable cell proliferation No detectable cell proliferation T601) (L12) inhibition at 3: l45nlv’l inhibition tration Sample concentration (186} [HM — 1.4l 111M} {18% 35M — ill-tit gilt/I} Detecteble cell proliferation Dctectahle cell proliferation T61; (CZ) inhibition only at 18:0 nM inhibition at T: 90 "M concentration concentration Detect is cell bration Detectable cell prolir’ etion T61", 3 (C ")It? . . .. . inhibition only at 1'80 nM inhibition at :_> 90 ttlv’l tration concentration {@3289} Similarly, CEO—Kl cells were challenged with the treprostinil compositions Toll" (R2 C2), Tel 3 (R2 Cg) at concentrationc g trorn l,4l gill/l to tilt? nl‘vl After 48 hours, the inhibitory effect on cell proliferation was determined, and all four of the treprostinil compositions exhibited lOO‘f/o inhibition, of cell proliferation at the higher concentrations.
Effect of tre n‘ostinil cont ositions on NR8383 cell roliferation {@281} Rat alveolar NR8383 cells were challenged with the same treprostinil compositions (above) as well as 1596 (Cg—TR 45 mol "/5, SSS—MK 55 mol 9/5), 'l‘ol2 {CZJFR ll} niol "/33, DMPE-PlK 90 nicl 9/5), T597 (Cg-TR 45 mol %, DSG~P2K 55 incl G/h), T598 (Cg— TR 45 mol "/5, DSCi—PZK 55 mol 9n), T6l3 (Cg—TR ll} moi (.345, DMPE—PlK 90 l‘l’lOl 0/6), T599 (Cm—TR 45 mol %, DSG—PLZK 55 mol 94$), T600 (CWTR 45 niol 9/07 DSG—PZK 55 niol %)i and at the same concentrations (0.23 {AM to 29 nM) as the Cl-lG—Kl cells above. Following a 72 hour incubation period, the inhibitory effect on cell proliferation was determined. {00282} Table 10 above summarizes the effect of the treprostinil composition on NR8383 cell proliferation. All of the treprostinil compositions demonstrated some {£- lO‘E/o) inhibition of'NR8383 cell eration. {@283} The effect oftreprostinil derivative nds in VlVO was ined by using rat models. Young male rats Spragne Bowley (Charles River) were used for the study" Rats anesthetized with hetamine/xylazine, placed on a heating pad and after surgical isolation and eatheterizatiori of the trachea, mechanically ventilated throughout the study.
{MEME A catheter was placed in the l artery for measurement of systolic {sys} and diastolic (dias) blood pressures. A thoraeotomy was perthrrned and a catheter inserted into the right ventricle and positioned in the pulmonary artery for the measurement of pulmonary arterial systolic and diastolic blood pressures. Oxygen tion (82102") was measured with a pulse oxhneter placed on the paw.
} With the rats ventilated on room air (F102 = 0511)a cardiovascular n'ieasurements were made under these normoxie eonditions, in order to induce hypoxia the F102 was reduced over a 30 min period until SaOZ fell to values hetwen 59—60%, and a ne hypoxia value for each of the parameters was determined.
{Nigel Groups of four rats each ed either 988, free stinil (l .7 rig/kg and ll) ugx’vligl. 01' a ition comprising Czw'l'R (€554); Cg-I'l‘R (T555: (fig—TR 4Q rnol 9:53, squalane 40 tool (375, Chol—PEGZh 10 mol %, DOPC ll} tool 0/5) (38:6 g)a Clo-TR @556: {Tm—"Hi 4t) inol %, squalane 40 mol %, Chol—PEGZR ll} mol %3 DOPC l0 nioli/{i} (ll—{Hi lug/kg))5 C12"TR (T568) l9®287§ The target dose varied slightly by weight due to the differences in molecular weight of the treprostinil derivative compositions as shown in Table ll below.
The actual achieved lung dose was about 5); lower than provided in Table ll (63, administration of l0 pig/kg yielded about 2 rig/kg in the lungs). The various treatments were delivered (via inhalation of ne‘oulized drug to the lungs of the rats, The pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), and heart rate of the rats were measured continuously for 180 minutes. The PAP signal was collected at ‘2.th points per second.
Table ll. Target {Poses in Acute a Rat Model Target Dose Target Dose {ngkg} (nmole/ltg) ‘l‘reprostinil Treporostinil derivative compound Table 11‘ Target Biases in Acute E-{ypexia Rat Medei *lndicates alkyl chain length at position R9 of the compound affomiula (A). {09288} The normalized variation of mean PAP {mPAfP} is shown as a percentage from the hypoxia baseline value at (i=0) in Figure 15. The hypoxia haseline PAP value was 100%, and "the elianges in pressure were measured in cemeaxiseh is: the hypexie baseline.
The ized tieh efmean SAP (mSAP) is shown as a percentage from, the hypexie baseline value in Figure 16. Heart rate is shown in Figure l? as a percentage Of the hypexie baseline value ever time.
Kl. cells in res ehse ts ShenamflnTR {same} A cell based Chinese hamster evary~Kl (:(Zli-iiiil—Kl) assay based on the GleSenserTM CAMP essay (Premega) was used as bed abeve in Example 4 to characterize the effect an" the fellewing compounds eh CAMP evels: a S—nohahylu'l‘R, is, the mmpmmd of Formula. (A) wherein R3 = 5~hehanyi (WM)9 9 C13—TR Le ,tlle eempmmd 01‘ Formala (A) wherein R3 C13 alhyl (\/\/\/\/\/\}7—), 9 CH—TR, 27.6., the eempeimd ef Formula (A) wherehi IR3 C14 alleyl (W)9 9 Cm—TR, 216., the compelled of Formula {A} wherein R3 = C16 alkyl {332%} CHO—K1 cells cemtrehsfeeted with the EPZ reeepter and serTM plasmid were nged with 5~h0nahyi—i’1'epmstinii (branched chain, SCg-TR) 01' treprestihii alkyl ester compounds having either a C32, C14 01" C15 straight chain alkyl gi‘eup at the R3 position of the above compound. CAMP levels were then measured every 5 minutes over a time course of 8 hours" Dose response curves at 0.5m, lhr, 2hr, 3hr, 4hr, Stir, 6hr, 7hr, and 8hr incubation time for S—nonanyln'l'R, CMJI‘R, and {fie—TR are provided in Figures l 8, '39, and 29 ,respectively. Like {Tm—TR and (Sm—TR, the potency of S—iiorianyl—TR increases with incubation time, ting a delay-release profile. The half maximal effective concentrations (E553) of the treprostinil nds were determined using the results from the CAM? assays. ECSO tbr S-N'onanylfl‘li, {EM-TR, and {Em-"ER are shown in, Ili'igures 18, 19, and 2G, respectively. {69291} Kinetic profile results from the lfi lih’l (top panel) and 5 itM (bottom panel) concentrations of (1312—7E‘R, (EMIE‘R, (Tm—'I‘R, or S-nonanylil'ls are provided at Figure 21.
