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  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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  • A61K31/33—Heterocyclic compounds
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  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C219/16—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by an inorganic acid or a derivative thereof
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  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
  • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/305—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups
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  • C07C59/40—Unsaturated compounds
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  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
  • C07C69/708—Ethers
  • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
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  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

• Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is a disease which can result in death and is characterized by increased pulmonary artery pressure and pulmonary vascular resistance.
• Many valuable pharmacologically active compounds, including some of interest with respect to PH and PAH, cannot be effectively administered orally for various reasons and are generally administered via intravenous or intramuscular routes. These routes of administration generally require intervention by a physician or other health care professional, and can entail considerable discomfort as well as potential local trauma to the patient.
• One example of such a compound is treprostinil and derivatives thereof, which has been used in the treatment of PH and PAH. See, for example, WO 2005/007081.
• the core chemical formula is (herein also labeled, Compound A):
• salts such as the sodium salt.
• Embodiments described herein including compounds, compositions, and devices, as well as methods of making and methods of using the same.
• One embodiment provides a compound represented by Formula (I)
• Z is -OH, -OR11, -N(R n )Ri2, -SR n , or P i ;
• Rn is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
• Ri2 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• Ri 8 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri5 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri5 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; and, Ri and R 2 are independently H or P 2 , wherein at least one of Ri and R 2 is P 2 , wherein
• P 2 is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are as defined above;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl and methoxy;
• Ri6 and Ri7 are independently in each occurrence H or alkyl
• Ri6 and Ri7 taken together with the atoms to which they attach optionally form a 3- to 6- membered ring; Ri8 and R19 are as defined above;
• Ri4 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Z is -OR11, -N(Rii)Ri2, -SRn, or P i ;
• Rn is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl;
• R 12 is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• R 18 and R 19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• Ri4 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• R15 and R 18 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri5 and Rig taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; and, Ri and R 2 are independently H or P 2 , wherein P 2 is selected from the group consisting of:
• n 1 , 2, 3, or 4;
• Ri4 and Ri ? are as defined above; Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl and methoxy;
• Ri6 and Ri7 are independently in each occurrence H or alkyl
• Ri6 and Ri7 taken together with the atoms to which they attach optionally form a 3- to
• Ri 8 and R19 are as defined above;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula I.
• R2 is selected from the group consisting of H and P2;
• P 2 is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are as defined above;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl and methoxy; Ri6 and Rn are independently in each occurrence H or alkyl;
• Ri 8 and R19 are as defined above;
• L 2 is selected from the group consisting of:
• m 1, 2, 3, or 4;
• X is NRi4, or O
• Ri4 is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted
• Ri6 and Rn are independently in each occurrence H or alkyl
• Rn is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
• R12 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• R 18 and R 19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• Ri4 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; Ri5 and taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri is selected from the group consisting of H and P 2 ;
• Li is a selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
• P2 is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• Ri6 and Ri7 are independently in each occurrence H or alkyl; Ri6 and Rn taken together with the atoms to which they attach optionally form a 3- to
• Ri 8 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• compositions are also provided including a composition comprising at least one compound according to Formula I, II, III, and IV and at least one other component.
• the composition is formulated for transdermal delivery.
• the composition is formulated for transdermal delivery with a patch.
• the composition can further comprise at least one solvent.
• the amount of the compound according to Formula I, II, III, or IV is adapted to provide a useful delivery profile for treatment of a human.
• the treatment is carried out on a subject, such as a mammal, but the subject is not a human.
• At least one advantage for at least one embodiment includes ability to tailor the chemical structure of a pharmaceutically useful motif for a particular uses including treatment and prophylactic use against, for example, PH and PAH.
• the drug delivery profile can be adapted for a particular application.
• At least one additional advantage for at least one embodiment includes ability to use the compounds to provide better bioavailability including use in transdermal drug delivery applications.
• prostacyclin analogs including treprostinil, and methods for their use are known. For example, they can be used in promoting vasodilation, inhibiting platelet aggregation and thrombus formation, stimulating thrombolysis, inhibiting cell proliferation (including vascular remodeling), providing cytoprotection, and preventing atherogenesis and inducing angiogenesis.
