WO2009152160A1 - Inhaled carbaprostacyclin and prostacyclin prodrugs for the treatment of pulmonary arterial hypertension - Google Patents

Inhaled carbaprostacyclin and prostacyclin prodrugs for the treatment of pulmonary arterial hypertension Download PDF

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Publication number
WO2009152160A1
WO2009152160A1 PCT/US2009/046764 US2009046764W WO2009152160A1 WO 2009152160 A1 WO2009152160 A1 WO 2009152160A1 US 2009046764 W US2009046764 W US 2009046764W WO 2009152160 A1 WO2009152160 A1 WO 2009152160A1
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optionally substituted
compound
compound according
pcy
independently
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PCT/US2009/046764
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French (fr)
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William Baker
Josh Van Veldhuizen
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Gilead Sciences, Inc.
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Publication of WO2009152160A1 publication Critical patent/WO2009152160A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • the instant invention relates to the preparation of prodrugs of carbaprostacyclins and prostacyclins for delivery to the lung by aerosolization to effectively treat pulmonary arterial hypertension.
  • Pulmonary Arterial Hypertension (PAH), formerly referred to as Primary Pulmonary Hypertension (PPH), is characterized by continuous high blood pressure in the pulmonary artery. The increased pulmonary vascular resistance leads to right ventricular failure and death. Impaired vascular and endothelial homeostasis may be manifested by reduced synthesis of prostacyclin (PGI 2 ), increased thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin-1 (Giad, A. & Saleh, D. 1995 ⁇ Engl J Med 333:214-221 ; Xue, C & Johns, R. A. 1995 JV Engl J Med 333: 1642- 1644).
  • PKI 2 prostacyclin
  • thromboxane production decreased formation of nitric oxide
  • endothelin-1 (Giad, A. & Saleh, D. 1995 ⁇ Engl J Med 333:214-221 ; Xue, C
  • PAH affects an estimated 50,000 patients in the United States, with only about 15,000 diagnosed and under treatment.
  • the cause of PAH may be unknown or result from other diseases that cause a restriction of blood flow to the lungs, including scleroderma, HIV and lupus. Symptoms of the disease include fatigue, shortness of breath on exertion, chest pain and dizziness. Left untreated, the median survival time following diagnosis may be as short as three years.
  • Flolan must be refrigerated during administration, has a half-life of only 3 to 5 minutes, and must be infused continuously.
  • Alternative prostanoids trepostinil (Remodulin*) and iloprost (Ilomedin ® ) are also used to treat PAH.
  • Trepostinil can be given intravenously or subcutaneously but the subcutaneous form is very painful.
  • An increased risk of sepsis with intravenous treprostinil has been reported by the CDC. Iloprost can be administered intravenously and has a longer half-life than treprostinil.
  • iloprost can be formulated for inhalation (Ventavis ® ).
  • This form of administration has the advantage of selective deposition in the lungs near the site of action of the drug leading to fewer systemic side effects.
  • Ventavis is self- administered 6 to 9 times a day during waking hours and a treatment session requires about 4 to 10 minutes total delivery time. Thus, significant patient time is consumed during the course of the day leading to reduced compliance and insufficient treatment during the sleeping hours.
  • inhaled prostacyclins with a longer duration of action to treat PAH.
  • the instant invention comprises inhalable phenylphosphate-prodrugs of prostacyclins for the treatment of PAH that are activated by phosphatases in the lungs releasing the component prostacyclins.
  • This avoids the peripheral systemic effects of the prostacyclins and provides a sustained release of the prostacyclin.
  • the frequency of administration is reduced compared to the inhaled prostacyclin alone leading to improved patient compliance and improved reduction of the pulmonary blood pressure during the hours of sleep.
  • the invention is a compound of Formula I:
  • each R ! and R 2 is, independently, optionally substituted C 1 -Ci O alkyl, optionally substituted C 2 -C] O alkenyl, optionally substituted C 2 -C]Q alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C f1 -C] 0 aryl, or optionally substituted heteroaryl; or R ! and R 2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S or NR :
  • each G 2 is independently CFb or O; each G 4 is independently optionally substituted Ci-Cg alkylene, optionally substituted C 2 -Cg alkenylene, or optionally substituted C 2 -Cg alkynylene wherein a carbon atom of said optionally substituted Cj-Cg alkylene is, optionally, replaced by O, S, NR 1 ; each G i5" i • s independently a bond or CH 2 ; each R 4 is independently
  • each R 5 is independently optionally substituted Ci-Cs alkyl, optionally substituted C 2 -Cg alkenyl, or optionally substituted C 2 -C & alkynyl wherein a carbon atom of said optionally substituted Ci-Cg alkyl is, optionally, replaced by O, S, NR J ;
  • L is O or -CH 2 O-; and A ⁇ is a pharmaceutically acceptable negative counter ion.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as a liquid or solid dosage form suitable for nebulization, pressurized metered dose inhalation or dry powder delivery.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula ⁇ , or a pharmaceutically acceptable salt thereof, as a liquid or dry powder that can be efficiently aerosolized by metered-dose inhalers; or jet, ultrasonic, pressurized, or vibrating porous plate nebulizers; whereby the predominant aerosol particles produced have a mass median aerodynamic diameter of about 1 to about 5 ⁇ m size range.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the salinity and pH of said composition is adjusted to permit generation of an aerosol well tolerated by patients.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the salinity and pH of said composition is adjusted to permit generation of an aerosol well tolerated by patients and provides optimal conditions for the activity of lung phosphatases.
  • the invention provides a method of treating pulmonary arterial hypertension comprising treating a subject in need thereof with a therapeutically effective amount of a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the invention provides processes and novel intermediates which are useful for preparing the compounds of Formula I.
  • the present invention comprises compounds of Formula I and pharmaceutically acceptable salts thereof and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amo ⁇ hous forms thereof.
  • the compounds, methods, and formulations comprising Formula I are effective treatments for pulmonary arterial hypertension which encompasses WHO Group I, Group II, Group III, Group IV, and Group V classifications.
  • the instant invention comprises a prodrug compound of Formula I comprising a phenylphosphate group and at least one prostacyclin.
  • the phosphate group of the phenylphosphate is cleaved from the prodrug by a phosphatase in the lung liberating one or more prostacyclins.
  • the compounds of Formula I have the following general features: a. A prostacyclin prodrug represented by
  • the phosphate moiety of the phenylphosphate prodrug of Formula I is efficiently cleaved by a lung phosphatase such as alkaline phosphatase as shown in Scheme A.
  • a lung phosphatase such as alkaline phosphatase as shown in Scheme A.
  • SAl a lung phosphatase
  • SA2 is hydrolyzed either chemically or enzymatically by an esterase to liberate the prostacyclin.
  • the phosphate moiety of the phenylphosphate prodrug of Formula I is efficiently cleaved by a lung phosphatase such as alkaline phosphatase as shown in Scheme B.
  • the resulting intermediate prostacyclin prodrug, SAl in a slower step, is hydrolyzed either chemically or enzymatically by an esterase to liberate the prostacyclin.
  • the prostacyclin prodrug comprising X 2 and/or X 3 may be the same or different from that in X 1 .
  • the compounds of Formula I can release one, two, or three prostacyclins and each of these prostacyclins may be the same or different.
  • each of the prostacyclins comprising X 1 , X 2 or X 3 may be released according to, at least, Scheme A or Scheme B.
  • the prostacyclin comprising X 1 , X", or X may be released in any order or sequence according to, at least, Scheme A or Scheme B.
  • the prostacyclin ester of the prodrug is hydrolyzed chemically or by a lung esterase to give a prostacyclin SC2 and another intermediate phenylphosphate prodrag SCl comprising a prostacyclin as shown in Scheme C.
  • the phosphate group of SCl is cleaved by a lung phosphatase to give a prostacyclin prodrug SC3.
  • the prostacyclin prodrug is then hydrolyzed chemicially or by a lung esterase to give the prostacyclin SC4.
  • X may also comprise a prostacyclin prodrug which may be the same or different prostacyclin comprising X 1 or X 2 . In these embodiments, it is intended that the prostacyclin comprising X 1 , X 2 , and X 3 may be hydrolyzed in any order.
  • the Z and G components comprising the highly polarized linking group represented by primarily determine which of the particular embodiments described in Schemes A-C are operable. The methods of selecting those components are described in the examples herein. Without being bound by theoiy. the combination of the highly polarized linking group and charged phosphate group comprising Formula I produces a highly polarized or charged molecule that interacts with the negative charges on the surface of cell membranes leading to sustained release of prostacyclins.
  • Z is a highly polarized center comprising a nitrogen atom or a sulfur atom that may bear a positive charge.
  • Z is ⁇ (NR l R 2 )A W , N(O)R 1 (N-oxide), S(O) (sulfoxide), S(O) 2 , ⁇ (SR')A H , a heterocyclene comprising ® (NR')A H or ⁇ SA H , or a heteroarylene comprising a NA , wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G ! -0-C(0)-PCY is directly bonded to a
  • Z is ⁇ (NR 1 R 2 JA ⁇ , ⁇ (SR 1 JA ⁇ , a heterocyclene comprising ⁇ (NR ! )A (" > or SA ⁇ , or a heteroarylene comprising a NA ⁇ ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G ' -0-C(O)-PCY is directly bonded to a NR or S of said heterocyclene or a N of said heteroarylene.
  • Z is ⁇ (NR ] R 2 )A (" ⁇ .
  • Z is @ (NR l R 2 )A H and R 1 and R 2 are independently methyl or ethyl.
  • Z is (SR ⁇ A ⁇ .
  • Z is a heterocyclene comprising (NR 1 JA ⁇ wherein the -CH 2 - group of -CH 2 -Z-G'-0-C(O)-PCY is directly bonded to a ⁇ NR 1 .
  • Z is a heterocyclene comprising SA* " * wherein the -CH 2 - group Of -CH 2 - Z-G -0-C(O)-PCY is directly bonded to a S of said heterocyclene.
  • Z is a heteroarylene comprising a NA ⁇ 1 wherein the -CH 2 - group of - CH 2 -Z-G 1 -0-C(O)-PCY is directly bonded to a ® N of said heteroarylene.
  • Z is N(O)R ! (N-oxide).
  • Z is S(O) (sulfoxide).
  • each R 1 and R 2 is, independently, optionally substituted C 1 -C 1O alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - Cio alkynyl, optionally substituted C 3 -C10 carbocyclyl, optionally substituted C 6 -Ci O aryl, or optionally substituted heteroaryl; or R ! and R 2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S, or NR 3 .
  • each R ! is, independently, optionally substituted C 1 -C 1O alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - Cio alkynyl, optionally substituted C 3 -C10 carbocyclyl, optionally substituted C 6 -Ci O aryl, or optionally substituted
  • R 1 and R 2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S, or NR 3 .
  • G 1 is independently a bond, optionally substituted C 1 -Ci O alkylene, optionally substituted C 2 -Ci O alkenylene, optionally substituted C 2 -Cio alkynylene, optionally substituted C3 ⁇ Cio carbocyclene, optionally substituted C 6 -C] O arylene, or optionally substituted heteroaryl ene; wherein one or more carbon atoms of said Cj -C 10 alkylene or C 3 -CjO carbocyclene is, optionally, replaced by O, S, NR 3 , -NR 3 C(O)- or -C(O)NR 3 -.
  • G 1 is a bond.
  • G 1 is optionally substituted Cj-Cio alkylene. In another embodiment, G 1 is optionally substituted C 2 -Cs alkylene. In another embodiment, G 1 is optionally substituted C 1 -C 10 alkylene wherein one or more carbon atoms of said C r C ⁇ ) alkylene is replaced by O, S, NR 3 , -NR 3 C(O)- or -C(O)NR 3 -. In another embodiment, G ! is optionally substituted C 2 -C 10 alkenylene. In another embodiment, G is optionally substituted C 2 -Ci 0 alkynylene. In another embodiment, G 1 is optionally substituted C 3 - Cio carbocyclene.
  • G 1 is optionally substituted C J -C JO carbocyclene wherein one or more carbon atoms of said C 3 -Ci O carbocyclene is replaced by O, S, NR 3 , -NR 3 C(O)- or -C(O)NR 3 -.
  • G 1 is optionally substituted C 6 -Ci 0 arylene.
  • G 1 is optionally substituted heteroaryl ene.
  • G 1 is optionally substituted C 2 -C f1 alkylene and Z is (NR 1 R 2 )A (") .
  • G 1 is optionally substituted C- 2 -C 6 alkylene
  • Z is ⁇ (NR 1 R 2 )A (") and each R ! and R 2 is independently methyl or ethyl.
  • each X 2 and X 3 is independently H, F, Cl,
  • Ci-C 3O alkyl optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkyl aryl wherein one to five carbon atoms of said C 1 -C 30 alkyl is optionally replaced by O, S, NR 3 , N(R 3 ) 2 + , or (-OCH 2 CH 2 O-CH- 2 CH 2 O-) n ; and X 1 is -CH 2 -Z-G ⁇ O-C(O)-PCY.
  • X 2 is H, F 5 Cl, Br, optionally substituted Ci-C 30 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Ci-C 30 alkyl is optionally replaced by O, S, NR 3 , N(R 3 J 2 + , or (-OCH 2 CH 2 O-CH- 2CH 2 O-J n ; and each X' and X 3 is independently -CH 2 -Z-G '-0-C(O)-PCY.