CAMP levels in response to CWTRS CHER, and 5~rtonertyleR at both concentrations increased over the first 1—1 .5 hours and were ned for at least 8 hours. The ranking of activity of the treprostinil nds was Clgw'l'R > Cog-TR > S—noriariyl—TR > Chg—TR. {@323 The results of the study showed that like the treprostinil elkyl ester compounds having a (312, CM or (316 straight chain alkyl ester group, S—noriariyl—"E‘R, is fittictioiial and, exhibits sustained CAMP activity. Thus, unlike free treprostiriil (see Example 4-), Swoonenyln TR lies a delayed release profile.
Examile g Comarisort of cells: adenosine moneershate cAMl’ activation in Cflflmlfl cells in res sense to (TH—TR formulatierls {lilllefl} A cell based Chinese hamster ovary-Kl (CBS—Kl) essay based on the GloSensorTM CAMP assay ega) was used. as described above in Example 4 to characterize the effect of different CirrTR tonsilletions on cAMP levels. The (EM—TR formulations are shown. below in ’l‘able l2. Composition "F679 does not se BOPC; ition T647 does not se DOPC or squalarte, The structure ofCH—TR is as tollews: 0‘"I IOH" Table 12,. Components of CI4~TR inrmuiations Hydrophobic E‘EGyiai‘ed ition Additive lipid (mo! 0/0) (moi %} Choi~ Squaw" Peon; (49 9‘5?) {'11) ‘24,) (IMJE'R Sqnalane (45 %) (45 %) Choi- (none) PEGZk {in 9/3) {99294} {THO-Kl cells (to—transiected with the EP2 receptor and GloSensorTM plasmid were challenged with treprostinil alhyl ester formuiations having a C14 straight chain allay}, ester group at the carboxylic acid position and having the components as indicated in Table 123 CAMP levels were then measured every 5 minutes over a time course of 8 hours.
{WES} A dose response curve at 0.51m; 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, 7hr," and 8hr incubation time for nd T679 is provided in Figure 22. The potency of T679 increases over the tion time, indicating a delay—release profile. The half maximal effiective tration (Eng) of T679 was determined. using the resnits from the CAM? fi and is also shown in Figore 2'2, {some} Kinetic profile comparisons for free treprostinil, T631, and T679 at ltlttlvl {top panel) and Sold, (bottom panel) are shown in Figure 23, Both T631 and T679 were less potent ed to free treprostinil. i-iowever, unlike free treprostinil, cAMl? activation increased overtime in response to both T631 and T679 and was sustained, for at least 8 hours.
The results of the study showed that the T679 formuiation, which is a (EM—TR without DQPC, is functional and exhibits a d release profile similar to the profile of the CM—TR T631. {06297} A dose response curve at 0.5m, 1hr, Zhn 3hr, 4hr, 5hr, (the 7hr, and 8hr incubation time for nd T647 is provided in Figure 24. Like T6795 the potency of T647 increases over the incubation time, indicating a delay~release profile. The half maximal effective concentration (E31350) of T647 was determined using the results them the CAM? assay? and is also shown in Figure 24. {fifiZRS} Kinetic profile isons for fine treprostinil, T63 l, and T647 at lllulvl (top panel) and Sold (bottom panel) are shown in Figure 25. Both T63l and, T647 were less potent compared to free treprostinil. However, unlike free treprostinil, cAl‘v’ll3i activation ii'lereaued over time in response to both T631 and T647 and was sustained, for at least 8 hours.
The results of the study showed. that the T647 fonnulaiion, which is a (EM-TR without DQPC or squalane, is functional and exhibits a. delayed release profile similar to the profile of the (EM-TR 37631.
Examle 9 - Functional CAM? s for trew-rostinii 3537i ester nanoartiele formulations {M3299} A cell based Chinese hamster ovary~Rl l) aseay haeed on the sorl‘M cAMP assay (Fromega) was used as described above in Example 4 to characterize the effect of treproutinii compositions on eAMF levels" The CAlVlP profiles of the following stinil compositions were tested in this study (see also 'l‘ahle 13): 9 "i555. {g—lR (I e the compound ole01niula(A)whenin R2 =W a W)Cu;IR (tie, he compound of Formula (A) wherein R2 = a 1568:W)C17IR (229., he compound of Formula (A) wherein R2 = a "£631: CWTR (i.€., the compound of Formula (A) wherein R2 = a "£623: CWTR (tie, the compound of Formula (A) wherein R2 = a "£637: meTR (tie, the compound of Formula (A) wherein R2: = Formulation Treprestinil Tieprostinil Squalane DOPC (moi Chol-PEG2k No. alkyl ester alkyl ester (1130196) %) ("10196) (ex—run *C‘x indicates alkyl chain length at position R2 of the compound of Formula (A). {lliliilllll {ll—lO—lil cells co~transfeeted with the EPZ receptor and GloSensorTM plasmid were challenged with the treprostinil alkyl ester compositions listed. above. CAMP levels were then measured. every 5 minutes over a time course of 8 hours. {tlfif’étll} A dose response curve at 0.5hr, lhr, 2hr, 3hr, 4hr, 5hr, 6hr, 7hr, and 8hr tion time for composition T637 (Cm—TR} is provided in Figure 26. The y of T7679 increases over the initial incubation time and then remains at. a sustained level. for at least 8 hours: indicating a delaywrelease profile. The half maximal effective concentration (131350) of T637 was detennined using the results item the CAR/ll? assays, and is also shown in Figure 26. {llillillZ} c e comparisons for free treprostinil, T555? T5565 T568, Tti3l1, T623, and, T637 at l (top panel) and fish’l (bottom panel} are shown in Figure '27 Each of the treprostinil alkyl ester nds were less potent compared to free treprostinil.