• these compounds may be used in the treatment of/for:
• ischemic diseases e.g., peripheral vascular disease, Raynaud's phenomenon, Scleroderma, myocardial ischemia, ischemic stroke, renal insufficiency
• heart failure including congestive heart failure
• conditions requiring anticoagulation e.g., post MI, post cardiac surgery
• thrombotic microangiopathy extracorporeal circulation
• central retinal vein occlusion e.g., atherosclerosis
• inflammatory diseases e.g., COPD, psoriasis
• hypertension e.g., preeclampsia
• reproduction and parturition cancer or other conditions of unregulated cell growth, cell/tissue preservation, and other emerging therapeutic areas where prostacyclin treatment appears to have a beneficial role.
• cardiovascular agents e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelial antagonists, and antiplatelet agents.
• Treprostinil is a chemically stable analog of prostacyclin. Although treprostinil sodium (Remodulin.®.) is approved by the Food and Drug Administration (FDA) for subcutaneous administration, treprostinil as the free acid has an absolute oral bioavailability of less than 10% and a very short systemic half life due to significant metabolism.
• FDA Food and Drug Administration
• alkyl refers to a monovalent saturated hydrocarbon group
• Cj -C s alkyl is an alkyl having from I to 8 carbon atoms and includes, for example, Ci-C 3 alkyl, C ; ⁇ C 5 alkyl, and Ci-C 7 alkyl.
• An alkyl may be linear or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.
• haloalkyl refers monovalent saturated hydrocarbon group attached to a one or more halogen selected from CI and F, Specific examples include 2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, and 2,2-difluoropropyl.
• heteroalkyl refers to a monovalent saturated hydrocarbon group attached to one or more he-tero atoms selected from O, N, and S.
• Cj -C s heteroalkyl is an alkyl having from 1 to 8 carbon atoms followed by a heteroatom selected from O, N, S and includes, for example, Ci-C 3 -OH, Ci-C 5-SH, and Ci-C 7 -NH 2 . it also includes C1-C2-0-C3-C4-OH, and C1-C2-NH-C3-C4-OH
• cycloalkyl refers to a monocyclic, bicyclic, or tricyclic monovalent saturated hydrocarbon ring system, The te m "C3-C14
• cycloalkyl refers to a cycloalkyl wherein the number of ring carbon atoms is from 3 to 14.
• C3-C 14 cycloalkyl include C3-C10 cycloalkyl and C3-C-6 cycloalkyl
• Bicyclic and tricyclic ring systems include fused, bridged and spirocyclic ring systems, More particular examples of cycloalkyl. groups include cyclopropyl, cyelobutyl, cyclopentyl, eyclohexyl, cycloheptyl, cis- and trans-decalynil, norbornyl, adamantyl, and spiro[4,5]decanyl.
• c cloheteroalk l refers to a monocyclic, bicyclic, or tricyclic monovalent saturated ring system wherein from 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of (), N and S.
• the term "3 to 14- membered cycloheteroalkyl” reiers to a cycloheteroalkyl wherein the number of ring atoms is from 3 to 14. Examples of 3 to 14-membered
• cycloheteroalkyl include 3 to 10- membered cycloheteroalkyl and 3 to 6-membered cycloheteroalkyl.
• Bicyclic and tricyclic ring systems include fused, bridged and spirocyclic ring systems.
• cycloheteroalkyl groups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, niorpholinyl, oxazolidinyL oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrroiidinyl, quinuelidmyl, tetrahydrofurany], thiomorpholinyl, and a- methyl- I, 3-dioxol-2-onyl.
• alkylcycloalkyl refers to a monocyclic, bicyclic, or tricyclic monovalent saturated hydrocarbon ring system.
• C3-C14 cycloalkyl refers to a cycloalkyl wherein the number of ring carbon atoms is from 3 to 14.
• C3- 4 cycloalkyl examples include C3-C10 cycloalkyl and C3-C6 cycloalkyl
• Bicyclic and tricyclic ring systems include fused, bridged, and spirocyclic ring systems linked to an alky] group which refers to a monovalent, saturated hydrocarbon group.
• Ci-C 8 alkyl is an alkyl having from 1 to 8 carbon atoms and includes, for example, Ci-C 3 alkyl. ⁇ ; ⁇ ( ' 5 alkyl, and C; -C 7 alkyl. Particular examples include cyclopropyl methyl, cyclopropyl ethyl, and cyclohexyl ethyl.