  • X 3 is H, F, Cl, Br, optionally substituted Cj-C 3O alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Cj-C 30 alkyl is optionally replaced by O, S, NR 3 , N(R 3 J 2 + , or (- OCH 2 CH 2 O-CH 2 CH 2 O-J n ; and each X ! and X 2 is independently -CH 2 -Z-G '-0-C(O)- PCY.
  • each X 1 , X 2 and X 3 is independently -CH 2 -Z-G '-0-C(OJ-- PCY.
  • X 3 is H and each X 1 and X 2 is independently -CH 2 -Z-G '-0-C(O)-PC Y.
  • X 1 is -CH 2 -Z-G '-0-C(OJ-PCY and PCY is
  • G is O. In another preferred embodiment of this aspect, G 2 is CH 2 . In another preferred embodiment of this aspect, G 5 is a bond. In another preferred embodiment of this aspect, G is -(CH? ⁇ -. In another preferred embodiment of this aspect, G 4 is -CH 2 OCH 2 -. In another preferred embodiment of this aspect, G 4 is -OCH 2 - or -CH 2 O-. In another preferred embodiment of this aspect, X 2 is H. In another preferred embodiment of this aspect, X " is H. In another preferred embodiment of this aspect, each X ⁇ and X J is H, In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A (") . In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A (") . In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A (") . In another preferred embodiment of this aspect, Z is
  • Z is a heterocyclene comprising (NR 1 )A ('] or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G '-0-C(O)-PC Y is directly bonded to a
  • NR 1 of said heterocyclene or a N of said heteroarylene and G 1 is optionally substituted C 1 -C 10 alkylene.
  • X 3 is -CH 2 -Z-G '-0-C(O)-PCY and PCY is
  • G " is O.
  • G 2 is CH 2 .
  • G 5 is a bond.
  • G is -(CH 2 ) ⁇ -
  • G 4 is -CH 2 OCH 2 -.
  • G 4 is -OCH 2 - or -CH 2 O-.
  • X' is
  • X ! is H
  • each X 2 and X s is H.
  • Z is (NR 1 R 2 ) A ('] and G 1 is optionally substituted Ci-C 10 alkylene.
  • G" is O.
  • G 2 is CH 2 .
  • G 5 is a bond.
  • G 4 is -(CEh) 3 -.
  • G 4 is "CH 2 OCH 2 -.
  • G 4 is -OCH 2 - or -CH 2 O-.
  • X ' is H.
  • Z is (NR i R 2 )A (") and G 1 is optionally substituted Ci-Cio alkylene.
  • G is O. In another preferred embodiment of this aspect, G 2 is CH 2 . In another preferred embodiment of this aspect, G 5 is a bond. In another preferred embodiment of this aspect, G 4 is -(CHi) 3 -. In another preferred embodiment of this aspect, G 4 is -CH 2 OCH 2 -. In another preferred embodiment of this aspect, G 4 is -OCH 2 - or -CH 2 O-. In another preferred embodiment of this aspect, X 3 is H. In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A ("> and G 1 is optionally substituted C
  • G" is O.
  • G 2 is CH 2 .
  • G 5 is a bond.
  • G is -(CHi) 3 -.
  • G 4 is -CH 2 OCH 2 -.
  • G 4 is -OCH?- Or-CH 2 O-.
  • Z is
  • NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Cj-Cio alkylene.
  • X " is H. In another embodiment of this aspect, X " is H. In another embodiment of this aspect, each X' and X " is H. In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A ⁇ "> and G 1 is optionally substituted C]-Ci O alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR !
  • X" is H. In another embodiment of this aspect, each X" and X is H. In another preferred embodiment of this aspect, Z is ' (NR R " )A and G 1 is optionally substituted Cj-Cio alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR 1 )A M or a heteroarylene comprising a NA H ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -
  • X ' is H.
  • Z is ® (NR'R 2 )A H and G 1 is optionally substituted Ci-C 10 alkylene.
  • NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Ci-Cio alkylene.
  • X rl is H.
  • Z is (NR ⁇ R 2 )A (") and G 1 is optionally substituted Cs-Cio alkylene.
  • Z is is a heterocyclene comprising (NR 1 ) ⁇ " - 1 or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G l -0-C(O)-PCY is directly bonded to a
  • NR 1 of said heterocyclene or a N of said heteroarylene and G 1 is optionally substituted Q-Cio alkylene.
  • Z is (NR 1 R 2 ) ⁇ and G 1 is optionally substituted Ci-Cjo alkylene.
  • each G 4 is independently optionally substituted C)-Cg alkylene. In another embodiment, each G 4 is independently optionally substituted Ci-Cg alkenylene. In another embodiment, each G 4 is independently optionally substituted C 2 -Cg alkynylene. In another embodiment, each G 4 is independently optionally substituted Cj-Cs alkylene wherein a carbon atom of said optionally substituted Ci-Cg alkylene is, optionally, replaced by O, S, NR " . In a preferred embodiment, each G 4 is independently -(CH 2 )S-. In another preferred embodiment, each G 4 is independently -CH 2 OCH 2 -. In another preferred embodiment, each G 4 is independently -OCH 2 - or -CH 2 O-.
  • each G 5 is independently a bond. In another embodiment each G 5 is independently -CH 2 -.
  • each R 4 is independently
  • each R 5 is independently optionally substituted C)-Cg alkyl. In another preferred embodiment of this aspect, each R 5 is independently optionally substituted C 2 -Cg alkenyl. In another preferred embodiment of this aspect, each R 5 is independently optionally substituted C 2 -Cs alkynyl. In another embodiment, each R 4 is independently optionally substituted C]-Cs alkyl wherein a carbon atom of said optionally substituted Ci-Cg alky] is, optionally, replaced by O, S, NR 3 . In another preferred embodiment of this aspect, each R 5 is independently - (CHo) 4 CHa. In another preferred embodiment of this aspect, each R ⁇ is independently
  • each R 4 is independently OH .
  • each R 5 is independently optionally substituted Ci-Cs alkyl.
  • each R 5 is independently optionally substituted C 2 -Cs alkenyl.
  • each R is independently optionally substituted C?-Cs alkynyl.
  • each R 4 is independently optionally substituted C 1 -C 8 alkyl wherein a carbon atom of said optionally substituted Ci-Cg alkyl is, optionally, replaced by O, S, NR .
  • each R is independently - (CHb) 4 CH 3 .
  • each R 5 is independently
  • each PCY is independently
  • each R is independently selected from
  • each R is
  • each R is
  • each R is
  • each PCY is independently
  • each R is independently selected from
  • each R is
  • each R is OH . In another embodiment of this aspect, each R is
  • each PCY is independently
  • each R 4 is independently selected from
  • each R 4 is
  • each R is . In another embodiment of this aspect, each R is A
  • each PCY is independently .
  • each R is independently selected
  • each R is
  • each R is
  • each PCY is independently .
  • each R 4 is independently selected from
  • each R is
  • each R is
  • each PCY is independently
  • each R is independently selected
  • each R is
  • each R is
  • each R 4 is
  • L is O. In another embodiment, L is -
  • Formula I is a compound or pharmaceutically acceptable salt thereof selected from
  • the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, suitable for treating PAH.
  • Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation.
  • the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 ⁇ m.
  • MMAD mass median aerodynamic diameter
  • the compound of Formula 1 is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).
  • Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate or equivalent nebulizers.
  • a jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets.
  • a vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.
  • compositions of the invention described above provide the drug formulated in a solution permitting delivery of a therapeutically efficient amount of the drug by nebulization provided that the aerosol generated by the nebulization meets criteria required for efficient delivery. Therefore, the nebulizer which aerosolizes the formulation of a compound of Formula I becomes an important feature of the invention.
  • the formulations which can be efficiently nebulized must contain small amounts of the compounds of Formula I which are delivered in small volumes and conform to certain ranges of pH and osmolality.
  • the compound of Formula I is preferably dissolved in a minimal volume of about 0.5 to about 7 niL of an aqueous solvent having a pH between about 4.5 and about 7.5 and comprising chloride, bromine or iodine ions.
  • the formulation has a shelf-life between about one and about two years.
  • the aqueous formulation of a compound of Formula I is prepared just prior to administration to assure the stability of the compound of and to assure a commercially acceptable shelf life of the drag.
  • the fo ⁇ nulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 ⁇ m and about 5 ⁇ m using a nebulizer able to aerosolize the formulation of the compound of Formula I into particles of the required MMAD.
  • a nebulizer able to aerosolize the formulation of the compound of Formula I into particles of the required MMAD.
  • the majority of aerosolized particles should not have a MMAD greater than about 5 ⁇ m. If an aerosol contains a large number of particles with a MMAD larger than 5 ⁇ m, the particles are deposited in the upper airways decreasing the amount of drug delivered to the optimal site of action in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 ⁇ m , then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
  • the solution or diluent used for preparation of the aerosol formulation of a compound of Formula I has a pH range from about 4.5 to about 7.5, more preferably between about 5.5 and about 7.0.
  • the pH of the formulation is an important feature for aerosolized delivery of the compounds of Formula I.
  • the aerosol is either acidic or basic, it can cause bronchospam and cough. Any aerosol with a pH of less than 4.5 typically induces bronchospasm. Aerosols with a pH between 4.5 and 5.5 will cause bronchospasm occasionally. Any aerosol having pH greater than 7.5 is to be avoided as the body tissues are unable to buffer alkaline aerosols.
  • Aerosols with controlled pH below 4.5 and over 7.5 result in lung initiation accompanied by severe bronchospam cough and inflammatory reactions.
  • aqueous formulations outside this pH range may contribute to more rapid degradation of the compounds of Formula I by increasing the cleavage of the esters, carbonate, and solvolytically labile groups in the compounds. Consequently, in a preferred embodiment, the aerosol formulation of a compound of Formula I is adjusted to a pH between about 4.5 and about 7.5 with a more preferred pH range from about 5.5 to about 7.0.
  • a particularly preferred pH range is about 5.5 to about 6.5.
  • Formula 1 may require adjustment of the osmolality of the aerosol formulation to emulate the physiological conditions found in the healthy lungs.
  • Bronchospasm or cough reflexes may not be totally repressed at the osmolality of the diluent for aerosolization, however, they can be sufficiently controlled and/or suppressed when the osmolality of the diluent is in a certain range.
  • the given osmolality controls bronchospasm and the chloride concentration, as a permeant anion, controls cough.
  • formulations for nebulization of compounds of Formula I will have an osmolality between about 50 and about 1200 m ⁇ sm/kg.
  • chloride ion or another anion may need to be added for successful and efficacious delivery of aerosolized compounds of Formula 1 but the amount may be lower than amounts provided and typically used for aerosols of other compounds.
  • the chloride anion can be substituted with bromine or iodine anions, since both are permeant anions.
  • bicarbonate may be wholly or partially substituted for chloride ion.
  • the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the compound of Formula 1 to the lung sufficient to promote pulmonary vasodilation and treat PAH.
  • the amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula I.
  • a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of Formula 1 into the airways.
  • at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof is delivered as a dry inhalable powder.
  • the compounds of the invention are administered endobronchially as a dry powder formulation to efficaciously deliver fine particles of compound into the endobronchial space using dry powder or inetered dose inhalers.
  • the compound of Formula I is processed into particles with, predominantly, MMAD between about 1 ⁇ m and about 5 ⁇ m by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 ⁇ m and about 5 ⁇ m are well know in the art.
  • excipients are added to the compound of Formula I before processing into particles of the required sizes.
  • excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.
  • Particle size determinations are made using devices well known in the art.
  • a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.
  • a compound of Formula I is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices.
  • dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; US5,522,385; US4,6 ⁇ 8,218; US4,667,668; US4, 805,81 1 and US5, 388.572.
  • dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; US5,522,385; US4,6 ⁇ 8,218; US4,667,668; US4, 805,81 1 and US5, 388.572.
  • One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber.
  • the second design is a factory-metered device in which each individual dose has been manufactured in a separate container. Both systems depend on the formulation of the drug into small particles of MMAD from 1 ⁇ m and about 5 ⁇ m, and often involve co-formulation with larger excipient particles such as, but not limited to, lactose.
  • Drag powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity.
  • Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of 1 ⁇ m to about 5 ⁇ tm.
  • a compound of Formula I is delivered as a dry powder using a metered dose inhaler.
  • metered dose inhalers and devices include those disclosed in US5,261 ,538; US5,544,647; US5,622,163; US4,955,371 ; US3,565,070; US3,36130 ⁇ and US6, 116,234.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 ⁇ m.
  • the compounds of Formula I are useful for treating pulmonary arterial hypertension.
  • the amount of active ingredient that may be combined with the excipients to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, is dosed in a therapeutically effective amount ranging from about 10 to about 5000 ⁇ g.
  • the dose will be determined by the host treated and the severity of the disease as determined by those physicians skilled in the art.
  • the drug will be administered four, three, two, or most preferably once a day.
  • a combination of an aerosol formulation of a compound of Formula I and a device significantly enhances the efficiency and speed of drug administration.
  • the average time for administration of other aerosolized drugs is 15-20 minutes per dose.
  • the time required for this treatment represents a significant burden to the patient and contributes to reduced compliance with the recommended dosage regimen.
  • the aerosolizable formulation of a compound of Formula I is delivered by a device capable of delivering a therapeutically effective dose in less than 15 minutes, more preferably in less than 10 minutes, and most preferably in less than 5 minutes,
  • a compound of the invention or “a compound of Formula I” means a compound of Formula 1 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.
  • Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • an alkyl group can have 1 to 30 carbon atoms (i.e, Cj-C 3O alkyl), 1 to 10 carbon atoms (i.e., Ci-C 10 alkyl), or 1 to 6 carbon atoms (i.e., Ci-C 6 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 J 2 ), 1 -butyl (n-Bu, n-butyl.
  • alkenyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 2 O alkenyl), 2 to 12 carbon atoms (i.e.. C 2 -C] 2 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • Alkynyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 2 O alkynyl), 2 to 12 carbon atoms (i.e., C 2 -C] 2 alkyne,), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl).
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 -ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyI (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1 ,3-propyl (-CH 2 CH 2 CH 2 -). 1 ,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkenyl ene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkenyl ene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • uArylalkyI refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical that is optionally substituted.
  • Typical arylalkyl groups include, but are not limited to, benzyl. 2 -phenyl ethan-1-yl, naphthylmethyl, 2-naphthylethan-l -yl, naphthobenzyl, 2-naphthophenyIethan-l -yl and the like.
  • the arylalkyl group can comprise 7 to 26 carbon atoms, e.g., the alkyl moiety is 1 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp 2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • the arylalkenyl group can comprise 8 to 26 carbon atoms, e.g., the alkenyl moiety is 2 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • “Arylalkynyl” refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 8 to 26 carbon atoms, e.g., the alkynyl moiety is 2 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • substituted in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc.
  • substituted alkyl means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH 3 , etc.), an amine (e.g., -NHCH 3 , -N(CHs) 2 , etc.), or a thioalkyl group (e.g., -SCH 3 ).
  • the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -O-CH 3 , etc.), an alkyl amine (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.), or a thioalkyl ether (e.g.,-CH 2 -S-CH 3 ).
  • an alkyl ether e.g., -CH 2 CH 2 -O-CH 3 , etc.
  • an alkyl amine e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.
  • a thioalkyl ether e.g.,-CH 2 -S-CH 3
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH 2 CH 2 -OH), an aminoalkyl group
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a Cj-C f , heteroalkyl group means a heteroalkyl group having 1 to 5 carbon atoms.
  • Heterocyde or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern
  • heterocycle includes a "carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
  • heterocycle or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings).
  • Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups,
  • a non-limiting example of a carbonyl substituted heterocyclyl is:
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrol yl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indole ⁇ yl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl.
  • pyrrolidinyl 2-pyrrolidonyl
  • pyrrolinyl tetrahydro furanyl
  • tetrahydroquinolinyl tetrahydroisoquinolinyl
  • decahydroquinolinyl octahydroisoquinolinyl
  • azocinyl triazinyl, 6H-L2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl
  • pyranyl isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H ⁇
  • carbon bonded heterocyclics are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetraliydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5 -pyridazinyl, 6-pyridazinyl, 2 -pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, ⁇ -pyrimidinyl, 2 -pyrazinyl, 3 -pyrazinyl, 5-pyrazinyl, 6- pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2 -imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1 -aziridyl, 1 ⁇ azetedy], 1 -pyrrol yl, 1-imidazolyl, 1-pyrazolyl, and l-piperidinyl.
  • Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CHb-, 2-(heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry.
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolyl methyl, oxazolylmethyl, thiadiazolylm ethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylniethyl, pyridinylm ethyl, pyridizylm ethyl, pyrimidylmethyl, pyrazinylm ethyl, etc.
  • heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolyl methyl, oxazolylmethyl, thiadiazolylm ethyl, etc.
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp" carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - alkenyl ene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 6 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • Heterocyclyl alkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp J carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - alkynylene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkynyl group comprises 6 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • suitable heteroaryl rings include all of those listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • Carbocycle or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), paitially unsaturated ⁇ e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings.
  • Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, 1- cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohcxyl, 1-cyclohcx-l -cnyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl.
  • Non-limiting examples of bicyclo carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl.
  • Carbocyclene refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic radical as described for "carbocycle” having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent carbocycle.
  • Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene-
  • Heteroarylalkyl refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • Non-limiting examples of heteroarylalkyl include -CH 2 -pyridinyl, -CEb-pyrrolyl, -CHi-oxazolyl, -CH 2 -indolyl, -Ctb-isoindolyl, -C Hi-purinyl, -CH ⁇ -furanyl, -CH ⁇ -thienyl, -CH 2 -benzofuranyl, -CHb-benzothiophenyl, -CH 2 -carbazolyl, -CH 2 -imidazolyl, -CHi-thiazolyl, -Ctk-isoxazolyl, -CH 2 -pyrazolyl, -CH 2 -isot hiazolyl, -CH?-quinolyl,
  • Linker or "link” means a chemical moiety comprising a covalent bond or a chain of atoms. Unless otherwise specified, the carbon atoms of this invention are intended to have a valence of four. In some chemical structure representations where carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substitutents needed to provide a valence of four should be assumed to be hydrogen. For example, 0H has the same meaning as
  • any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na + , Li + , K + ' Ca + ⁇ and Mg + ⁇ ), ammonium and NR 9 4 + (wherein R 9 is Ci-C 4 alkyl).
  • Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene-l ,5-disulfonic acid, polygal
  • Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NR 4 + (wherein R 10 is independently selected from H or a Ci-C 4 alkyl group).
  • Certain embodiments of Formula I comprise positively charged quaternary N and ternary S atoms which will have a negative counter ion A (" ⁇ . It is intended that the negative counter ions A ⁇ will be pharmaceutically acceptable.
  • Non-limiting examples of pharmaceutically acceptable negative counter ions comprise the anions of organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene- 1,5-disulfonic acid, polygalacturonic acid, malonic acid, sulf
  • salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mii ⁇ or images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • a compound of Formula 1 and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures.
  • the crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conform ers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conform ers of the same molecule (conformational pseudopolymorphism).
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula 1 and their pharmaceutically acceptable salts.
  • a compound of Formula I and its pharmaceutically acceptable salts may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents, may be used to create the amorphous forms of the instant invention.
  • the instant invention comprises all amorphous forms of the compounds of Formula I and their pharmaceutically acceptable salts.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • terapéuticaally effective amount is the amount of compound of Formula I present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by inhalation.
  • the precise amount will depend upon numerous factors, for example the particular compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.
  • variable PCY comprises a prostacyclin or carbaprostacyclin or a derivative thereof. Any reference to the term “prostacyclin” herein, is intended to encompass the terms prostacyclin, carbaprostacyclin, or a derivative of either.
  • normal saline means water solution containing 0.9% (w/v) NaCl.
  • diluted saline means normal saline containing 0,9% (w/v) NaCl diluted into its lesser strength.
  • quarter normal saline or "14 NS” means normal saline diluted to its quarter strength containing 0.225% (w/v) NaCI.
  • MMAD mass medium aerodynamic diameter.
  • predominantly means including at least 70% but preferably 90% of particle sizes between 1 ⁇ m and 5 ⁇ m.
  • mutant prodrug refers to a bipartite or tripartite prodrug in which specific bond(s) of the compound are broken or cleaved by the action of an enzyme or by biological process thereby producing or releasing a drug and the carrier which is a synergistic drug of the drug to which it is linked.
  • the present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.
  • 1,2,2,6,6-Pentamethylpiperidine (23 ⁇ L, 126 ⁇ mol) and methanesulfonyl chloride (5.5 ⁇ L, 69 ⁇ mol) were added to a stirring solution of compound represented in Exampie 5 (20 mg, 63 ⁇ mol) in CH 2 Cl 2 (0.6 mL) at 0 0 C.
  • the reaction mixture was stirred for 2 h at 22 0 C then quenched with 10 % (w/v) citric acid (2 mL) and the aqueous was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with satd. NaHCO 3 (3 mL), brine (3 mL), dried over Na?S ⁇ 4 , and concentrated.
  • the title compound is synthesized using terf-butyldimethylsilyl chloride (3 equiv.) and imidazole (4 equiv) to a solution of iloprost in dichlorm ethane.
  • the title compound is synthesized using /erf-butyldimethylsilyl chloride (3 equiv.) and imidazole (4 equiv) to a solution of treprostinil in dichlormethane.
  • Blood samples (approximately 2 mL, or as much as possible) were collected from 6 animals per time point via cardiac puncture (following euthanasia via CO 2 inhalation) into tubes containing K2EDTA. All blood samples were placed on wet ice (or an ice block) following collection. The samples were centrifuged and the plasma was separated and stored frozen at approximately -7O 0 C until analysis. Immediately following blood collection, the lungs from each animal were removed, blotted dry, weighed, and homogenized with 5 mL of 20 mM aqueous sodium EDTA solution on ice. The homogenate was stored at approximately -7O 0 C until analysis. Intratracheal Dosing Procedure
  • the animals were anesthetized with isofhirane vapors utilizing a precision vaporizer (3-5%, 5 to 10 minutes).
  • the rat was suspended by the upper incisors on an incline rack in a supine position. And the rat's tongue was gently retracted to the side to allow access to the back of the throat, which was illuminated with an appropriate lighting device.
  • a Penn CenturyTM Microsprayer ® (Model IA-I B), was attached to a glass tuberculin syringe, was visually inserted into the trachea. Placement in the airway was confirmed by "pulling/pushing" the barrel of the glass syringe.
  • a vacuum or resistance of the barrel indicated that the cannula was in the esophagus. If this occured, the Microsprayer was removed and the procedure reinitiated. No resistance of the barrel assured placement in the airway, and the glass syringe was removed.
  • a luer-lock tip syringe (containing the appropriate volume of test article and approximately 0.1 niL of air) was attached to the Microsprayer, with the air in the syringe displaced above the test article, allowing for full delivery of the test article.
  • the test article was delivered into the airways by pushing the plunger of the syringe on inhalation.
  • the rat remained suspended on the incline rack for an additional 10 to 20 seconds to allow further distribution of the test article into the lungs.
  • Example 9 was administered to rats by the intratracheal route (0.5 mg/kg) and was efficiently cleaved to Example 2 in vivo.
  • lung concentrations of tetrahydro PG12 produced from the prodrug were much higher for 4 hours in the lung with a Cmax of 8 micrograms/g whereas the lung concentration of tetrahydro PGI2 given directly was rapidly cleared ( ⁇ 300 ng/g).

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Abstract

Phenylphosphonate prodrugs comprising one or more prostacyclins are provided for the treatment of pulmonary arterial hypertension. Also provided are inhalable formulations of the prodrugs for delivery by aerosolization or dry powder. The compounds and formulations are useful for producing pulmonary vasodilation and for treating pulmonary arterial hypertension.

Description

INHALED CARBAPROSTACYCLIN AND PROSTACYCLIN PRODRUGS FOR THE TREATMENT OF
PULMONARY ARTERIAL HYPERTENSION
Field of the Invention The instant invention relates to the preparation of prodrugs of carbaprostacyclins and prostacyclins for delivery to the lung by aerosolization to effectively treat pulmonary arterial hypertension.
Background, of the Invention
Pulmonary Arterial Hypertension (PAH), formerly referred to as Primary Pulmonary Hypertension (PPH), is characterized by continuous high blood pressure in the pulmonary artery. The increased pulmonary vascular resistance leads to right ventricular failure and death. Impaired vascular and endothelial homeostasis may be manifested by reduced synthesis of prostacyclin (PGI2), increased thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin-1 (Giad, A. & Saleh, D. 1995 Η Engl J Med 333:214-221 ; Xue, C & Johns, R. A. 1995 JV Engl J Med 333: 1642- 1644).
PAH affects an estimated 50,000 patients in the United States, with only about 15,000 diagnosed and under treatment. The cause of PAH may be unknown or result from other diseases that cause a restriction of blood flow to the lungs, including scleroderma, HIV and lupus. Symptoms of the disease include fatigue, shortness of breath on exertion, chest pain and dizziness. Left untreated, the median survival time following diagnosis may be as short as three years.
Current therapies for PAH utilize calcium channel antagonists, prostacyclins, endothelin receptor antagonist and long-term anticoaglulant therapy. Each of these therapies has limitations and side effects. Prostacyclins are often considered the most effective treatment for PAH. These drugs dilate systemic and pulmonary arterial vascular beds leading to reduced blood pressure in the pulmonary arteries. However, these drugs have disadvantages in terms of their route of administration and/or stability and duration of action. Epoprostenol (marketed as FlolanR) is administered by continuous infusion requiring a semi -permanent central venous catheter. This delivery system can cause sepsis and thrombosis. In addition, Flolan must be refrigerated during administration, has a half-life of only 3 to 5 minutes, and must be infused continuously. Alternative prostanoids trepostinil (Remodulin*) and iloprost (Ilomedin®) are also used to treat PAH. Trepostinil can be given intravenously or subcutaneously but the subcutaneous form is very painful. An increased risk of sepsis with intravenous treprostinil has been reported by the CDC. Iloprost can be administered intravenously and has a longer half-life than treprostinil.
Alternatively, iloprost can be formulated for inhalation (Ventavis®). This form of administration has the advantage of selective deposition in the lungs near the site of action of the drug leading to fewer systemic side effects. However, Ventavis is self- administered 6 to 9 times a day during waking hours and a treatment session requires about 4 to 10 minutes total delivery time. Thus, significant patient time is consumed during the course of the day leading to reduced compliance and insufficient treatment during the sleeping hours. Clearly, there is a need for inhaled prostacyclins with a longer duration of action to treat PAH.