However, unlike free treprostinil, CAMP tion increased and then remained, at a sustained level for at least 8 hours in response to each of the treprostinil elkyl ester cornpountlsi indicating that each of these compounds is functional and exhibits a delayed release profile. The ranking order of activity for these compounds was ’l‘SSS/TSSo > T568 > T63l > T623 > T637.
Exam is it? — Enz 'matic conversion kinetics of branched tre rostinll corn onntls {fitlEtlS} A set of studies was conducted to determine the conversion kinetics to stinil of linear treprostinil compounds versus various branched treprostinil compounds. i).4mM of linear CgJT‘R or branched treprostinil compounds 2*dimetliyl-l—propanlelTR, 3,3- tliniethyhl-butanyl~TR,, Z—ethyLl-butanyhTR S—nonanyl—TRfi or snylnTR (see below for structures) were incubated with ()2 ll esterase at 37 "C for l hour, and the conversion (‘34; of total) was calculated at 0.25, (3.5g 0.75, or l hour ineuhation time. s Cg‘TR (Leo the compound of Formula (A) n R3 =W) e 2—dimethyl—l~propanyl—TR (5.6., the compound of Formula {A} wherein R2 e 3fi3ndimethyi—l—hutanyi—TR (128.3 the compound of Formula (A) wherein R3 = > The first three eompositione (F5568, T631 and T623) are heiieved to form iipid neooparticies, Whiie the last three compositions (T636, T635 and T636) are believed to form es.
Table 14. Aiky] ester formulations used in Examp‘ie ‘1}.
DMPE" Formulation Treprosiioii emulate,sw 1/ DOPC, .(moi (3"noleave-- silky] ester ,. 1.x No. silky] ester (moi 3/0} 0/6) (mol 9/5) (moi,. . \ 0/6) {W309} T568 and ’1‘630: R (5.6., the compound of Forrmiia (A) wherein R3 {fifiiiiti} T63i and T635: CirTR one" the compound of Formula (A) wherein R3 = lllllfllll T623 and T636: ngn’l‘R (118., the compound of Formula (A) wherein R3 = {$03123 Nelnilized treprostinil (FREE) solution and treprostinil allryl ester formulations were administered (at l5 nniol/kg, or 6 ing/lrg TRE equivalent) to anaesthetisedmventilated rats (6—hour studies) or to conscious rats by nose—only inhalation {24—hour studies). Blood and lung samples were collected at specified time points. ’l‘RE and treprostinil allryl ester concentrations in. blood plasma and lung tissue were measured by l-ll?l_.C/'l\4lS/l\/ls analysis, Anasthitmd\emildtwdRats {(313313} Male Sprague Dawley rats were anaesthetised and prepared with endotracheal tube for ventilation The right femoral vein was cannulated to facilitate blood collections. al lung samples x 'ere taken for analysis only 6 hours alter dosing Aeroneb® izer and a controller (Aerogen, Galway, d} were used to produce aerosol of a mass median aerodynamic diameter (MMAD) between ’25 um and 4 um and at a rate of (it inL/niin to provide an estimated pulmonary dose of {i rig/kg A SARw839/’AP Small Animal Ventilator (CWE lne.,, Ardmorei, PA) set up at ventilator tidal volume (VT) of 8 nil/leg, rate. of 90 breaths/min, was used to deliver nebulized test articles of volume 250 all. Systemic blood pressure (rnSAP), heart rate (HR)e and arterial oxygen saturation (SaOZ). logic ters were measured during normoxia (fraction of inspired oxygen [Frfigl 0.21, 82102 f: 96%} and for 2 to 3 hours during hypoxia (Fifi; = 6.10, 82103 ’4 50%).
Conscious Nose—Onl ' inhalationI {993%} Male Cprague Dawley rats were placed in restraining tubes and exposed to nebuliserl drugs Via the Jaeger—N‘l’ll NosemOnly Directedmli'low lnhalation Exposure System (CH loglesi od, NI) (Figure El), Test articles (6 mL at specific concentration) were nehulised using the Aerone‘h nebuliser to deliver a predetennined estimated ary dose" Blood and lung tissue s were taken at selected times after nebulization of the drugs over a 24—hour period. {80315} ated rats treated with nebulized lRE solution had the highest blood plasma concentration (Cmax) (3.5 rig/nil), which occurred immediately after dosing {Figure 32, left). Measurable levels of TRE were not seen beyond 4 hours in tlie lilood plasma and by 6 hours in the lungs. In contrast, ventilated rats d with nelmlized TPDQLNP had lower blood plasma ’l‘RlEL (Imax values, ranging from 0.2 rig/"ml; to 0.6 ng/mL {table 15, Figure 329 left}. At 6 hours, treprostinil alkyl ester ed in the lung at levels that ranged from ltll) ng/g to 4th rig/g tissue ol’TRE equivalent (Figure 33}. Treprostinil detected in the lung was speculated to be generated due to treprostinil alkyl ester ysis during sample preparation. When dosing with mieellar TPDi blood plasma levels of TRE were higher than with TPD lipid nanoparticle formulations, ting that nanoparticles play an additional role in slow—reh:ase effect (Figure 32, comparison of left and right graphs}. In the 24—hour studies in rats dosed with 'l’PlLlipid nanoparticle formulations (nose—only inhalation), TREE.