• alkylheterocycloalkyl refers to an alkyl that refers to a monovalent, saturated hydrocarbon group.
• Cj-C alkyl is an alkyl having from 1 to 8 carbon atoms and includes, for example, Ci-C 3 alkyl, C C 5 alkyl, and -C 7 alkyl attached to cycloalkyl which refers to a monocyclic, bicyclic, or tricyclic monovalent saturated ring system wherein from 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of O, N, and S,
• the term "3 to 14- membered heterocvcioalkyl reiers to a heterocvcioalkyl wherein the number of ring atoms is from 3 to 14, Examples of 3 to 14-membered heterocycloalkyl include 3 to 10- membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl.
• Bicyclic and tricyclic ring systems include fused, bridged and spirocyclic ring systems, Specific examples include N-ethylmorphoiine, N-ethylpiperidine, 4-ethylpiperidine, 1 -methyl- 4-ethyipiperidine, and N-ethylpiperazine.
• aryl refers to a monovalent aromatic carbocyclic ring system, which may be a monocyclic, fused bicyclic, or fused tricyclic ring system.
• Ce-Cu aryl reiers to an aryl having from 6 to 14 ring carbon atoms.
• An example of C 6 -Ci 4 aryl is Ce-Cio aryl. More particular examples of aryl groups include phenyl, naphthyl, anthracy], and phenanthryl.
• heteroaryl refers to unsaturated aromatic heterocyclyl radicals.
• heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, tetrazolyl, etc; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyi,
• benzimidazolyl quinolyl, benzotrazolyl, tetrazolopyridazinyl, etc.
• unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, oxadiazoiyl, etc.
• unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms
• unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl, etc.; and unsaturated condensed heterocyclyl group containing 1. to 2 sulfur atoms and 1 t 3 nitrogen atoms.
• alkylaryl refers to aryl- substituted alkyl radicals such as benzyl, diphenyl methyl, and phenylethyl.
• alkylheteroaryl refers to heteroaryl-- substituted alkyl radicals such as imidazoylmethyl, thiazoylmethyl, and pyridylethyl.
• alkyl, haloalkyl, heieroaikyl, cycloalkyl, cycloheteroalky 3 , alkvlcycloalkyl, alkylheterocycloalkyl , aryl, heteroaryl, alkylaryl, and alkylheteroary, are understood to cover in some optional embodiments wherein they form rings.
• groups such as R 14 , R 15 , R i6 , R 17 , R 18 , and R 19 can form rings with other groups R 14 , 15, ie, R17, Rig, and R 19 .
• ⁇ lie term substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkoxy, alkoxy, aryloxy, aminocarbonyl, alkyl am inocarbonyl, aryi aminocarbonyl, alkoxycarbony], aryloxycarbonyl, alkylhalo, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylarainoalkyl, arylammoalkyl, hydroxy!, alkyloxyalkyl, carboxyalkyl, alkoxycarbony] alkyl, aminocarbonyl alkyl,
• a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
• the compound is a pharmaceutically acceptable acid addition salt.
• pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention.
• pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
• Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
• Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
• Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
• hydrate means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
• solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
• a position designated as having deuterium when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%.
• a position designated as having deuterium typically has a minimum isotopic enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in said compound.
• isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
• a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
• any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
• a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic
• a compound of the invention contains less than 10%, preferably less than 6%, and more preferably less than 3% of all other isotopologues combined, including a form that lacks any deuterium.
• the compound contains less than "X"% of all other isotopologues combined, including a form that lacks any deuterium; where X is any number between 0 and 10 (e.g., 1, 0.5, 0.001), inclusive.
• Compositions of matter that contain greater than 10% of all other isotopologues combined are referred to herein as "mixtures" and must meet the parameters set forth below.
• deuterium/hydrogen present in the active, free base form of the compound of Formula I or II do not include the isotopic composition of hydrolyzable portions of prodrugs, or of counterions.
• isotopologue refers to species that differ from a specific compound of this invention only in the isotopic composition of their molecules or ions.
• the present invention provides a compound represented b Formula I:
• At least two sub-embodiments are provided to define further Formula I.