Summary of the Invention
In one aspect, the instant invention comprises inhalable phenylphosphate-prodrugs of prostacyclins for the treatment of PAH that are activated by phosphatases in the lungs releasing the component prostacyclins. This avoids the peripheral systemic effects of the prostacyclins and provides a sustained release of the prostacyclin. As a result, the frequency of administration is reduced compared to the inhaled prostacyclin alone leading to improved patient compliance and improved reduction of the pulmonary blood pressure during the hours of sleep.
In one aspect, the invention is a compound of Formula I:
Figure imgf000004_0001
Formula 1 or a pharmaceutically acceptable salt thereof, wherein: each X1, X2 and X'3 is independently H, F. Cl, Br, optionally substituted C]-C3O alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aϊkylaryl or a group represented by -CH2-Z-G1 ~O-C(=O)-PCY; wherein one to five carbon atoms of said Ci-C30 alkyl is optionally replaced by O, S, NR3, N(R3^+A*"*, or (- OCH2CH2O-CH2CH2O-),,; provided that at least one of X1, X2, or X3 is the group represented by -CH2-Z-G - 0-C(O)-PCY; n is 1 -10;
Z is w (NR1ROA1"', N(O)R' (N-oxide), S(O) (sulfoxide), S(=O)2, Φ w ,(SR > IlΛ)AΛ (w->, a heterocyclene comprising (NR )AH or SA , or a heteroarylene comprising a
NA1" , wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of - CH2-Z-G!-O-C(=O)-PCY is directly bonded to a ® NR1 or Φ S of said heterocyclene or a N of said heteroarylene; each R! and R2 is, independently, optionally substituted C1-CiO alkyl, optionally substituted C2-C]O alkenyl, optionally substituted C2-C]Q alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Cf1-C]0 aryl, or optionally substituted heteroaryl; or R! and R2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S or NR :
- 3 each G is independently a bond, optionally substituted Ci-Cjo alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-Ci0 alkynylene, optionally substituted C3-C10 carbocyclene, optionally substituted Cf1-C1O arylene, or optionally substituted heteroarylene; wherein one or more carbon atoms of said CI-C10 alkylene or C3-C10 carbocyclene is, optionally, replaced by O, S, NR3, -NR3C(O)- or - C(O)NR3-; each R3 is independently H or Ci -C4 alkyl; each PCY is independently
Figure imgf000005_0001
OH > OH or OH wherein: each G2 is independently CFb or O; each G4 is independently optionally substituted Ci-Cg alkylene, optionally substituted C2-Cg alkenylene, or optionally substituted C2-Cg alkynylene wherein a carbon atom of said optionally substituted Cj-Cg alkylene is, optionally, replaced by O, S, NR1; each G i5" i •s independently a bond or CH2; each R4 is independently
Figure imgf000005_0002
each R5 is independently optionally substituted Ci-Cs alkyl, optionally substituted C2-Cg alkenyl, or optionally substituted C2-C& alkynyl wherein a carbon atom of said optionally substituted Ci-Cg alkyl is, optionally, replaced by O, S, NR J;
L is O or -CH2O-; and A^ is a pharmaceutically acceptable negative counter ion.
In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as a liquid or solid dosage form suitable for nebulization, pressurized metered dose inhalation or dry powder delivery.
In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula ϊ, or a pharmaceutically acceptable salt thereof, as a liquid or dry powder that can be efficiently aerosolized by metered-dose inhalers; or jet, ultrasonic, pressurized, or vibrating porous plate nebulizers; whereby the predominant aerosol particles produced have a mass median aerodynamic diameter of about 1 to about 5 μm size range. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the salinity and pH of said composition is adjusted to permit generation of an aerosol well tolerated by patients.
In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the salinity and pH of said composition is adjusted to permit generation of an aerosol well tolerated by patients and provides optimal conditions for the activity of lung phosphatases.
In another aspect, the invention provides a method of treating pulmonary arterial hypertension comprising treating a subject in need thereof with a therapeutically effective amount of a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides processes and novel intermediates which are useful for preparing the compounds of Formula I. In another aspect, the present invention comprises compounds of Formula I and pharmaceutically acceptable salts thereof and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amoφhous forms thereof.
In another aspect, the compounds, methods, and formulations comprising Formula I are effective treatments for pulmonary arterial hypertension which encompasses WHO Group I, Group II, Group III, Group IV, and Group V classifications.
Detailed Description of the Invention
In one aspect, the instant invention comprises a prodrug compound of Formula I comprising a phenylphosphate group and at least one prostacyclin. Without being bound by theory, the phosphate group of the phenylphosphate is cleaved from the prodrug by a phosphatase in the lung liberating one or more prostacyclins.
In another aspect, the compounds of Formula I have the following general features: a. A prostacyclin prodrug represented by
Figure imgf000007_0001
b. A highly polarized linking group represented by
S -f r>1 r
that links the carbonyl group of the prostacyclin prodrug to a phenylphosphate group c. A phenylphosphate group represented by
Figure imgf000008_0001
Without being bound by theory, in one embodiment, the phosphate moiety of the phenylphosphate prodrug of Formula I is efficiently cleaved by a lung phosphatase such as alkaline phosphatase as shown in Scheme A. The resulting intermediate prostacyclin prodrug, SAl, in a slower step, is solvolyzed to produce another intermediate prodrug of the prostacyclin, SA2. Subsequently, SA2 is hydrolyzed either chemically or enzymatically by an esterase to liberate the prostacyclin.
Scheme A.
Figure imgf000008_0002
solvolysis
-G1
Figure imgf000008_0003
hydrolysis PCY (chemical or PCY enzymatically SA2 mediated) Without being bound by theory, in another embodiment, the phosphate moiety of the phenylphosphate prodrug of Formula I is efficiently cleaved by a lung phosphatase such as alkaline phosphatase as shown in Scheme B. The resulting intermediate prostacyclin prodrug, SAl, in a slower step, is hydrolyzed either chemically or enzymatically by an esterase to liberate the prostacyclin.
Scheme B
Figure imgf000009_0001
hydrolysis (chemical or enzymatically mediated)
Figure imgf000009_0002
In other embodiments, X2 and/or X3 may also be -CH2-Z-G !-O-C(=O)-PCY and. therefore, comprise a prostacyclin prodrug. In these embodiments, the prostacyclin prodrug comprising X2 and/or X3 may be the same or different from that in X1. It is intended that the compounds of Formula I can release one, two, or three prostacyclins and each of these prostacyclins may be the same or different. Without being bound by theory, each of the prostacyclins comprising X1 , X2 or X3 may be released according to, at least, Scheme A or Scheme B. In addition, it is intended that the prostacyclin comprising X1, X", or X may be released in any order or sequence according to, at least, Scheme A or Scheme B.
Without being bound by theory, in another embodiment, the prostacyclin ester of the prodrug is hydrolyzed chemically or by a lung esterase to give a prostacyclin SC2 and another intermediate phenylphosphate prodrag SCl comprising a prostacyclin as shown in Scheme C. Subsequently, the phosphate group of SCl is cleaved by a lung phosphatase to give a prostacyclin prodrug SC3. The prostacyclin prodrug is then hydrolyzed chemicially or by a lung esterase to give the prostacyclin SC4. Although the prostacyclin in the ortho position is cleaved first as depicted in Scheme C, it should be understood that in some embodiments the prostacyclin in the para position may be hydrolyzed first instead of the prostacyclin in the ortho position. In other embodiments, X" may also comprise a prostacyclin prodrug which may be the same or different prostacyclin comprising X1 or X2. In these embodiments, it is intended that the prostacyclin comprising X1, X2, and X3 may be hydrolyzed in any order.
Scheme C
Figure imgf000010_0001
lung phosphatase
Figure imgf000010_0002
At least, all of the embodiments represented by Schemes A-C are within the scope of the phenylphosphate prodrugs of Formula I.
In another aspect, the Z and G components comprising the highly polarized linking group represented by
Figure imgf000011_0001
primarily determine which of the particular embodiments described in Schemes A-C are operable. The methods of selecting those components are described in the examples herein. Without being bound by theoiy. the combination of the highly polarized linking group and charged phosphate group comprising Formula I produces a highly polarized or charged molecule that interacts with the negative charges on the surface of cell membranes leading to sustained release of prostacyclins.
In one aspect, as represented in Formula 1, Z is a highly polarized center comprising a nitrogen atom or a sulfur atom that may bear a positive charge. In one embodiment of Formula I, Z is Φ (NRlR2)AW, N(O)R1 (N-oxide), S(O) (sulfoxide), S(O)2, θ (SR')AH, a heterocyclene comprising ® (NR')AH or φ SAH, or a heteroarylene comprising a NA , wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G!-0-C(0)-PCY is directly bonded to a
NR or S of said heterocyclene or a N of said heteroarylene. In another embodiment, Z is Φ (NR1R2JA^, Φ (SR1JA^, a heterocyclene comprising θ (NR!)A("> or SA^, or a heteroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G ' -0-C(O)-PCY is directly bonded to a NR or S of said heterocyclene or a N of said heteroarylene. In another embodiment. Z is θ (NR]R2)A("}. In another embodiment, Z is @ (NRlR2)AH and R1 and R2 are independently methyl or ethyl. In another embodiment, Z is (SR^A^. In another embodiment, Z is a heterocyclene comprising (NR1JA^ wherein the -CH2- group of -CH2-Z-G'-0-C(O)-PCY is directly bonded to a θ NR1. In another embodiment, Z is a heterocyclene comprising SA*"* wherein the -CH2- group Of -CH2- Z-G -0-C(O)-PCY is directly bonded to a S of said heterocyclene. In another embodiment, Z is a heteroarylene comprising a NA^1 wherein the -CH2- group of - CH2-Z-G1 -0-C(O)-PCY is directly bonded to a ® N of said heteroarylene. In another embodiment, Z is N(O)R! (N-oxide). In another embodiment, Z is S(O) (sulfoxide). In another embodiment, Z is S(==O)2-
In another embodiment of Formula I, each R1 and R2 is, independently, optionally substituted C1-C1O alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2- Cio alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-CiO aryl, or optionally substituted heteroaryl; or R! and R2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S, or NR3. In another embodiment, each R! and R" is, independently, optionally substituted CrC6 alkyl. In another embodiment, R1 and R2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S, or NR3.
In another embodiment of Formula I, G1 is independently a bond, optionally substituted C1-CiO alkylene, optionally substituted C2-CiO alkenylene, optionally substituted C2-Cio alkynylene, optionally substituted C3~Cio carbocyclene, optionally substituted C6-C]O arylene, or optionally substituted heteroaryl ene; wherein one or more carbon atoms of said Cj -C 10 alkylene or C3-CjO carbocyclene is, optionally, replaced by O, S, NR3, -NR3C(O)- or -C(O)NR3-. In one embodiment, G1 is a bond. In another embodiment, G1 is optionally substituted Cj-Cio alkylene. In another embodiment, G1 is optionally substituted C2-Cs alkylene. In another embodiment, G1 is optionally substituted C1-C10 alkylene wherein one or more carbon atoms of said CrCκ) alkylene is replaced by O, S, NR3, -NR3C(O)- or -C(O)NR3-. In another embodiment, G! is optionally substituted C2-C10 alkenylene. In another embodiment, G is optionally substituted C2-Ci0 alkynylene. In another embodiment, G1 is optionally substituted C3- Cio carbocyclene. In another embodiment, G1 is optionally substituted CJ-C JO carbocyclene wherein one or more carbon atoms of said C3-CiO carbocyclene is replaced by O, S, NR3, -NR3C(O)- or -C(O)NR3-. In another embodiment, G1 is optionally substituted C6-Ci 0 arylene. In another embodiment, G1 is optionally substituted heteroaryl ene. In a preferred embodiment, G1 is optionally substituted C2-Cf1 alkylene and Z is (NR1R2)A("). In another preferred embodiment, G1 is optionally substituted C- 2-C6 alkylene, Z is φ (NR1R2)A(") and each R! and R2 is independently methyl or ethyl. In another embodiment of Formula I, each X2 and X3 is independently H, F, Cl,
Br, optionally substituted Ci-C3O alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkyl aryl wherein one to five carbon atoms of said C1-C30 alkyl is optionally replaced by O, S, NR3, N(R3)2 +, or (-OCH2CH2O-CH- 2CH2O-)n; and X1 is -CH2-Z-G^O-C(O)-PCY. In another embodiment, each X! and X2 is independently H, F, Cl, Br, optionally substituted C1-C30 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Cj-C3O alkyl is optionally replaced by O, S, NR3, N(R3J2 """, or (- OCH2CH2O-CH2CH2O-)!,; and X3 is -CH2-Z-G '-0-Cf=O)-PCY. In another embodiment, each X2 and X3 is H and X1 is -CH2-Z-Gl-O-C(=O)-PCY. In another embodiment, each X1 and X2 is H and X3 is -CH2-Z-G1 -O-C(=O)-PCY. in another embodiment, X2 is H, F5 Cl, Br, optionally substituted Ci-C30 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Ci-C30 alkyl is optionally replaced by O, S, NR3, N(R3J2 +, or (-OCH2CH2O-CH- 2CH2O-Jn; and each X' and X3 is independently -CH2-Z-G '-0-C(O)-PCY. In another embodiment, X3 is H, F, Cl, Br, optionally substituted Cj-C3O alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Cj-C30 alkyl is optionally replaced by O, S, NR3, N(R3J2 +, or (- OCH2CH2O-CH2CH2O-Jn; and each X! and X2 is independently -CH2-Z-G '-0-C(O)- PCY. In another embodiment, each X1, X2 and X3 is independently -CH2-Z-G '-0-C(OJ-- PCY. In a preferred embodiment, X1 is H and each X2 and X3 is independently -CH2-Z- G'-O-C(=OJ-PCY. In another preferred embodiment, X3 is H and each X1 and X2 is independently -CH2-Z-G '-0-C(O)-PC Y.