Cniax was higher than in ventilated animals and showed close to first—order ntial decline. Blood plasma trations oi’TRE in rats that received dosing with C 1.»; and Cw treprostinil alkyl ester lipid nanopartiele formulations were maintained at greater than {ll rig/ml; for up to 24 hours," (levels corresponding to activity in acute hypoxia studies) (Figure 34, top). Lung levels of total lRE + 'l‘l’D were imately it)"5 higher than plasma lRE and also exhibited exponential decline in rats administered treprostinil alliyl ester lipid nanoparticle ations (Figure 34, 'bettom), ’l‘able lo r shows the pharmaeokineties of treprostinil in rats after dosing with the nosemonly stystern with the nehulized treprostinil alltyl ester lipid nanopartiele formulations at the estimated pulmonary dose of 6 gig/kg! Figure 35 further shows that release kinetics of treprostinil from inhaled C; (will formulations over 24 hours is independent of dose (nose only dosing). Time in figure 35 corresponds to the time after beginning of nehulization of a 6 roL suspension ization period was 30 min, to 60 min). Figure 38 shows that animals treated with T568 and T623 had a survival benefit (surviving beyond 200 minutes) compared with animals treated with free treprostinil or PBS). Specifically; Figure 38 shows the pulmonary arterial pressure in animals treated with various lipid nanoparticle lbrmulations, PBS and treprostinil. Furthermore, ent with T568 and T623 showed little impact on systemic haemodynamies (Figure 39). Finally, treprostinil alkyl ester nanoparticle ations were shown to convert sloly to treprostinil, providing consistent blood plasma levels with reduced peak values (Figure 4G).
Table 15 Plasma colrineties of treprostinil in ated rats after closing with nehulized treprostinil solution or formulated stinil alliyl ester suspension at an estimated pulmonary dose of 6 rig/kg Solution Lipid, Nanopartieles Mieelles (T6305 T635 and T636) (T568, T63l and T623) r568 T631 11323 'rssa tress ’1‘636 (CK-TR) (Cu-TR) (CWTR) (Cm—TR) (emits) grew—rs} (Clara) Table 15. Plaarrla phamlaeokmeticg of tt‘ept‘oetlnll in ventilated rats after desitlg with nebulizetl treprostinil selution or lbrmulated tirlil alleyl ester suspension at an estimated pulmonary dese OHS gig/leg AUC Mil 9.72 €9.11 (1125* h/mL) Cmax Trnax (l1) .........................................................................................................................................................................................................................................
Table 16. Pltarmaeekinetics eftt‘epmstlnll in rats after desihg with the. nese~enly stystem with the nebulizetl treprostinil alkyl ester lbrmulatiorts (T568, TéBl and T623) at the estimated ary dese 0156 ag’kg Cempmmd immediately post dose (lPD) (gig/kg) Lung apparent ellimination rate (ltd) Plasma maximum concentration, (Cmax) IP13 4.03; (rig/mi) Plasma apparent elirnlnatien rate (li' ) 0.30 ll.l4 illll3lfi§ lnllaled TPDS are present in the lungs for an extended duratien and are asaeeia‘ted with a slow. sustained release efTRE into the bleed. This duratien ef activity is increased with 'I'PD formulated in lipid nanopartieleg. atien in Begs i:fl@317_i 'I‘welve beagle dogs; ol’elther sex were randomly assigned to different inhaled doses 0f treprostinil in l?’BS at the compound at a (A) wherein R3, = W)((71511?) femtuiated in a lipid rtiele fermulatien (T623) that is suspended in PBS (see "table l4), with hath given by nebulizer.
Fermulatiens were nebulized with an Aeroneb zer {MMADz 2.5—4 gm) delivered inte a 500 ml expansien chamber. Formtllatiens were rtehttlized for 2 min at ventilatm' settings of 9t) nil/’hreath, l5 breaths/min (delivered volume = 2.7 L} and collected on a filter. Drag amount {pg} on the filter was measured by HPLC to calculate the concentration of drug delivered through the ventilator circuit (pg/L). {dfiSlSE Dosin’ietry was performed in propotel—anesthetized dogs in which nehulized drugs were introduced into a mixing ol'iarnber interposed on the atory limb of a canine ator. Technical trials were performed before each, experiment to measure the concentration of drug (pg/I.) delivered for each breath. The inhaled drug dose (pg/leg) was calculated using the formula: inhaled Ding Dose (pg/leg} = Ding Cone. ) \ Minute Ventilation (LI/min.) >< Time (min) / Body Weight (kg). After delivery of the drugs, the dogs were disconnected from. the respirator and blood samples were collected over a ’72 h period to measure the treprostinil plasma concentrations by HFLC/MS/MS. Clinical signs were monitored over this 72 hr. period. iilltldlll‘i Use of the etized, intahated and ventilated approach ed ucibility n dogs to achieve the targeted inhaled dose for both treproatinil (5 i l and lo :l: 2 rig/kg) and (Em—TR (7.1-.- l, 22 :t; l, 46 :l: l and 95 :l: l brig/kg)" At inhaled doses. ofS and lo rig/kg, treprostinil plasma Cinax values for dogs dosed with treprostinil (2"? and 5.9 ng/rnh reapectively) were. between lS-ZO fold higher compared to treprostinil levels; achieved upon dosing with similar inhaled doses {7 and 22 gig/kg) of (Tm—TR in the T623 formulation {3.2 and 9.3 in reapectively) (Figure 36), rmore, the planina levela of treprostinil were sustained over a 48 hour period with inhalation of T623 hut disappeared within a few hours following inhalation of treprostinil (Figure 36). Coughing and rapid shallow breathing were absent during deliveryr of stinil to anesthetized, ventilated, dogs but were present during the recovery period. Dogs receiving T623 showed no signs of respiratory irritation with inhaled. doses as high as 46 gig/kg.
(Iomparison of (316 Alkyl Ester Lipid Nanopartiele 'i‘i'eprostinil ation to (In and C14 Alkyl Ester Lipid rtlele Treprostinil Formulations {09329} Twelve 1oeagle dogs: were expected to inhaled treprostinil and three treprostinil allryl ester lipid nanopartiele formulations: €568 {dodeeyl~treprostinil, (Smirk), 'l‘63l (tetradeeyl—treprostinih ClinTR) and T623 {hexadecyhtreprostinil, CmfilR). The components of each ation are provided in Table 14, above.