• R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R 36 are independently H or deuterium;
• Z is -OH, -OR11, -N(R n )Ri2, -SR n , or P i ;
• Rn is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
• R12 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• R 18 and R 19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• Ri4 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring
• Ri5 and R 18 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring
• Ri5 and R 19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; and, Ri and R 2 are independently H or P 2 , wherein at least one of Ri and R 2 is P 2 , wherein
• P 2 is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are as defined above;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl and methoxy;
• Ri6 and Ri7 are independently in each occurrence H or alkyl
• Ri6 and Ri7 taken together with the atoms to which they attach optionally form a 3- to
• Ri 8 and R19 are as defined above;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; wherein Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula I.
• Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula I.
• the Z, Ri, and R2 groups are not linked to each other, in contrast to Formulae II, III, and IV described herein.
• Ri is P2 and R2 is H. In another embodiment, Ri is H and R2 is P2. In another embodiment, Ri is P2 and R2 is P2.
• P2 can be more particularly described.
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of:
• P2 is selected from the group consisting of
• P2 is selected from the group consisting of: X M 3 ⁇ 43 ⁇ 4 6 - RR i l 7 7 X°
• P2 is selected from the group consisting of:
• R 20 , R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 , R 32 , R33, R34, R35, and R 36 are H.
• Z is -ORn, -N(Rn)Ri 2 , or Pi. In another embodiment, Z is Pi. In another embodiment, Z is -OH, -ORn, -N(Rn)Ri 2 , or Pi. In another embodiment, Z is -OH.
• Z is not -OH and Rn is not unsubstituted or substituted benzyl.
• Z is -OR11, -N(Rii)Ri2, -SRn, or P i ;
• Rn is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl;
• R12 is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• Ri 8 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• R 14 and R 18 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri5 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri5 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring; and, Ri and R2 are independently H or P2, wherein P2 is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are as defined above;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from the list consisting of halo, methyl and methoxy;
• Ri6 and Ri7 are independently in each occurrence H or alkyl
• Ri6 and Ri7 taken together with the atoms to which they attach optionally form a 3- to 6- membered ring; Ri8 and R19 are as defined above;
• Ri4 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula I.
• Z is -ORn . In one embodiment, Z is -N(Rn)Ri 2. In one embodiment, Z is -SRn . In one embodiment, Z is Pi. In one embodiment, Z is ORn and R 11 is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl. In one
• Z is Pi.
• Rn is haloalkyl, or more particularly, fluoroalkyl.
• Ri is hydrogen or R 2 is hydrogen. In one embodiment, Ri is hydrogen and R 2 is P 2 . In one embodiment, Ri is P 2 and R 2 is hydrogen. In one embodiment, Ri and R 2 are hydrogen. In one embodiment, Ri and R 2 are P 2 .
• At least one of R 20 , R21, R22, R23, R24, R25, R26, R27, R28, R 29 , R30, R31, R32, R33, R34, R35, and R 36 are deuterium.
• R 20 , R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R 32 , R33, R34, R35, and R 36 are hydrogen.
• Z is -OH, -OR n , or p l 5
• Rn is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl,
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; and, Ri and R2 are independently H or P 2 , wherein at least one of Ri and R2 is P 2 , wherein
• P2 is selected from the group consisting of:
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• the present invention provides a compound re resented by Formula II:
• R2 is selected from the group consisting of H and P2;
• P 2 is selected from the group consisting of:
• m 1, 2, 3, or 4;
• Ri4 and R15 are as defined above;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the list consisting of halo, methyl and methoxy; Ri6 and Rn are independently in each occurrence H or alkyl;
• Ri 8 and R19 are as defined above;
• R 20 , R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R36 are H. In one embodiment, at least one of R20, R21, R22, R 23 , R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R 36 are deuterium.
• Li is a selected from the group consisting of -O-alkyl- C(O)-, -O-alkyl-OC(O)-. In one embodiment, Li is -O-alkylene-C(O)-. In one embodiment, Li is -O-alkylene-OC(O)-. In one embodiment, the alkylene group of claim 41 is a C1-C5 alkylene group. In one embodiment, the alkylene group of claim 41 is a CI alkylene group.