In another aspect of Formula L X1 is -CH2-Z-G '-0-C(OJ-PCY and PCY is
Figure imgf000013_0001
In a preferred embodiment of this aspect, G is O. In another preferred embodiment of this aspect, G2 is CH2. In another preferred embodiment of this aspect, G5 is a bond. In another preferred embodiment of this aspect, G is -(CH?^-. In another preferred embodiment of this aspect, G4 is -CH2OCH2-. In another preferred embodiment of this aspect, G4 is -OCH2- or -CH2O-. In another preferred embodiment of this aspect, X2 is H. In another preferred embodiment of this aspect, X" is H. In another preferred embodiment of this aspect, each X~ and XJ is H, In another preferred embodiment of this aspect, Z is (NR1R2)A("). In another preferred embodiment of this aspect, Z is
(NR1R2)A(") and G1 is optionally substituted C1-C]O alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR1 )A('] or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G '-0-C(O)-PC Y is directly bonded to a
NR of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR^A*"'1 or a heteroarylene comprising a NA(**; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G'-O-C(=O)-PCY is directly bonded to a
NR1 of said heterocyclene or a N of said heteroarylene and G1 is optionally substituted C1-C10 alkylene.
In another aspect of Formula I, X3 is -CH2-Z-G '-0-C(O)-PCY and PCY is
Figure imgf000014_0001
In a preferred embodiment of this aspect, G" is O. In another preferred embodiment of this aspect, G2 is CH2. In another preferred embodiment of this aspect, G5 is a bond. In another preferred embodiment of this aspect, G is -(CH2)^- In another preferred embodiment of this aspect, G4 is -CH2OCH2-. In another preferred embodiment of this aspect, G4 is -OCH2- or -CH2O-. In another preferred embodiment of this aspect, X' is
_ i3 _ H. In another preferred embodiment of this aspect, X! is H, In another preferred embodiment of this aspect, each X2 and Xs is H. In another preferred embodiment of this aspect, Z is (NR1 R2) A('] and G1 is optionally substituted Ci-C10 alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR )A('} or a heteroarylene comprising a NAH; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G '-O-C(=O)-PCY is directly bonded to a
NR of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR )A or a heteroarylene comprising a NA(^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G1-O-C(=O)-PCY is directly bonded to a NR1 of said heterocyclene or a N of said heteroarylene and G ! is optionally substituted Ci-Cio alkylene.
In another aspect of Formula I, each X! and X3 is independently -CH2-Z-G '-O- C(=O)-PCY and PCY is
Figure imgf000015_0001
OH ' OH or OH In a preferred embodiment of this aspect, G" is O. ϊn another preferred embodiment of this aspect, G2 is CH2. in another preferred embodiment of this aspect, G5 is a bond. In another preferred embodiment of this aspect, G4 is -(CEh)3-. In another preferred embodiment of this aspect, G4 is "CH2OCH2-. In another preferred embodiment of this aspect, G4 is -OCH2- or -CH2O-. In another preferred embodiment of this aspect, X' is H. In another preferred embodiment of this aspect, Z is (NRiR2)A(") and G1 is optionally substituted Ci-Cio alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR1)^"' or a heteroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z- G!-O-C(=O)-PCY is directly bonded to a ® NR1 of said heterocyclene or a ® N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR )A or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CHi- group of -CH2-Z-G '-O-C(=O)-PC Y is directly bonded to a NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Ci-C10 alkylene.
In another aspect of Formula I, each X1 and X2 is independently -CHo-Z-G1 -O- C(=O)-PCY and PCY is
Figure imgf000016_0001
In a preferred embodiment of this aspect, G is O. In another preferred embodiment of this aspect, G2 is CH2. In another preferred embodiment of this aspect, G5 is a bond. In another preferred embodiment of this aspect, G4 is -(CHi)3-. In another preferred embodiment of this aspect, G4 is -CH2OCH2-. In another preferred embodiment of this aspect, G4 is -OCH2- or -CH2O-. In another preferred embodiment of this aspect, X3 is H. In another preferred embodiment of this aspect, Z is (NR1R2)A("> and G1 is optionally substituted C|-Cjo alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR !)A("' or a heteroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z- G'-O-C(=O)-PCY is directly bonded to a Θ NR! of said heterocyclene or a ® N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NRl)A(") or a heteroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G '-0-Ct=O)-PCY is directly bonded to a NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted C1-CiO alkylene.
In another aspect of Formula I, each X1, X2 and X3 is independently -CHi-Z-G1- O-C(=O)-PCY and PCY is
Figure imgf000017_0001
OH OH or OH
In a preferred embodiment of this aspect, G" is O. In another preferred embodiment of this aspect, G2 is CH2. In another preferred embodiment of this aspect, G5 is a bond. In another preferred embodiment of this aspect, G is -(CHi)3-. In another preferred embodiment of this aspect, G4 is -CH2OCH2-. In another preferred embodiment of this aspect, G4 is -OCH?- Or-CH2O-. In another preferred embodiment of this aspect, Z is
(NR1R2JA^ and G1 is optionally substituted C]-C1 O alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR )A or a heteroarylene comprising a NA*"-1; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G'-0-C(=O)-PCY is directly bonded to a
NR of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR^A^ or a heteroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G1 -O-C(=O)-PCY is directly bonded to a
NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Cj-Cio alkylene.
In another aspect of Formula I, X! is -CH2-Z-Gi-O-C(=O)-PCY and PCY is
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
In another embodiment of this aspect, X" is H. In another embodiment of this aspect X" is H. In another embodiment of this aspect, each X' and X" is H. In another preferred embodiment of this aspect, Z is (NR1R2)A<"> and G1 is optionally substituted C]-CiO alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR!)A(*) or a heteroarylene comprising a NA(^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CHo-Z-G ]-O-C(=O)-PCY is directly bonded to a NR of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR^A*"'1 or a heleroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G'-O-C(=O)-PCY is directly bonded to a NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Cj-Cio alkylene.
In another aspect of Formula I, X3 is -CH2-Z-G1 -O-C(=O)-PCY and PCY is
Figure imgf000019_0001
In another embodiment of this aspect, X" is H. In another embodiment of this aspect, each X" and X is H. In another preferred embodiment of this aspect, Z is ' (NR R" )A and G1 is optionally substituted Cj-Cio alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR1 )AM or a heteroarylene comprising a NAH; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -
CH2-Z-G!-O-C(=O)-PCY is directly bonded to a ® NR5 of said heterocyclene or a φ N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR )A or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CHi-Z-G1 -O- C(=O)-PCY is directly bonded to a NR of said heterocyclene or a N of said heteroarylene and G] is optionally substituted Ci-Cio alkylene.
In another aspect of Formula 1, each X1 and X3 is independently -CH2-Z-G1 -O- C(=O)-PCY and PCY is
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
In another embodiment of this aspect, X' is H. In another preferred embodiment of this aspect, Z is ® (NR'R2)AH and G1 is optionally substituted Ci-C10 alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NRI)A(") or a heteroarylene comprising a NA ,(-). , wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G '-0-Q=O)-PC Y is directly bonded to a
NR of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR^A^ or a heteroarylene comprising a θ- NA Λ1-). ; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G -O-C(=O)-PCY is directly bonded to a
NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Ci-Cio alkylene.
In another aspect of Foπnula I, each X1 and X2 is independently -CH2-Z-G!-0- C(=O)-PCY and PCY is
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
In another embodiment of this aspect, X rl is H. In another preferred embodiment of this aspect, Z is (NRΪR2)A(") and G1 is optionally substituted Cs-Cio alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR )AW or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G '~O-C(=O)-PCY is directly bonded to a
NRS of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR1)^"-1 or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-G l -0-C(O)-PCY is directly bonded to a
NR1 of said heterocyclene or a N of said heteroarylene and G1 is optionally substituted Q-Cio alkylene.
In another aspect of Formula I, each X1, X and X3 is independently -CH2-Z-G - O-C(=O)-PCY and PCY is
Figure imgf000024_0001
Figure imgf000024_0002
another preferred embodiment of this aspect, Z is (NR1R2)^ and G1 is optionally substituted Ci-Cjo alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR1JA^ or a heteroarylene comprising a NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH^-Z-G '-O- C(=O)-PCY is directly bonded to a NR1 of said heterocyclene or a N of said heteroarylene. In another preferred embodiment of this aspect, Z is is a heterocyclene comprising (NR ')A("' or a heteroarylene comprising a NA("}; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of -CH2-Z-Gi-0-C(=0)-PCY is directly bonded to a NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Ci-Cio alkylene.
In another embodiment of Formula I, each G4 is independently optionally substituted C)-Cg alkylene. In another embodiment, each G4 is independently optionally substituted Ci-Cg alkenylene. In another embodiment, each G4 is independently optionally substituted C2-Cg alkynylene. In another embodiment, each G4 is independently optionally substituted Cj-Cs alkylene wherein a carbon atom of said optionally substituted Ci-Cg alkylene is, optionally, replaced by O, S, NR" . In a preferred embodiment, each G4 is independently -(CH2)S-. In another preferred embodiment, each G4 is independently -CH2OCH2-. In another preferred embodiment, each G4 is independently -OCH2- or -CH2O-.
In another embodiment of Formula I, each G5 is independently a bond. In another embodiment each G5 is independently -CH2-.
In another aspect of Formula ϊ, each R4 is independently
Figure imgf000025_0001
. In a preferred embodiment of this aspect, each R5 is independently optionally substituted C)-Cg alkyl. In another preferred embodiment of this aspect, each R5 is independently optionally substituted C2-Cg alkenyl. In another preferred embodiment of this aspect, each R5 is independently optionally substituted C2-Cs alkynyl. In another embodiment, each R4 is independently optionally substituted C]-Cs alkyl wherein a carbon atom of said optionally substituted Ci-Cg alky] is, optionally, replaced by O, S, NR3. In another preferred embodiment of this aspect, each R5 is independently - (CHo)4CHa. In another preferred embodiment of this aspect, each R^ is independently
Figure imgf000025_0002
In another aspect of Formula I, each R4 is independently OH . In a preferred embodiment of this aspect, each R5 is independently optionally substituted Ci-Cs alkyl. In another preferred embodiment of this aspect, each R5 is independently optionally substituted C2-Cs alkenyl. In another preferred embodiment of this aspect, each R is independently optionally substituted C?-Cs alkynyl. In another embodiment, each R4 is independently optionally substituted C1-C8 alkyl wherein a carbon atom of said optionally substituted Ci-Cg alkyl is, optionally, replaced by O, S, NR . In another preferred embodiment of this aspect, each R is independently - (CHb)4CH3. In another preferred embodiment of this aspect, each R5 is independently
Figure imgf000026_0001
In another aspect of Formula I, each PCY is independently
Figure imgf000026_0002
. In another embodiment of this aspect each R is independently selected from
r
Figure imgf000026_0003
OH
In another embodiment of this aspect, each R is
Figure imgf000027_0001
OH In another embodiment of this aspect, each R is
_ In another embodiment of this aspect, each R is
Figure imgf000027_0002
OH In another aspect of Formula L each PCY is independently
Figure imgf000027_0003
. In another embodiment of this aspect each R is independently selected from
Figure imgf000027_0004
OH OH or
Figure imgf000027_0005
4 .
In another embodiment of this aspect, each R is
Figure imgf000027_0006
OH In another embodiment of this aspect, each R is OH . In another embodiment of this aspect, each R is
Figure imgf000028_0001
In another aspect of Formula I, each PCY is independently
Figure imgf000028_0002
, In another embodiment of this aspect each R4 is independently selected from
Figure imgf000028_0003
In another embodiment of this aspect, each R4 is
Figure imgf000028_0004
OH In another embodiment of this aspect, each R is
Figure imgf000028_0005
. In another embodiment of this aspect, each R is A
OH
In another aspect of Formula I, each PCY is independently . In another embodiment of this aspect each R is independently selected
Figure imgf000029_0001
Figure imgf000029_0002
In another embodiment of this aspect, each R is
Figure imgf000029_0003
OH In another embodiment of this aspect, each R 4 i •s
In another embodiment of this aspect, each R is
Figure imgf000029_0004
OH In another aspect of Formula I, each PCY is independently
Figure imgf000030_0001
. In another embodiment of this aspect each R4 is independently selected from
Figure imgf000030_0002
In another embodiment of this aspect, each R 4 i •s
Figure imgf000030_0003
OH In another embodiment of this aspect, each R is
Figure imgf000030_0004
OH . In another embodiment of this aspect, each R is
Figure imgf000030_0005
OH
In another aspect of Formula I, each PCY is independently
. In another embodiment of this aspect each R is independently selected
Figure imgf000031_0001
Figure imgf000031_0002
OH
In another embodiment of this aspect, each R is
Figure imgf000031_0003
OH In another embodiment of this aspect, each R is
. In another embodiment of this aspect, each R4 is
Figure imgf000031_0004
OH
In another embodiment of Formula I, L is O. In another embodiment, L is -
CH^O-.