{M321} Dosinietry was performed in propofol~anesthetized, artificially ventilated dogs in which zed drugs were introduced into a mixing chamber interposed on the inspiratnry limb 0f the respiratnr. 'l‘eehnical trials were performed before each experiment measuring the enneentratien of drug (gig/L) per breath, minute vei'itila'tien and time required tn achieve a targeted pulmonary dose. After recovery item the anesthesia, blood s were ted over ‘72 h and plasma le 7els of TRE measured by HPLG’l‘vfile’h/lft‘s, Clinical signs (eeugh, rapid shallow breathing, emesis and pale gents} were alsn inenitered. {@322} At a ed pulmonary dose of l8 itgfi'kg, hlasnia levels (if stinil were highest for tree treprnstinil (Crnax 5.9 : {3,6 rig/ml) immediately after dosing hut eerresponding Cniax values fer (Zn-TR, {Challis and C15u’l'R were 5m, 13- and 20~fold lewer.
Plasma treprostinil was below the level of quantification by 4 h after inhaled free treprestinil, but was sustained for 48~‘72 h after d treprestinil alkyl ester ferinnlatinns.
{M323} Base—dependent increases in (Smart and AUC were seen with inhaled R (6—90 gig/leg) with a iged presence ei‘treprestinil in the plasma fer up tn 72 h at higher deses. Adverse clinical signs were seen with free treprnstinil and Cuil‘R at a targeted rinse ef l8 , but not with C14~TR and CrawTRi in the dese—respense study with Gus—TR, adverse clinical signs were seen in only I ring at a targeted pnln‘annary dose 0f 90 gag/kg {@324} Based upon this PK study in dogs, inhaled (LN—TR in a iiariepaiticle atinn prevides sustained presence of treprnstinil in the plasma and lewer side effect petential than inhaled free treprestinil at eernnarahle doses. ii.AlkrlEster ’i‘remstinil Ferninlatien {@325} T748, a lipid nanepartiele {7.16 allryl ester treprestinil thrrnnlatien having the fellewing components, was Characterized.
C16—TR Squalane ’EG’Zk (incl ‘34)) {me} 0/6) {met ’34)) {903226} Assessment of the 'l‘elerabilit‘y and Pharmaeelrineties (PK) 0f 'l'reprostinil in Rats administerd T748 lipid rianopartiele ternmlatien {99327} To assess whether repeated dosing with inhaled (Sm—TR is well tnlerated and alters FK, rats were d t0 C m—"l‘R fer l 4—eonseeutive days. {@3328} 5 groups (n = 4 per group) of Sprague Dawley rats were exposed tn inhaled phesphate hut‘fered saline (PBS) or 4 doses at" (Ira—TR (0.6, l8, 6 and lit rig/kg) given by nebulization in a nosemonly tion chamber. Cohorts of rats were studied after l, 7 and l4 daily inhaled doses of Gig—TR and blood samples were ted at l, 3, t3} and 24 hri, and lungs liar rested at 24 hr. alter the last dose of the drug. Concentrations of treprostinil and {316~TR. in the. plasma and lungs were measured by l-lPLC/h/lS/h/lS. Body weights were recorded daily and organ weights , heart, liver} were measured 24 hr. alter the last drug dose. {09329} There were no tolerabiiity issues or significant s ive to PBS) in body s and organ weights after inhalation of {jig-TR for l4—eonsecutive days.
Increasing inhaled doses of C15~TR (0.648 rig/leg) sed the plasma Crnax and AUC but this was not consistently affected upon repeated dosing. 'l‘here was some variability in Alli: between days 1 and 14 within the different dosing groups with 2 of the r-‘l doses (1.8 and lit rig/leg) showing no difference, and the other 2 doses (0.6 and ti rig/kg) showing a 3- to 4—fold se in AUC by day 14. The presence of CWTR was not detected in the plasma at any dose. However, relatively high concentrations of Gig—TR (approximately l,0(l()—fold higher than plasma treprostinil) were found in the lungs. inhaled Clsu'l‘R produced a doseudependent increase in the concentration of {iiéwTR in the lungs, but this was not changed by repeated dosing for l4~consecutive days. iht‘l33tti inhaled C 161112; (0.648 rig/kg) was well tolerated with no evidence of hotly weight and organ weight change after dosing for l4 consecutive days.
Effect of C16 Alkyl Ester Lipid Nanoparticle Tre'prostinit Formulation on the Cough Reflex in Guinea Pigs {M831} in this study, the tussive effects of inhaled treprostinil and a lipid iianopaiticle formulation of the alltyl ester hexadecyl-treprostinil (CWTR), were studied in guinea pigs. {@332} Three groups of male Dunkin E-lartley guinea pigs were placed in a whole body plethysmograph and exposed to aerosolized phosphate buffered saline (PBS), TRE (l— 300 ug/rnl} and CWTR lipid article lormulation 1748 {3G gig/ml}, respectively. T62; has the following components: {MESS} Aerosols were ted with an Ultra—Nob ?ro nehulizer (nehulizer output €3.36 mtg/min.) that was mixed with inspired air delivered at a rate of 2 . "the PBS or drugs were delivered for 10 min" and the number of coughs recorded during and for 20 min. after the delivery. Coughs were detected by visual observations" plethysrnograph recordings and cough sounds. {tltlflilcll Exposure to aerosolized PBS did not induce cough. TREE exposure did not tently evoke cough in the animals tested until the re concentration was equal to or greater than 3t) ug/mL. The cough response was characterized by bouts of high tiequency cough with lowered cough sounds compared to the typical cough sound induced by citric acid or cansaicin. TREE at a nehulized concentration of 3t) gig/"mil produced consistent cough in 7 of 7 guinea pigs with l-4 cough bouts and a total number of coughs averaging 36 :: 9 coughs. in contrast, inhaled (3155111 lipid nanoparticle formulation at a nehuli'zed concentration of 30 tig/ nil did not induce cough, no events, in 6 0th guinea pigs; {69335} The results in this study demonstrate that inhaled TRE induces cough in guinea pigs, the profile of which is Somewhat similar to that previously described (type ll coughs) with inhaled prostaglandins in guinea. pigs (Malier and Belvisia 2010). Gn the other hand, inhaled (jig-TR lipid nanoparticle formulation, did not induce cough and, suggests that this formulation may ate some of the local ad rerse side effects such as cough seen with inhaled TRE therapy in .