• the present invention also provides a compound
• L2 is selected from the group consisting of:
• m 1, 2, 3, or 4;
• Ri4 is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted
• Ri6 and Ri7 are independently in each occurrence H or alkyl
• R 16 and R 17 taken together with the atoms to which they attach optionally form a 3- to 6- membered ring;
• Rn is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;
• Ri2 is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• Pi is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• Ri 8 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• Ri4 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri4 and R19 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• Ri5 and R ⁇ taken together with the atoms to which they attach optionally form a 5- to 7- membered ring;
• L2 is selected from the group consisting of:
• At least one of R 20 , R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R36 are deuterium, or they are all hydrogen.
• Another embodiment is a compound represented by Formula IV, wherein in Formula II, the Li group links to R 2 rather than Ri :
• Ri is selected from the group consisting of H and P2;
• Li is a selected from the group consisting of -O-alkylene-C(O)-, -O-alkylene-OC(O)-, or a bond;
• P2 is selected from the group consisting of:
• n 1, 2, 3, or 4;
• Ri4 and R15 are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;
• Ri4 and R15 taken together with the atoms to which they attach optionally form a 5- to 7- membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy;
• Ri6 and Ri7 are independently in each occurrence H or alkyl; Ri6 and Rn taken together with the atoms to which they attach optionally form a 3- to
• Ri 8 and R19 are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(alkyl), -CONH 2 , aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy;
• At least one of R 20 , R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, and R36 are deuterium, or they are all hydrogen.
• Rioo and R200 are independently selected from the group consisting of H,
• R 900 Riooo CONR 900 Riooo, CR 9 ooRioooOCOP 3 R9ooRiooo wherein, R 900 and R 100 o are independently selected from H, alkyl, and cycloalkyl.
• R300, R400, R500, R600, R700 and Rgoo is independently selected from the group consisting of H and deuterium.
• X is O, NHR 12 oo, or S
• P 3 is N or O
• Rnoo is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• R1200 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• alkylcycloheteroalkyl aryl, heteroaryl.
• Rioo > R200 are H.
• R300, R400, R500, R 6 oo, R700 and Rgoo are H.
• X is O.
• Rnoo is selected from
• X is NHR ⁇ oo-
• Rnoo is chosen from
• X is O.
• R300, R400, R500, R600, R700 and Rgoo are H.
• Rnoo is alkyl.
• R2000 is independently selected from the group consisting of H, CONR9000R10000, CR9000R10000OCOPR9000R10000. wherein, R9000 and R10000 are independently selected from H, alkyl, cycloalkyl.
• R3000, R4000, R5000, Reooo, R7000 and R 800 o is independently selected from the group consisting of H, deuterium.
• P is N, O
• R12 000 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• n is an integer between 1-7; and enantiomers of Formula II(AA), pharmaceutically acceptable salts of the compounds of Formula II(AA) and polymorphs of Formula II(AA).
• Rn is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl.
• R03, R04, R05, R06, R07 and R08 is independently selected from the group consisting of H, deuterium.
• X is O, NR012, S
• R 0 12 is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,
• alkylcycloheteroalkyl aryl, heteroaryl.
• Coupling conditions may also include or not include an additive, including but not limited to DMF, HOSu, HOBT, or HO AT, and may or may not include one or more nucleophilic or non-nucleophilic bases or additives including, but not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and/or imidazole.
• Coupling conditions also may be run in a suitable solvent or solvent mixture including, but not limited to DCM, THF, DMF, dioxane, ethyl acetate, acetonitrile.
• the activated acid can be isolated and purified or can be treated directly with ZH. Alternately, ZH can be present during the coupling conditions.
• acylation conditions are identical to coupling conditions as described above.
• the acylation conditions may or may not include one or more nucleophilic or non-nucleophilic bases or additives including but not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine, and/or imidazole and may be run in a suitable solvent or solvent mixture including, but not limited to DCM, THF, DMF, dioxane, ethyl acetate, and acetonitrile.
• the compounds of formula I where R2 is H can be synthesized according to scheme 3 starting from the compound of formula I where Rl is H and R2 is PG as defined above, by employing acylation conditions using ROH or RY as defined above followed by deprotection conditions as defined above.
• the compounds of scheme II can be synthesized according to Scheme 4 starting from the compound of scheme I where Z is OH and R2 is PG as defined above, by employing lactonization conditions.