In another embodiment, Formula I is a compound or pharmaceutically acceptable salt thereof selected from
Figure imgf000032_0001
Figure imgf000033_0001
In another aspect, the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, suitable for treating PAH. Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation.
Preferably, the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 μm. Preferably, the compound of Formula 1 is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).
Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate or equivalent nebulizers. A jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets. A vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.
Certain compositions of the invention described above provide the drug formulated in a solution permitting delivery of a therapeutically efficient amount of the drug by nebulization provided that the aerosol generated by the nebulization meets criteria required for efficient delivery. Therefore, the nebulizer which aerosolizes the formulation of a compound of Formula I becomes an important feature of the invention. However, only some formulations of the compounds of Formula I can be efficiently nebulized using a given device, as the devices are sensitive to the physical and chemical properties of the formulation. Typically, the formulations which can be efficiently nebulized must contain small amounts of the compounds of Formula I which are delivered in small volumes and conform to certain ranges of pH and osmolality.
For delivery by nebulizer, the compound of Formula I is preferably dissolved in a minimal volume of about 0.5 to about 7 niL of an aqueous solvent having a pH between about 4.5 and about 7.5 and comprising chloride, bromine or iodine ions. In a preferred embodiment, the formulation has a shelf-life between about one and about two years. In another embodiment, the aqueous formulation of a compound of Formula I is prepared just prior to administration to assure the stability of the compound of and to assure a commercially acceptable shelf life of the drag.
In a preferred embodiment, the foπnulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 μm and about 5 μm using a nebulizer able to aerosolize the formulation of the compound of Formula I into particles of the required MMAD. To be optimally therapeutically effective and to avoid upper respiratory and systemic side effects, the majority of aerosolized particles should not have a MMAD greater than about 5 μm. If an aerosol contains a large number of particles with a MMAD larger than 5 μm, the particles are deposited in the upper airways decreasing the amount of drug delivered to the optimal site of action in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 μm , then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
In a preferred embodiment, the solution or diluent used for preparation of the aerosol formulation of a compound of Formula I has a pH range from about 4.5 to about 7.5, more preferably between about 5.5 and about 7.0. The pH of the formulation is an important feature for aerosolized delivery of the compounds of Formula I. When the aerosol is either acidic or basic, it can cause bronchospam and cough. Any aerosol with a pH of less than 4.5 typically induces bronchospasm. Aerosols with a pH between 4.5 and 5.5 will cause bronchospasm occasionally. Any aerosol having pH greater than 7.5 is to be avoided as the body tissues are unable to buffer alkaline aerosols. Aerosols with controlled pH below 4.5 and over 7.5 result in lung initiation accompanied by severe bronchospam cough and inflammatory reactions. In addition, aqueous formulations outside this pH range may contribute to more rapid degradation of the compounds of Formula I by increasing the cleavage of the esters, carbonate, and solvolytically labile groups in the compounds. Consequently, in a preferred embodiment, the aerosol formulation of a compound of Formula I is adjusted to a pH between about 4.5 and about 7.5 with a more preferred pH range from about 5.5 to about 7.0. A particularly preferred pH range is about 5.5 to about 6.5.
Patients suffering from acute or chronic lung diseases have increased sensitivity to various chemical agents and have a high incidence of bronchospastic asthmatic or cough incidents. Their airways are particularly sensitive to hypotonic or hypertonic and acidic or alkaline conditions and to the presence of any permeant ion such as chloride. Any imbalance in these conditions or a presence of chloride above certain concentrations leads to bronchospastic or inflammatory events and/or cough which inpairs treatment with inhalable formulaltions. The compounds of Formula I comprise several charged centers that potentially comprise ionic counter ions that would contribute to the tonicity of the aerosol formulation. The solution for the aerosol formulation of the compounds of
Formula 1 may require adjustment of the osmolality of the aerosol formulation to emulate the physiological conditions found in the healthy lungs.
Bronchospasm or cough reflexes may not be totally repressed at the osmolality of the diluent for aerosolization, however, they can be sufficiently controlled and/or suppressed when the osmolality of the diluent is in a certain range. The given osmolality controls bronchospasm and the chloride concentration, as a permeant anion, controls cough. In a preferred embodiment, formulations for nebulization of compounds of Formula I will have an osmolality between about 50 and about 1200 mθsm/kg. Certain amounts of chloride ion or another anion may need to be added for successful and efficacious delivery of aerosolized compounds of Formula 1 but the amount may be lower than amounts provided and typically used for aerosols of other compounds. In this latter regard and in another embodiment, the chloride anion can be substituted with bromine or iodine anions, since both are permeant anions. In another embodiment, bicarbonate may be wholly or partially substituted for chloride ion.
When formulated and delivered according to the method of the invention, the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the compound of Formula 1 to the lung sufficient to promote pulmonary vasodilation and treat PAH. The amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula I. In a preferred embodiment, a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of Formula 1 into the airways. In a preferred embodiment, at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.
In another embodiment of the instant invention, a compound of Formula I or a pharmaceutically acceptable salt thereof, is delivered as a dry inhalable powder. The compounds of the invention are administered endobronchially as a dry powder formulation to efficaciously deliver fine particles of compound into the endobronchial space using dry powder or inetered dose inhalers. For delivery by DPI, the compound of Formula I is processed into particles with, predominantly, MMAD between about 1 μm and about 5 μm by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 μm and about 5 μm are well know in the art. In one embodiment, excipients are added to the compound of Formula I before processing into particles of the required sizes. In another embodiment, excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.
Particle size determinations are made using devices well known in the art. For example a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.
In another preferred embodiment, a compound of Formula I is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices. Non-limiting examples of dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; US5,522,385; US4,6ό8,218; US4,667,668; US4, 805,81 1 and US5, 388.572. There are two major designs of dry powder inhalers. One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber. The second design is a factory-metered device in which each individual dose has been manufactured in a separate container. Both systems depend on the formulation of the drug into small particles of MMAD from 1 μm and about 5 μm, and often involve co-formulation with larger excipient particles such as, but not limited to, lactose. Drag powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs. In preferred embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of 1 μm to about 5 μtm.
In another preferred embodiment, a compound of Formula I is delivered as a dry powder using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in US5,261 ,538; US5,544,647; US5,622,163; US4,955,371 ; US3,565,070; US3,36130ό and US6, 116,234. In preferred embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 μm.
The compounds of Formula I are useful for treating pulmonary arterial hypertension. The amount of active ingredient that may be combined with the excipients to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A compound of Formula I, or a pharmaceutically acceptable salt thereof, is dosed in a therapeutically effective amount ranging from about 10 to about 5000 μg. The dose will be determined by the host treated and the severity of the disease as determined by those physicians skilled in the art. Preferably, the drug will be administered four, three, two, or most preferably once a day. In another aspect of the invention, a combination of an aerosol formulation of a compound of Formula I and a device significantly enhances the efficiency and speed of drug administration. Currently, for example, the average time for administration of other aerosolized drugs, such as for example tobramycin, is 15-20 minutes per dose. The time required for this treatment represents a significant burden to the patient and contributes to reduced compliance with the recommended dosage regimen. In a preferred embodiment, the aerosolizable formulation of a compound of Formula I is delivered by a device capable of delivering a therapeutically effective dose in less than 15 minutes, more preferably in less than 10 minutes, and most preferably in less than 5 minutes,
DEFINITIONS Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product. As used herein, "a compound of the invention" or "a compound of Formula I" means a compound of Formula 1 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. Similarly, with respect to isolatable intermediates, the phrase "a compound of Formula (number)" means a compound of that formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof. "Alkyl" is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can have 1 to 30 carbon atoms (i.e, Cj-C3O alkyl), 1 to 10 carbon atoms (i.e., Ci-C10 alkyl), or 1 to 6 carbon atoms (i.e., Ci-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3J2), 1 -butyl (n-Bu, n-butyl. -CH2CH2CH2CH3), 2-methyl-l -propyl Q- Bu, i-butyl, -CH2CH(CH3),), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2- propyl <t-Bu, t-butyl, -C(CH3)3), 1-ρentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CHs)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3 -methyl -1 -butyl (-CH2CH2CH(CH3 )2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), l-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-
CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CHB)2CH2CH2CH3), 3-methyl-2- pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3),), 3- methyl-3-pentyl (-C(CH3)(CH2CH3),), 2-methyl-3-pentyl (~CH(CH2CH3)CH(CH3)2), 2,3- dimethyl-2-butyl (-C(CH3)2CH(CH3)2)? 3,3-dimethyϊ-2 -butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).
""Alkenyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C2O alkenyl), 2 to 12 carbon atoms (i.e.. C2-C]2 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).
"Alkynyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C2O alkynyl), 2 to 12 carbon atoms (i.e., C2-C]2 alkyne,), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C=CH), propargyl (-CH2C≡CH), and the like.
"Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,1 -ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyI (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1 ,3-propyl (-CH2CH2CH2-). 1 ,4-butyl (-CH2CH2CH2CH2-), and the like.
" Alkenyl ene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, and alkenyl ene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenyl ene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-). "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C~), propargyl (-CH2CsC-), and 4-pentynyl (-CH2CH2CH2C=CH-).
"Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. uArylalkyI" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical that is optionally substituted. Typical arylalkyl groups include, but are not limited to, benzyl. 2 -phenyl ethan-1-yl, naphthylmethyl, 2-naphthylethan-l -yl, naphthobenzyl, 2-naphthophenyIethan-l -yl and the like. The arylalkyl group can comprise 7 to 26 carbon atoms, e.g., the alkyl moiety is 1 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
"Arylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also a sp2 carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein. The arylalkenyl group can comprise 8 to 26 carbon atoms, e.g., the alkenyl moiety is 2 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. "Arylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, but also an sp carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein. The arylalkynyl group can comprise 8 to 26 carbon atoms, e.g., the alkynyl moiety is 2 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. The term "substituted" in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc. , for example, "substituted alkyl", "substituted alkylene", "substituted aryl", "substituted arylalkyl", "substituted heterocyclyl", and "substituted carbocyclyl" means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include, but are not limited to, -R, -O", =0, -OR, -SR, -SR2 4 A*"', -S", -NR2, -N+R3A^, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2,
=N2, -N3, -NHCf=O)R, -NHC(=0)NR2, -C(=0)R, -C(=O)NRR -S(O)2-, -S(O)2OH, -S(= O)2R, -OSeO)2OR, -S(O)2NR2, -S(O)R, -OP(O)(OR)2, -P(O)(OR)2, -P(=O)(O")2ϊ -P( O)(OH)2, -P(O)(OR)(O"), -C(O)R, -C(O)X, -C(S)R, -C(O)OR, -C(O)O", -C(S)OR, -C (O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, -C(=NR)NRR, or halogen (halo) (i.e., F, Cl, Br, or I); and each R is independently H, alkyl, aryl, arylalkyl, carbocyclyl, or heterocycle. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
One skilled in the art will recognize that substituents and other moieties of the compounds of Formula ϊ should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of Formula I which have such stability are contemplated as falling within the scope of the present invention.
"Heteroalkyl" refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S. For example, if the carbon atom of the alkyl group which is attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CHs)2, etc.), or a thioalkyl group (e.g., -SCH3). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g.,-CH2-S-CH3). If a teπninal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group
(e.g., -CH2NH2), or an alkyl thiol group (e.g., -CH2CH2-SH). A heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A Cj-Cf, heteroalkyl group means a heteroalkyl group having 1 to 5 carbon atoms.
"Heterocyde" or "heterocyclyl" as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern
Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1 , 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds. A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). The terms "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups, A non-limiting example of a carbonyl substituted heterocyclyl is:
Figure imgf000043_0001
Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrol yl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indoleπyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl. pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydro furanyl , tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-L2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H~quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morphoHnyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:
Figure imgf000044_0001
By way of example and not limitation, carbon bonded heterocyclics are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetraliydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5 -pyridazinyl, 6-pyridazinyl, 2 -pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, ό-pyrimidinyl, 2 -pyrazinyl, 3 -pyrazinyl, 5-pyrazinyl, 6- pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2 -imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1 -aziridyl, 1~ azetedy], 1 -pyrrol yl, 1-imidazolyl, 1-pyrazolyl, and l-piperidinyl.
"Heterocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety). Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CHb-, 2-(heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl" portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms. Examples of heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolyl methyl, oxazolylmethyl, thiadiazolylm ethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylniethyl, pyridinylm ethyl, pyridizylm ethyl, pyrimidylmethyl, pyrazinylm ethyl, etc. "Heterocyclylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also a sp" carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - alkenyl ene- moiety). The heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkenyl group comprises 6 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
"Heterocyclyl alkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or spJ carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - alkynylene- moiety). The heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkynyl group comprises 6 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms. "Heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of those listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
"Carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl), paitially unsaturated {e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, 1- cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohcxyl, 1-cyclohcx-l -cnyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclo carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl. "Carbocyclene" refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic radical as described for "carbocycle" having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent carbocycle.
"Arylheteroalkyl" refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein. The aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group can have the general formulae -alkylene-
O-aryl, -alkylene-0-aIkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkyl ene-S-aryl, -alkylene-S-alkylene-aryϊ, etc. In addition, any of the alkyl ene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.
"Heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl include -CH2-pyridinyl, -CEb-pyrrolyl, -CHi-oxazolyl, -CH2-indolyl, -Ctb-isoindolyl, -C Hi-purinyl, -CH^-furanyl, -CH^-thienyl, -CH2-benzofuranyl, -CHb-benzothiophenyl, -CH2 -carbazolyl, -CH2-imidazolyl, -CHi-thiazolyl, -Ctk-isoxazolyl, -CH2-pyrazolyl, -CH2-isot hiazolyl, -CH?-quinolyl, -CHi-isoquinolyl, -CH2-pyridazyl, -CH2-pyrimidyI, -CHa-pyrazy I, -CH(CH3)-pyridinyl, -CH(CH3)-pyrrolyl, -CH(CH3)-oxazolyl, -CH(CH3)-indolyI, -CH( CH3)-isoindoIyl, -CH(CH3)-purinyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-be nzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl5 -CH(CH3)-imidazolyl, -C H(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazoIyl, -CH(CH3)-isothiazoIyl, ~C H(CH3)-quinoIyl, -CH(CH3)-isoquinoIyl, -CH(CH3)-pyridazyl, -CH(CH3)-pyrimidyl, -CH (CH3)-pyrazyl, etc. The term "optionally substituted" in reference to a particular moiety of the compound of Formula 1 (e.g., an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more substituents.
"Linker" or "link" means a chemical moiety comprising a covalent bond or a chain of atoms. Unless otherwise specified, the carbon atoms of this invention are intended to have a valence of four. In some chemical structure representations where carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substitutents needed to provide a valence of four should be assumed to
Figure imgf000048_0001
be hydrogen. For example, 0H has the same meaning as
Figure imgf000048_0002
Any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na+, Li+, K+' Ca+^ and Mg+^), ammonium and NR9 4 + (wherein R9 is Ci-C4 alkyl). Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene-l ,5-disulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3- naphthoate, 1 -hydroxy-2-naphthoate pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfoiiic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromine, and iodine. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NR 4 + (wherein R10 is independently selected from H or a Ci-C4 alkyl group).
Certain embodiments of Formula I comprise positively charged quaternary N and ternary S atoms which will have a negative counter ion A("}. It is intended that the negative counter ions A^ will be pharmaceutically acceptable. Non-limiting examples of pharmaceutically acceptable negative counter ions comprise the anions of organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene- 1,5-disulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, l -hydroxy-2- naphthoate pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like. Non-limiting examples of pharmaceutically acceptable inorganic negative counter ions comprise chloride, bromide, iodide, hydroxide, sulfate and phosphate.
For therapeutic use, salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
The term "crural" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not miiτor images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1, D and L, or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with S, (-), or 1 meaning that the compound is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula 1 and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.
A compound of Formula 1 and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conform ers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conform ers of the same molecule (conformational pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula 1 and their pharmaceutically acceptable salts.
A compound of Formula I and its pharmaceutically acceptable salts may also exist as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less. Additives, including solvents, may be used to create the amorphous forms of the instant invention. The instant invention comprises all amorphous forms of the compounds of Formula I and their pharmaceutically acceptable salts.
The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).
Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "R" or "R1", then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines, -™™™~ , indicate the site of covalent bond attachments to the adjoining substructures, groups, moieties, or atoms.
The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above.
The term "therapeutically effective amount", as used herein, is the amount of compound of Formula I present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by inhalation. The precise amount will depend upon numerous factors, for example the particular compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.
The variable PCY comprises a prostacyclin or carbaprostacyclin or a derivative thereof. Any reference to the term "prostacyclin" herein, is intended to encompass the terms prostacyclin, carbaprostacyclin, or a derivative of either.
The term "normal saline" means water solution containing 0.9% (w/v) NaCl. The teπn "diluted saline" means normal saline containing 0,9% (w/v) NaCl diluted into its lesser strength.
The term "quarter normal saline" or "14 NS" means normal saline diluted to its quarter strength containing 0.225% (w/v) NaCI.
The term "MMAD" means mass medium aerodynamic diameter. The term "predominantly" means including at least 70% but preferably 90% of particle sizes between 1 μm and 5 μm.
The term "mutual prodrug" as used herein refers to a bipartite or tripartite prodrug in which specific bond(s) of the compound are broken or cleaved by the action of an enzyme or by biological process thereby producing or releasing a drug and the carrier which is a synergistic drug of the drug to which it is linked.
The present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.
I. PREPARATION OF THE COMPOUNDS OF THE INVENTION
Examples
The foregoing may be better understood from the following examples, which are presented for the purposes of illustration and are not intended to limit the scope of the inventive concepts. Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.
Table 1. List of abbreviations and acronyms.
Figure imgf000053_0001
Figure imgf000054_0001
The compounds of Formula I are synthesized according to general Scheme I.
Scheme I
Figure imgf000055_0001
Figure imgf000055_0002
Scheme Il
loride,
Figure imgf000056_0001
Figure imgf000056_0002
Example 3 Example 2
Figure imgf000056_0003
A mixture of sodium prostacyclin (637 mg, 1.70 mmol) and 10% palladium on carbon (190 mg, 0.18 mmol) in methanol (17 mL) was stirred under an atmosphere of hydrogen for two days. The mixture was filtered through Celite and concentrated. The residue was brought up in dichlorm ethane (17 ml) and to this solution was added tert- butyldimethylsilyl chloride (1.025 g, 6.8 mmol) and imidazole (579 mg, 8.5 mmol). The resulting solution stirred for 18 h and concentrated. To the residue was added potassium carbonate (400 mg), tetrahydrofuran (20 mL), and methanol (6 mL). The mixture stirred for 6 h and concentrated. The residue was brought up in dichloromethane (50 mL) and 10% citric acid in water (50 mL). The organic layer was removed and the aqueous layer was washed twice with dichloromethane (2 X 25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Chromatography (gradient: 0- 60% ethyl acetate in hexanes; R/ = 0.4, 2/1, hexanes/ethyl acetate) afforded the product as a clear oil (526 mg, 900 mmol, 53%). ES/MS cacld. For C32H64NaO5Si2: 607.4; Found: 607.5 (M+Nah).
Example 2
Figure imgf000057_0001
Stirred a solution of a compound represented in Example 1 (22 mg, 38 μmol) in a solution of 2N HC] in dioxane (0.4 mL) for 24 h and concentrated. Added a solution of IN sodium hydroxide in water (0.5 mL) and diethyl ether (2 mL) and stirred vigorously for 30 min. The organic layer was discarded and the aqueous was washed with diethyl ether (2 X 2 mL). The organic layers were discarded. The aqueous layer was acidified with a solution of 1 N HCl in water (1 mL) and washed with diethyl ether (3 X 2 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a clear oil (1 1 mg, 31 μmol, 81 %). ES/MS cacld. for C2OH36NaO5: 379.3; Found: 379.3 (M+Na+).
Example 3
Figure imgf000058_0001
To a solution of compound represented in Example 1 (188 mg, 322 μmol), A-
(dimethylamino)pyridine (2 mg, 16 μmol), triethyl amine (135 μL, 1.8 mmol) in dichloromethane (3 m L) at 0 0C was added trymethylacetic chloride (44 μL, 354 μmol). The reaction was allowed to warm to 22 0C and stirred for 1 h. To this solution was added 2-dimethyaminoefhanol (39 μL, 386 μmol) and the resulting solution stirred for 4 h. A saturated solution of sodium bicarbonate (10 mL) was added and the mixture was washed with dichlorm ethane (3 X 10 mL). The combined organic layers were dried over sodium sulfate, filtered, absorbed onto silica and purified by silica gel chromatoghraphy (R/ = 0.3, 0.2 % triethyl amine, 2.5 % methanol in dichloromethane) to give a clear oil (155 mg, 236 μmol, 73%). ES/MS cacld. for C36H74NO5Si2: 656.5; Found: 656.4 (M+H+). Example 4
Figure imgf000058_0002
A solution of compound represented in Example 3 (470 mg, 716 mmol), tetrabutylammonium floride (IM in THF, 2.15 mL, 2.15 mmol) in tetrahydrofuran (5 mL) was stirred for 24 h and concentrated. A saturated solution of sodium bicarbonate (20 mL) and the mixture was washed with ethyl acetate (3 X 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and absorbed onto silica and purified by silica gel chromatoghraphy (gradient: 2.5% to 10 % methanol in dichlorom ethane with 0.2% triethylamine; R/-= 0.1 , 0.2 % triethyl amine, 2.5 % methanol in dichloromethane) to give a clear oil (290 mg, 678 μtnol, 95%). ES/MS cacld. for C24H46NO5: 428.3; Found: 428.4 (M+H+).
Example 5
Figure imgf000059_0001
To a solution of salicyl aldehyde (1.45 mL, 13.8 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (2.3 mL, 15.2 mmol), and 4-(dimethylamino)pyridine (0.17 g, 1.4 mmol) in tetrahydrofuran (15 mL) at 0 0C was added a solution of di-tert- butyl phosphobromidate (5.65 g, 20.7 mmol) in tetrahydrofuran (10 mL). The mixture stirred for 18 h and concentrated. Ethyl acetate (100 mL) was added and the organic layer was washed with 10% citric acid (2 X 50 mL), 0.5 N NaOH (2 X 50 mL), dried over sodium sulfate, filtered through a pad of activated basic alumina, and concentrated. The residue was brought up in tetrahydrofuran (20 mL) and cooled to -78 0C. To this solution was added sodium borohydride (1.6 g, 42 mmol) and then MeOH(1.5 mL). The reaction solution was allowed to warm to room temperature and stirred for 4 h. The solution was diluted with dichloromethane (10OmL) and carefully quenched with 10% citric acid (50 niL). The organic layer was washed with a saturated solution of sodium bicarbonate in water (50 niL), and brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purified by silica gel chromatography (R/-= 0.3, 5/1, hexanes/ethyl acetate) to give a white solid (2.49 g, 7.86 mmol, 57%). ES/MS cacld. for C15H2SNaO5P: 339.1 ; Found: 339.0 (M+Na*).
Example 6
Figure imgf000060_0001
The title compound was synthesized as described in Example 5, substituting the salicylaldehyde for 4-hydroxybenzaldhehyde. ES/MS cacld. for CisHasNaOsP: 339.1 ; Found: 339.1 (M+Na+).
Example 7
Figure imgf000060_0002
Sodium hydride (7 mg, 0.3 mmol) was added to a stirring solution of tetrabutyl ammonium iodide (4 mg, 1 1 μmol) and salicyl aldehyde (14 mL, 193 μmol) in dimethylformamide (0.5 mL). Reaction stirred for 15 min. To this solution was added a solution of di-tert'butyl chloromethyl phosphate (50 mg, 193 μmol) in dimethylformamide (0.5 mL). The resulting reaction mixture stirred for 18 h at 50 0C. A saturated solution of sodium bicarbonate in water (10 niL) was added and the aqueous layer was washed with ethyl acetate (3 X 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was brought up in tetrahydrofkran (0.4 mL) and cooled to -78 0C. To this solution was added sodium borohydride (22 mg, 0.58 mmol) and then MeOH(25 μL). The reaction solution was allowed to warm to room temperature and stirred for 4 h. The solution was diluted with dichloromethane (15mL) and carefully quenched with 10% citric acid (5 mL). The organic layer was washed with a saturated solution of sodium bicarbonate in water (5 mL), and brine (5 mL), dried over sodium sulfate, filtered and concentrated. Purified by silica gel chromatography (R/-= 0.3, 1/1, hexanes/ethyl acetate) to give a white solid (36 mg, 114 μmol, 54%). ES/MS cacld. for C16H27NaO6P: 369.1; Found: 369.2 (M+Na+).
Example 8
Figure imgf000061_0001
The title compound was synthesized as described in Example 7, substituting the salicylaldehyde with 4-hydroxybenzaldhehyde. ES/MS cacld. for Cj6H27NaOeP: 369.1; Found: 369.2 (M+Na+).
Example 9
Figure imgf000062_0001
1,2,2,6,6-Pentamethylpiperidine (23 μL, 126 μmol) and methanesulfonyl chloride (5.5 μL, 69 μmol) were added to a stirring solution of compound represented in Exampie 5 (20 mg, 63 μmol) in CH2Cl2 (0.6 mL) at 0 0C. The reaction mixture was stirred for 2 h at 22 0C then quenched with 10 % (w/v) citric acid (2 mL) and the aqueous was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with satd. NaHCO3 (3 mL), brine (3 mL), dried over Na?Sθ4, and concentrated. The resulting clear oil was stirred with compound represented Example 4 (20 mg, 47 μmol), NaI (1 mg, 7 μmol), and CH3CN (100 μL) for 18 h. The reaction mixture was concentrated, brought up in CHCl3 (2 mL), washed with water (2 mL) and brine (2 mL), dried over Na2SO4, filtered and concentrated. The residue was loaded onto a short plug of silica in minimal CH2Cl2 and the plug was washed with EtOAc to remove impurities then with 4:1 CH2Cl2ICH3OH to elute desired product. To the resulting residue was dissolved in dichloromethane (300 μL) was added 4 N HCl in dioxane (150 μL). The reaction mixture was stirred for 2 hr then concentrated to dryness. The solid was dissolved in 1 :1 MeCN:water and lyophilized to give a white solid (8 mg, 13 μmol, 28%) ES/MS cacld. for C31Hs3NO9P" :614.3; Found: 614.4 (M+). Example 10
Figure imgf000063_0001
The title compound was synthesized as described in Example 9, substituting the compound represented in Example 5 with the compound represented in Example 6.
ES/MS cacld. for C3 IH53NO9P+IOHJ; Found: 614.4 (M+).