Exam le 14 — Ac 'lation ot’Trc rostlnil Berivatlves {tlilfliltil rostinil or treprostinil ester derivatives {c.g., derivatized with alkyl or alkenyl groups at the carhoxylic acid moiety as prepared in e l) are acylated as follows. lillll337l The nd of Example 1 (0.05 mol) or treprostinil is dissolved in it) mL of dichlorornethane at 0 0C. Din'iethylamihopyridine is added, {20 innit/ii)n and then a solution of an acyl chloride RtiCOXTl (2.1 equivalents) at 0 "(I (wherein R is R5 or R6 as descrihed herein) is added to the compound of Example 1 or treprostinil‘ The solution is allowed to stir and warm to 23 0C over l hour, The reaction is monitored by thin layer tography, and when no futther change is observed, the reaction is quenched with NaHCOg {sat} and the quenched mixture is extracted with dichloromethane (3 s it} mi). The comhined organic ts are dried over anhydrous sodium sulfate, and the solvent is d under . to afford the crude product. Purification is ett‘eeted by column chromatography on silica gel with 2% methanol in dichloromethane. {83338} A l scheme for synthesis of the acylated treprostinil~derivatives is shown below (R2 is described herein, for example as it or a linear or branched alkyl group): O O H DMAP H H H H5 6H 5 5 o >60 Y {(39339} Other acylalion techniques known in the art, including selective acyfiatien 01'" each of the ary ls, can be employed. in additien, R: can be selected such that the R2 group can be selectively remm/ed fimm the compound of Example 11 after acylatien 0f the semndary hydraxyl functionallfies. Such pmtecting greup strategies are well knevm te these skilled in the art, and are described in, eg Peter GM, Wales and Theedma W.
Greene, Greenefis l’rotective Groups fin Organic. Synthesis, 4th n, Wiley (2006:), which is ineerpm‘ated herein by reference in its entirety £01" all pumases. l n exemplaly scheme of such a process is shewn below: R2\O)% gees-4i}: Sis (3f (gamma: o: o‘ {99341} To a solutien of (1R,2R,3aS,9aS)~[[2,3,321,4,9,9a—hexal‘;ydte~2-liydmxy~l— [(3S)~3allyili'exyectyl}ll’l—benz{flinden—S-yl]0x.y}aeetie acid (ti'epi'nstinil) {78.1 mg, 201} wholes) dissolved in 1,4mDioxane (2.0 mL) was added ylamine (TEA) (98 pl, 700 wholes, 3.5 equivalents), acetic anhydride (166 1.11., 1,768 nn'inles, 8.8 lents), and a catalytic amount of dimetliylaminepyridine (DIVE/11’}. The en e was allewed to shake at 40 CC for 72 hours. Solvent was renieved under reduced pressure to yield a thick. colorless Oil. The crude material was dissolved in hexanes and washed with a selntion ef saturated 1151111303 (3 X 5 mL). The organic layers were combined and solvent was renieved using a gentle strean'l of wanned N2 gas and gentle heat te yield a thick, colorless ail. The crude al was dissolved in 29% "PrOH/Hexanes, passed thmugh a 0.45 nm syringe filter, and submitted to preparatom 1-1 PILC pnrilieatien. Selvent was removed item the purified material. using a gentle stream of warmed N2 gas and gentle heat tn yield a thick celerless ell. The pure material was suspended in ethyl lactate fer e and was submitted te analytical HPLC for tralien ination. {119342} C16-'l'R-0Ac: 73% overall yield. The eempeund was alsn characterized by N‘wiR speetmseepy: {1193431 1H NMR (500 MHZ, CDC13} 5 0.89 (t, .l 7.0 11:21, 6H), 2 (in, 3311), 1.43—1.46 (in, 2H), 1.49—1.66 (in, 8H), 1.8941 .93- (m, ’lH), 1.99 (s, 3H), 2.06 (s, 3H), 2.30— 2.35 (in, 211), 2.47 {d 01" d, J 14.5 1-12., .1 6.0 Hz, ill), 2.55 ((1 0f (1, J 15.0 Hz, J 6.0 Hz, 1H), 2.76 (d, of d, .l = 14.5 1-12, 1 = 6.0 Hz, 111), 2.90 (d (if d, .l = 15.0 112,1 = 6.0 Hz, 111), 4.19 (t, J 7.0 Hz, 211), 4.62 (s, 2H), 4.73—4.74 (m, 1H}, 4.87 (p, 3 6.11 Hz, 1H), 6.63 (d, 1 so in, in), as: (d, .1 8.0 in, in), 7.68 (t, 3 at) 1-12, 11-11ppm; "(it NMR(125 MHZ, CDCl-g) 5 141.2, 14.3, 21.5 (2), 22.7, 22.9, 251, 26.1} (2), 28.3, 28.8, 29.4, 29.6, 29.7, 29.8, 29.9, 31.9, 32.1. 33.6, 33.7, 34.3, 37.8, 40.7. 49.0, 65.6, 66.2, 74.6, 7.9.1), 169.8, 121.8, 126.4, 127.6,140.7,155.1,169.6,171.G,171.lppm.
Exam 1e 15 "8711111153313 of he restinil amide derivatives {119344} Tt'epifestinil is available eemmeteially, and can be synthesized, for example, by the metheds disclosed in US. Patent Nos {5,765,l t7 and 393. Synthesis of prostaglandln derivatives is described in US. Patent. Ne. 4,668,814. The diselesures OfU.S. l’atent NOS. 6,765,117; 8,497,393 and 4,668,814 are each incorperated by reference in their entireties fer all purposes. {1111345} To a solutien of ('1R,2R,3aS,9aS)~[[2,3,3-21,4,9,9a—hexa11ydro~2~hydroxy~1— [(3333 1111111021}001'.ij 111—111211211111111111—S-yljoxyjaeetie 110111 (1‘. e.trepmsti11i1) (7X1 mg, 201} 1111101es) ved 111 1 ,4mDioxa11e (20 1111;) was added triethylamihe (TEA) (98 11L 700 1111101es, 3.5 equivalents), a1ky1ar1'1i11e R} N112 (240 gametes, 1.2 equivalents), 211111 a solution, 111’ P321301) (364 mg, 7110 1111101es, 3.5 echtivalehts) disseived, 111 2.09 1111. MeCN (acetonitrde). {1111346} The reaction mixture was heated to 40 CC and a1,lowed to shake at approximately 100 11.1111 overnight. t was 1'e111oved under reduced re to yield the crude pmduet as a thick ve110w oil The product was ted {1-11 extraction) from the C111 by ed washings with 20°/0 "PrOH/Hexanes (3 x 3 1111.). Soiveht was removed from the organic extract using a gentle stream of warmed N3 gas and gehde heat to yield a thick, slightly ye1lovv oil. The crude material was dissolved 111 20% "PrOH/Hexanes? passed through a 0.45 1.1111 syringe filter, and submitted to preparatory 1}: purification. Solvent was removed from the purified materiai using a geh‘de stream of warmed N2: gas and gentle heat to y1'e1d a thick, e01or1ess 011, The pure material was suspended 111 ethy1 lactate 1111' sterage and was submitted to analytical HPLC for caneentratien determination. 47} The foflowmg treprostinil amide derivatives of Fo1111111a. B were made by the synthesis scheme provided above. (Table 17) Percentage y1‘e1d is a1so provided 111 parentheses.