• lactonization conditions can be found in Chemical Reviews (2007), 107, 239 and Beilstein Journal of Organic Chemistry (2012), 8, 1344, and include, but are not limited to 2,4,6-trichlorobenzoic anhydride, TEA and DMAP; 4-nitrobenzoic anhydride, TEA, and DMAP; 2-chloro-l- methylpyridinium iodide and tributyl amine; 2,2'-dipyridyl disulfide and
• the lactonization reactions may be run in a suitable solvent or solvent mixture including, but not limited to DCM, THF, DMF, dioxane, ethyl acetate, acetonitrile and toluene.
• an activated carbonyl equivalent including but not limited to phosgene, carbonyl diimidazole, or 4-nitrophenyl chloroformate
• an activated carbonyl equivalent including but not limited to phosgene, carbonyl diimidazole
• compositions described herein can be used alone or in combination with other components as known in the art.
• formulations of multiple ingredients can be prepared that are adapted for use in prophylactic and therapeutic treatments.
• the composition can be in the form of, for example, a solid, liquid, semisolid, solution, suspension, or emulsion formulation.
• Water can be used as a formulation agent. It can be in pure form or combined with one or more excipients.
• the compound is formulated in matrix form, comprising a matrix material in which drug is contained or dispersed.
• the matrix material further controls release of the drug by controlling dissolution and/or diffusion of the drug from the reservoir, and may enhance stability of the drug molecule while stored in the reservoir.
• the drug is formulated with an excipient material that is useful for accelerating release, e.g., a water-swellable material that can aid in pushing the drug out of the reservoir and through any tissue capsule over the reservoir. Examples include hydrogels and osmotic pressure generating agents known in the art.
• the drug is formulated with a penetration enhancer(s). The penetration enhancer further controls release of the drug by facilitating transport of the drug across the skin into the local administration site or systemic delivery.
• the drug can be dispersed in a matrix material, to further control the rate of release of drug.
• This matrix material can be a "release system,” as described in U.S. Pat. No. 5,797,898, the degradation, dissolution, or diffusion properties of which can provide a method for controlling the release rate of the chemical molecules.
• the release system may provide a temporally modulated release profile (e.g., pulsatile release) when time variation in plasma levels is desired or a more continuous or consistent release profile when a constant plasma level as needed to enhance a therapeutic effect, for example.
• Pulsatile release can be achieved from an individual reservoir, from a plurality of reservoirs, or a combination thereof. For example, where each reservoir provides only a single pulse, multiple pulses (i.e., pulsatile release) are achieved by temporally staggering the single pulse release from each of several reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into a single reservoir.
• Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of molecules through it over an extended period.
• continuous release can be approximated by releasing several pulses of molecules in rapid succession ("digital" release).
• the active release systems described herein can be used alone or on combination with passive release systems, for example, as described in U.S. Pat. No. 5,797,898.
• the pharmaceutical agent can be formulated with one or more
• excipients include bulking agents, wetting agents, stabilizers, crystal growth inhibitors, antioxidants, antimicrobials, preservatives, buffering agents (e.g., acids, bases), surfactants, desiccants, dispersants, osmotic agents, binders (e.g., starch, gelatin), disintegrants (e.g., celluloses), glidants (e.g., talc), diluents (e.g., lactose, dicalcium phosphate), color agents, lubricants (e.g., magnesium stearate, hydrogenated vegetable oils) and combinations thereof.
• the excipient is a wax or a polymer.
• the polymer comprises polyethylene glycol (PEG), e.g., typically one having a molecular weight between about 100 and 10,000 Daltons (e.g., PEG 200, PEG 1450).
• PEG polyethylene glycol
• the polymer comprises poly lactic acid (PLA), poly glycolic acid (PGA), copolymers thereof (PLGA), or ethyl-vinyl acetate (EVA) polymers.
• the excipient material comprises a
• compositions e.g., sesame oil.
• the excipient material includes a saturated drug solution. That is, the excipient material comprises a liquid solution formed of the drug dissolved in a solvent for the drug. The solution is saturated so that the solvent does not dissolve the solid matrix form of the drug. The saturated solution acts as a non- solvent excipient material, substantially filling pores and voids in the solid matrix.
• the excipient material comprises a pharmaceutic ally- acceptable perhalohydrocarbon or unsubstituted saturated hydrocarbon.