Example 11
Figure imgf000063_0002
The title compound was synthesized as described in Example 9, substituting the compound represented in Example 5 with the compound represented in Example 7. ES/MS cacld. for C32H55NO10P+:644.4; Found: 644.4 (M+).
Example 12
Figure imgf000064_0001
The title compound was synthesized as described in Example 9, substituting the compound represented in Example 5 with the compound represented in Example 8. ES/MS cacld. for C32H55NO!ϋP+:644.4; Found: 644.4 (M+).
Prophetic Examples
Example 13
Figure imgf000064_0002
The title compound is synthesized using terf-butyldimethylsilyl chloride (3 equiv.) and imidazole (4 equiv) to a solution of iloprost in dichlorm ethane.
Figure imgf000065_0001
The title compound is synthesized as described in Example 4, substituting the compound represented in Example 3 with the compound represented in Example 14.
Figure imgf000065_0002
The title compound is synthesized as described in Example 3, substituting the compound represented in Example 1 with the compound represented in Example 13.
Example 16
Figure imgf000066_0001
OH OH
The title compound is synthesized as described in Example 9, substituting the compound represented in Example 5 with the compound represented in Example 14.
Example 17
Figure imgf000066_0002
The title compound is synthesized using /erf-butyldimethylsilyl chloride (3 equiv.) and imidazole (4 equiv) to a solution of treprostinil in dichlormethane.
Example 18
Figure imgf000067_0001
The title compound is synthesized as described in Example 4, substituting the compound represented in Example 3 with the compound represented in Example 17.
Example 19
Figure imgf000067_0002
OH OH
The title compound is synthesized as described in Example 3, substituting the compound represented in Example 1 with the compound represented in Example 18.
Example 20
Figure imgf000068_0001
The title compound is synthesized as described in Example 9, substituting the the compound represented in Example 5 with the compound represented in Example 19.
Example 21
General Procedure for Intratracheal Administration of Mutual Prodrugs to Rats and Lung and Plasma Bioanalytical Analysis
Thirty-six male Sprague-Dawley rats were fasted overnight and through four (4) hours postdose (total fasting time not to exceed 24 hours). AU rats received a single intratracheal (IT) dose of mutual prodrug from Example 9 as described.
Blood samples (approximately 2 mL, or as much as possible) were collected from 6 animals per time point via cardiac puncture (following euthanasia via CO2 inhalation) into tubes containing K2EDTA. All blood samples were placed on wet ice (or an ice block) following collection. The samples were centrifuged and the plasma was separated and stored frozen at approximately -7O0C until analysis. Immediately following blood collection, the lungs from each animal were removed, blotted dry, weighed, and homogenized with 5 mL of 20 mM aqueous sodium EDTA solution on ice. The homogenate was stored at approximately -7O0C until analysis. Intratracheal Dosing Procedure
The animals were anesthetized with isofhirane vapors utilizing a precision vaporizer (3-5%, 5 to 10 minutes). The rat was suspended by the upper incisors on an incline rack in a supine position. And the rat's tongue was gently retracted to the side to allow access to the back of the throat, which was illuminated with an appropriate lighting device. A Penn Century™ Microsprayer® (Model IA-I B), was attached to a glass tuberculin syringe, was visually inserted into the trachea. Placement in the airway was confirmed by "pulling/pushing" the barrel of the glass syringe. A vacuum or resistance of the barrel indicated that the cannula was in the esophagus. If this occured, the Microsprayer was removed and the procedure reinitiated. No resistance of the barrel assured placement in the airway, and the glass syringe was removed. A luer-lock tip syringe (containing the appropriate volume of test article and approximately 0.1 niL of air) was attached to the Microsprayer, with the air in the syringe displaced above the test article, allowing for full delivery of the test article. The test article was delivered into the airways by pushing the plunger of the syringe on inhalation. The rat remained suspended on the incline rack for an additional 10 to 20 seconds to allow further distribution of the test article into the lungs.
Results from animal pharmacokinetic studies support the invention concept (Chart 1). Example 9 was administered to rats by the intratracheal route (0.5 mg/kg) and was efficiently cleaved to Example 2 in vivo. When compared to the same dose of tetrahydro PGI2 (Example T) given as a non-prodrug, lung concentrations of tetrahydro PG12 produced from the prodrug were much higher for 4 hours in the lung with a Cmax of 8 micrograms/g whereas the lung concentration of tetrahydro PGI2 given directly was rapidly cleared (<300 ng/g). By contrast, plasma drug levels for Example 9 and tetrahydroPGΪ2 (Example T) were only measurable up to one hour after dosing, but both drug concentrations were low (Chart 2). These data support the concept of extending the residence time and concentration of a carbaprostcyclin in the lung using the prodrug technology of the instant invention. Chart 1. Prodrug (Example 9) and Tetrahydro PGI2 (Example 2) Concentration in the Lung After 0.5 mg/kg IT Administration of the Prodrug
12000
■ Exampie 9 cone.
■ Exampie 2 cone
Figure imgf000070_0001
Chart 2. Plasma Drug Levels of Prodrug Example 9 and TetrahydroPGI2
(Example 2) After IT Administration of 0.5 mg/kg Example 9 to Rats
Figure imgf000070_0002
Figure imgf000071_0001
BLQ < 1.00000 ng/mL
All references cited herein are hereby incorporated in their entirety as if each reference was individually and specifically incorporated in its entirety.

Claims

In the claims:
1. A compound of Formula 1:
Figure imgf000072_0001
] O Formula I or a pharmaceutically acceptable salt thereof, wherein: each X1, X2 and X3 is independently H, F, Cl, Br, optionally substituted C1-C30 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted 15 alkylaryl or a group represented by -CH2-Z-G1-O-C(=O)-PCY; wherein one to five carbon atoms of said C1-C30 alkyl is optionally replaced by O, S, NR1, N(R3)2 +AM, or (- OCH2CH2O-CH2CH2O-)n; provided that at least one of X!, X", or X" is the group represented by -CH2-Z-G1- 0-C(O)-PCY; 0 n is 1-10;
Z is ® {NR!R2)AH, N(O)R1 (N-oxide), S(O) (sulfoxide), S(O)2, ® (SRl)AH, a heterocyclene comprising (NR1JA^ or SA^, or a heteroarylene comprising a
NA^; wherein when Z is said heterocyclene or said heteroarylene the -CH2- group of - CH2-Z-G '-0-C(O)-PCY is directly bonded to a ® NR1 or θ S of said heterocyclene or a 5 N of said heteroarylene; each R1 and R2 is, independently, optionally substituted Ci -C 10 alkyl, optionally substituted C2-C 10 alkenyl, optionally substituted C2-C10 alkynyl . optionally substituted C3-C]Q carbocyclyl, optionally substituted C6-CiO aryl, or optionally substituted heteroaryl; or R and R" taken together with the nitrogen to which they are attached foπn a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S or NR3; each G1 is independently a bond, optionally substituted C1-C1O alkylene, optionally substituted C2-CiO alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C3-C]O carbocyclene, optionally substituted C6-CiO arylene, or optionally substituted heteroarylene; wherein one or more carbon atoms of said Ci-Ci0 alkylene or C3-C 10 carbocyclene is, optionally, replaced by O, S, NR3, -NR3C(O)- or - C(O)NR3-; each R3 is independently H or C1-C4 alkyl; each PCY is independently
Figure imgf000073_0001
OH OH or OH wherein: each G2 is independently CH? or O; each G is independently optionally substituted Cj-Cg alkylene, optionally substituted Co-Cs alkenylene, or optionally substituted CI-CR alkynylene wherein a carbon atom of said optionally substituted Ci-Cs alkylene is, optionally, replaced by O, S, NR3; each G' is independently a bond or CH2; each R4 is independently
Figure imgf000073_0002
each R5 is independently optionally substituted Ci-C8 alkyl, optionally substituted
C2-Cg alkenyl, or optionally substituted C2-Q alkynyl wherein a carbon atom of said optionally substituted C]-Cg alkyl is, optionally, replaced by O, S, NR3;
L is O or -CH2O-; and
A("' is a pharmaceutically acceptable negative counter ion.
2. A compound according to claim 1 wherein X1 is -CH2-Z-G1 -O-C(=O)-PCY.
3. A compound according to claim 1 or 2 wherein X3 is -CH2-Z-G1 -O-C(=O)-PCY.
4. A compound according to any one of claims 1-3 wherein X2 is -CH2-Z-G!-O- Ct=O)-PCY.
5. A compound according to any one of claims 1-4 wherein each X1, X , and X is independently -CH2-Z-G1 -O-C(=O)-PC Y.
6. A compound according to any one of claims 1-5 wherein at least one Z is ® (NR'R2)AH
7. A compound according to any one of claims 1-5 wherein at least one Z is® (SR')AH.
8. A compound according to any one of claims 1-5 wherein at least one Z is a heterocyclene comprising ® (NR1JA1"' wherein the -CH2- group of -CH2-Z-G1-0-C{=0)- PCY is directly bonded to a Φ NR1.
9. A compound according to any one of claims 1 -5 wherein at least one Z is a heterocyclene comprising Θ SAH wherein the -CH2- group of-CH2-Z-G'-O-C(=O)-PCY is directly bonded to a S of said heterocyclene.
10. A compound according to any one of claims 1-5 wherein at least one Z is a heteroarylene comprising a NA( wherein the -CH2- group of -CHo-Z-G -O~C(=O)- PCY is directly bonded to a N of said heteroarylene.
1 1. A compound according to any one of claims 1-5 wherein at least one Z is N(O)R1 (N-oxide).
12. A compound according to any one of claims 1-5 wherein at least one Z is S(O) (sulfoxide).
13. A compound according to any one of claims 1-5 wherein at least one Z is S(=O)?.
14. A compound according to any one of claims 1-13 wherein at least one of G is a bond.
15. A compound according to any one of claims 1-13 wherein at least one of G ! is optionally substituted CrCio alkylene.
16. A compound according to any one of claims 1-13 wherein at least one of G! is optionally substituted C2-CiO alkenylene.
17. A compound according to any one of claims 1-13 wherein at least one of G1 is optionally substituted Ca-C10 alkynylene.
18. A compound according to any one of claims 1 -13 wherein at least one of G is optionally substituted C3-C]O carbocyclene.
19. A compound according to any one of claims 1-13 wherein at least one of G is optionally substituted Ce-Cio arylene.
20. A compound according to any one of claims 1-13 wherein at least one of G is optionally substituted heteroarylene.
21. A compound according to any one of claims 1-13 wherein at least one of G1 is optionally substituted Ci-C10 alkylene or optionally substituted C3-C io carbocyclene wherein one or more carbon atoms of said Cj-Cio alkylene or C3-C io carbocyclene is, optionally, replaced by O, S, NR3, -NR3C(O)- or -C(O)NR3-.
22. A compound according to claim 1-21 wherein at least one PCY of Formula I is
Figure imgf000077_0001
or
23. A compound according to any one of claims 1-22 wherein L is a bond.
24. A compound according to any one of claims 1 -22 wherein L is -(CH2O)-.
25. A compound according to any one of claims 1 -24 wherein X1 is -CH.2-Z-G1 -O- C(O)-PCY, Z of Xs is ® (NR1R2JA''' and G1 of X! is optionally substituted C1-C10 alkylene.
26. A compound or pharmaceutically acceptable salt thereof selected from
Figure imgf000078_0001
Figure imgf000079_0001
, and
Figure imgf000079_0002
27. A process for the synthesis of a compound of any one of claims 1-26.
28, An inhalable formulation for the treatment of pulmonary arterial hypertension and comprising from about 10 μg to about 5000 μg of at least one compound as in any one of claims 1-26.
29. An inhalable formulation according to claim 28 wherein said formulation is a solution adapted for aerosolization and administration by atomizing, jet, ultrasonic, pressurized, vibrating porous plate or equivalent nebulizers.
30. An inhalable formulation according to claims 28 or 29 wherein the pH of said formulation is between about 4.5 to about 7.5.
31. An inhalable formulation according to any one of claims 28 to 30 wherein the osmolality of said formulation is about 50 to about 1200 mθsm/kg.
32. An inhalable formulation according to any one of claims 28 to 31 wherein said formulation comprises chloride, bromide, iodide, or bicarbonate ions.
33. An inhalable formulation as in claim 28, wherein the inhalable formulation is a dry powder and adapted for use in a dry powder inhaler or metered dose inhaler.
34. An inhalable formulation as in any one of claims 28 to 33 wherein the inhalable particles have a mass median aerodynamic diameter of about 1 to about 5 μm.
35. A method for producing pulmonary vasodilation comprising administering to a patient in need of such treatment an effecth'e amount of an inhalable formulation comprising about 10 μg to about 5000 μg of at least one compound as in any one of claims 1-26.
36. A method of treating pulmonary arterial hypertension comprising administering to a patient in need of such treatment an effective amount of an inhalable formulation comprising about 10 μg to about 5000 μg of at least one compound as in any one of claims 1-26.
37. A method as in claim 35 or 36 wherein the inhalable formulation is delivered to the lung, a phosphate group of said compound is cleaved by an endogenous enzyme and an ester group of said compound is cleaved by an endogenous esterase to deliver a therapeutically effective amount of one or more prostacyclins or carbaprostacyclins represented by H-O-C(=O)-PCY.
38 The use of a compound in any one of claims 1 -26 for the manufacture of a medicament for treating pulmonary arterial hypertension in a patient.
39. A compound or method as described herein.
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