R1\N)1\/o 01" I HOH!- 170111111111 (13) Fremstmil 3.1111111: dertvahves Yietd Command ahhreviatieh Tabig 3.7. Tm mstinii amide derivafi‘vw R1 gmug) Yield C01npmmd abbreviatien N91: Ala—EE—TR—A ined Not (:S'Ejy'AEESEL-T'R-A determined Not iLeun'EVEJI'RmA determined {WMSE {lg—"E‘R—A and (Egg—'i‘R—A were charactarized by NMR spectmsmpy.
NMR Characterization of (Ti’i—‘ii‘R—A H\I\/R(\00 MHZ, CDilzN09€Mq )Hz, 6H), 1.17 (q,.l=l ZGHZ, 1H), 130— l.'70 (m, is H), l.8l~l.83 (m, 1H), 1.80—1.93 (m, 1H), 2.20 (p, 3 6.0 mi iii), 22242.23 (hi, hi), 2.47—2.54 (hi, 2H), 275—28261}, 2H), 3.16 (sextet, 3' = 4.6 Hz, 1H), 3.35 (q. .l = 7.0 Hz, 2H), 3.63 (s, 1H), 373-380(8-1, 1H), 4.48 (s, 2H) 6.55. (s, 1H), 8.7s (a, .t 7.5 Hz, ill), (:85 (at 7.5 Hz, 1H), 7.11 a, J 7.5 Hz, iii) ppm "C NMR (15 845-42., {3013" .3, 228 22.9, 25.6, 26.4, 267(2), 28.8, 29.2, 31.6, 32.1, 33.6, 33.8, 35.l, 37.7, 39.2, 4-1.4, 41.6, 46.5, 52.4, 68.4, 72.9, "(3.4, 122.2, 126.8, 127.3, 143.2, 54.5, N387 ppm; l'iiRMS (ESE, 2:2:1 MeC‘N, MeOH, H20): m": = 47435717 ({M4H}*).
NMR Characterization of C l2—TR—A i-{RMS (1581, 212:1 MeCN, MeOI-i, H20): m/z 55845999 {iM-l-HY} {96.34% Selected treprostihil derivatives were evaiuated for the use in a metered dese inhaler (MUS). Four ester derivatives, dodeeyl—treprostinil (Cm—TR), tetradeeyl—treprestihil (C,43121}, hexadecyi—treprostihi1 (Clmn'I‘R), and the branched Chain riohaiiyl—treprestiiiil (56:79— TR), and two amide derivatives, —A and C12~TR~A (see Tahle l7) were tested for iitym hydrofluoroalkane propellants HEA l 34a and HEA22/ with added ethanol idd35tl§ 5 mg of each treprostinil compound was added in a glass bottle. Specific ai'riouiit of ethanol was added by weight. An MD] valve was erimped to each bottle, and HFA pi‘epeilarit added through the valve to the total volume of 5 mL. Compounds were allowed to dissolve for 24 hours at room ature. The formulatiehs were assessed visually for solubility. The goal was to estimate the minimum ethanol concentration required to solubilize each compound in propellant. {@351} Soluble sairiples presented as clear and coloriess solutions. Less than soluble samples had a thin wapor ring of varieits density visible on the bottle surface at the liquidwapor interface. Non—soluble s had white precipitate or ls formed.
Ethanol was added as a solubility aid. As it can he seen from the solubility tables below (Table 18 and Table 19), compounds that were not soluble at 3% added ethanol became soluble at 10 or 13% added ethanol.
Table is Solubility chart ot iml prgdmgsm it"A 11g4& with addedethaml 'E‘ahie 18. iity chart effl'epmstinii prodmgs in E-iFA-l 343 with added i. 13 "3/5 EEQH 1 {E% EEQH EtOH Etmi E")H S — soluble; R — thin iiquidwapor ring is Visible; P — precipitate is ViSibiC; 11/5: — net evaluated.
Tame 18. Solubility chart of trepmstinii derivatives in HFA~227 with added ethane}.
HFA-ZZ"? EH}H i i}% EH}H EEGH EtflH Eti)H S — soluble; R — thin fiquidwapor ring is Visible; P — precipitate is Visible; 11/e — nut evaluated.
Amide Linked Tre restinil Nana article Formuiatien in Ventiiated Rats {99352} Maie Sprague Dav/Rey rats (N23) were anestl'ietized and prepared with endetraeheal tube fer 'ventiiation. "B"he right i vein was eannuiated to: facilitate 'bieed collections. Rats were administered the lipid nanoparticle formulation T763, which has the following components: (Cjz—TR—A, 45 mol %, squalane 45 mol 9/1), DSPE—PEG’ZQGS ll} mol 0/6). {@353} Aeroneb® nehulizer and a controller (Aerogen, Dangan, Galway, lreland) were used to produce aerosol ofa mass n'tedian aerodynamic diameter (MMAD) between 2.5. um and 4 am and at a rate of ()gl ntL/min. :41 A EAR—830,1’AP Small Animal Ventilator (CWE 1116.9, Ardmore, PA) set up at ventilator tidal volume (VT) of 8 nil/kg, rate of 99 breaths/5min was used to deliver nehttlized test articles of volume 300 hit. The targeted close was 6 tag/kg of 'l‘reprostinil equivalent. {99355} The plasma level of treprostinil were cantly lower than when nanopartiele formulation 17568 (Cu—TR. 40 me! %, squalane 4t) moi %, ehoLPEGZk 10 mol %, DOPC 10 inol %), containing CWTR alleyl ester was used with the same dose. This suggests that the sion rate of the amide eroding is much slower than the rate for the ester prodrug of treprostinil.