• a pharmaceutic ally- acceptable perhalohydrocarbon or unsubstituted saturated hydrocarbon See, for example, U.S. Pat. No. 6,264,990 to Knepp et al., which describes anhydrous, aprotic, hydrophobic, non-polar liquids, such as biocompatible perhalohydrocarbons or unsubstituted saturated hydrocarbons, such as perfluorodecalin, perflurobutylamine, perfluorotripropylamine, perfluoro-N-methyldecahydroquindine, perfluoro-octohydro quinolidine, perfluoro-N-cyclohexylpyrilidine, perfluoro-N,N-dimethylcyclohexyl methylamine, perfluoro-dimethyl-adamantane, perfluorotri-methylbicy
• the pharmaceutically acceptable excipient material comprises dimethyl sulfoxide (DMSO), glycerol, or ethanol.
• Test 1 Human liver microsomal stability assay was conducted by incubating 0.5 uM test compounds at 37°C for up to 45 minutes in 50 mM of potassium phosphate buffer (pH 7.4) containing 0.5 mg of microsomal protein and 50 ⁇ ⁇ of NADPH generating system (7.8 mg of glucose 6-phosphate, 1.7 mg of NADPH and 6 U of glucose 6-phosphate dehydrogenase) per mL in 2% w/v of sodium bicarbonate). At 0, 5, 15, 30 and 45 min., an aliquot was taken, quenched with internal standard containing stop solution. No co-factor controls at 45 minutes were also prepared. After incubation, the samples were analyzed by LC-MS/MS.
• Peak area ratios of analyte to internal standard were used to calculate the intrinsic clearance.
• the intrinsic clearance (CLint) was determined from the first order elimination constant by non-linear regression. Formation of the active drug Compound A over the time course was also monitored by LCMS/MS analysis.
• Test 2 Human plasma stability assay was conducted by incubating 0.5 uM test compounds at 37°C for up to 120 minutes in heparinated human plasma. At 0, 5, 15, 30, 60 and 120 min., an aliquot was taken, quenched with internal standard containing stop solution. After incubation, the samples were analyzed by LCMS/MS. Peak area ratios of analyte to internal standard were used to calculate the half-life. Formation of the active drug Compound A over the time course was also monitored by LCMS/MS analysis.
• Test 3 Human skin homogenate stability assay was conducted, in the same way as in human liver microsomal stability assay, by incubating 0.5 uM test compounds at 37°C for up to 45 minutes in 50 mM of potassium phosphate buffer (pH 7.4) containing 0.5 mg of human skin homogenate protein and 50 ⁇ L of NADPH generating system (7.8 mg of glucose 6-phosphate, 1.7 mg of NADPH and 6 U of glucose 6-phosphate dehydrogenase) per mL in 2% w/v of sodium bicarbonate). At 0, 5, 15, 30 and 45 min., an aliquot was taken, quenched with internal standard containing stop solution. No co-factor controls at 45 minutes were also prepared.
• Test 4 Human hepatocyte stability assay was conducted by incubating 0.5 uM test compound at 37°C for up to 240 minutes. Cryopreserved human hepatocytes were obtained from Celsis IVT ( Baltimore MD). Cells were thawed according to vendor's instructions and were suspended in William's Medium E to 0.5 million cells/mL. Test compounds were spiked into the cell suspension to initiate the reactions. At 0, 10, 30, 60, 120 and 240 min., an aliquot was taken, quenched with internal standard containing stop solution. After incubation, the samples were analyzed by LC-MS/MS. Peak area ratios of analyte to internal standard were used to calculate the intrinsic clearance. The intrinsic clearance (CLint) was determined from the first order elimination constant by non-linear regression. Formation of the active drug Compound A over the time course was also monitored by LCMS/MS analysis.
• reaction mixture was diluted with MTBE and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography. This resulting material was dissolved in MeOH/THF (4 ml), treated with Amberlite IR120H and stirred 24 hr. The reaction mixture was filtered and concentrated to yield [2-hydroxy-l-(3-hydroxy- octyl)-2,3,3a,4,9,9a-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy]-acetic acid 1,2- dimethyl-propyl ester (16 mg) as an oil.
• the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography. This resulting material was dissolved in MeOH/THF (4 ml), treated with Amberlite IR120H and stirred 24 hr. The reaction mixture was filtered and concentrated to yield treprostinil 2-hydroxy lactone (8 mg) as an oil.

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