} While the described invention has been described with reference to the specific ments thereof it should he understood by those skilled in the art that various changes may he made and equivalents may be tuted t departing from the true spirit and scope of the invention. in addition, many modifications may he made to adopt a particular situation, material, ition of matter, s, process step or steps, to the objective spirit. and scope of the described invention, All such modifications are intended to be within the scope of the claims appended hereto. {@3357} Patents, patent applications, patent application publications, journal articles and protocols referenced herein are incorporated by reference in their entireties, for all purposes.
I/
Claims (38)
1. A compound of a (III), Formula (III), wherein R1 is NH, R2 is a linear C5-C18 alkyl, R5 is H and R6 is H.
2. The compound of claim 1, n R2 is heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadectyl.
3. The compound of claim 1 or 2, wherein R2 is a hexadecyl.
4. A composition comprising a compound of any one of claims 1-3.
5. The composition of claim 4, further comprising a PEGylated lipid.
6. The composition of claim 5, wherein the PEGylated lipid ses PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.
7. The composition of claim 5 or claim 6, wherein the PEGylated lipid comprises PEG2000.
8. The composition of any one of claims 5-7, wherein the lipid portion of the PEGylated lipid is terol.
9. The ition of any one of claims 5-7, wherein the lipid portion of the PEGylated lipid is a phospholipid.
10. The composition of any one of claims 5-7, wherein the lipid portion of the PEGylated lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or royl glycerol (DSG).
11. The composition of claim 10, wherein the lipid portion of the PEGylated lipid is distearoyl phosphatidylethanolamine .
12. The composition of any one of claims 5-7, wherein the PEGylated lipid is cholesterol- PEG2000, DSPE-PEG1000 or DSG-PEG2000.
13. The composition of claim 10 or 11, wherein the PEGylated lipid is DSPE-PEG2000.
14. The composition of any one of claims 5-13, further comprising a hobic ve.
15. The composition of claim 14, wherein the hydrophobic additive is a terpene.
16. The composition of claim 15, wherein the terpene is ne.
17. The composition of any one of claims 4-16, wherein the composition is in the form of a dry powder.
18. Use of a nd according to any one of claims 1-3, or a composition of any one of claims 4-17, for the manufacture of a ment effective in the treatment of pulmonary hypertension (PH) in a patient in need thereof.
19. The use of claim 18, wherein the medicament is formulated for pulmonary stration to the patient.
20. The use of claim 19, wherein the medicament is formulated for pulmonary administration to the patient via a metered dose inhaler, a dry powder inhaler, or a nebulizer.
21. The use of claim 19 or 20, wherein the pulmonary administration comprises administration via a nebulizer.
22. The use of claim 19 or 20, wherein the pulmonary administration ses administration via a dry powder inhaler.
23. The use of claim 19, wherein the composition of claim 17 is used for the manufacture of the medicament, the medicament is formulated for the pulmonary administration to the patient, and the pulmonary administration comprises administration via a dry powder inhaler.
24. The use of claim 18, wherein the medicament is formulated for oral, nasal, intravenous or aneous administration.
25. The use of any one of claims 18-24, wherein the patient is a World Health Organization (WHO) Group I PH t, WHO Group II PH patient, WHO Group III PH patient, WHO Group IV PH patient, or WHO Group V PH patient.
26. The use of claim 25, wherein the t is a WHO Group I PH patient.
27. The use of claim 25, wherein the patient is a WHO Group III PH patient.
28. The use of any of claims 18-24, wherein the pulmonary ension is pulmonary arterial hypertension (PAH).
29. The use of claim 28, wherein the patient is a class I PAH patient, a class II PAH patient, a class III PAH patient, or a class IV PAH t, as categorized by the New York Heart Association (NYHA).
30. The use of any one of claims 18-24, wherein the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.
31. The use of any one of claims 18-24, n the pulmonary hypertension is portopulmonary ension (PPH).
32. The use of any one of claims 18-24, wherein the pulmonary hypertension is idiopathic pulmonary arterial hypertension.
33. The use of any one of claims 18-24, wherein the pulmonary hypertension is familial pulmonary arterial hypertension.
34. The use of any one of claims 18-24 and 27, wherein the pulmonary hypertension is associated with interstitial lung disease.
35. The use of any one of claims 18-34, wherein the medicament is ated to be administered once daily.
36. The use of any one of claims 18-34, wherein the medicament is formulated to be administered twice daily.
37. The use of any one of claims 18-34, wherein the medicament is formulated to be administered three times daily.
38. Use of a nd of any one of claims 1-3, or a composition of any one of claims 4-17, for the manufacture of a medicament effective in the treatment of pulmonary fibrosis in a patient in need thereof. Insmed Incorporated By the Attorneys for the Applicant SPRUSON & FERGUSON Per:
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361895680P | 2013-10-25 | 2013-10-25 | |
| US61/895,680 | 2013-10-25 | ||
| US201361910703P | 2013-12-02 | 2013-12-02 | |
| US61/910,703 | 2013-12-02 | ||
| US201461950967P | 2014-03-11 | 2014-03-11 | |
| US61/950,967 | 2014-03-11 | ||
| US201462028758P | 2014-07-24 | 2014-07-24 | |
| US62/028,758 | 2014-07-24 | ||
| US201462042123P | 2014-08-26 | 2014-08-26 | |
| US62/042,123 | 2014-08-26 | ||
| NZ719297A NZ719297B2 (en) | 2013-10-25 | 2014-10-24 | Prostacyclin compounds, compositions and methods of use thereof |
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| NZ758464A NZ758464A (en) | 2021-03-26 |
| NZ758464B2 true NZ758464B2 (en) | 2021-06-29 |
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