Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J69/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
  • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
  • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
  • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
  • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16

Definitions

• the present invention relates to compounds in the form of prodrugs, in particular, compounds that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug.
• the present invention also relates to compositions and methods of using such prodrugs.
• CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of U.S. Provisional Patent Application No. US 62/970,607, filed on February 5, 2020; U.S. Provisional Patent Application No. US 63/009,533, filed on April 14, 2020; and U.S. Provisional Patent Application No.
• Neurosteroids are steroids synthesized within the brain and modulate neuronal excitability by rapid non-genomic actions.
• Circulating steroid hormones serve as precursors for the synthesis of neurosteroids, which are produced locally in the hippocampus and other brain structures. Imbalances in neurosteroid levels are implicated in numerous diseases, disorders, and conditions.
• pregnane neurosteroids for example, allopregnanolone and allotetrahydrodeoxycorticosterone
• androstane neurosteroids for example, androstanediol and etiocholanone.
• Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids increases both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety and stress.
• Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents.
• the lymphatic system consists of a specialized network of vessels, nodes and lymphoid tissues that are distributed throughout the body in close proximity to the vascular system.
• lymphatic system plays a number of key roles in immune response, fluid balance, nutrient absorption, lipid homeostasis, and tumor metastasis. Due to the unique anatomical and physiological characteristics of the lymphatic system, targeted drug delivery to and through the lymphatic system has been suggested as a means to improve both pharmacokinetic and pharmacodynamic profiles. [0006] Lymphatic drug transport has the potential to enhance oral bioavailability through avoidance of first pass metabolism, to alter systemic drug disposition, and to enhance efficacy against lymph or lymphocyte mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune disease, lymph resident infections and transplant rejection.
• intestinal lymph lipoproteins that are assembled in intestinal absorptive cells (enterocytes) in response to lipid absorption. Association with these lipoproteins subsequently promotes drug transport into the lymph since their size precludes ready diffusion across the vascular endothelium lining the blood capillaries that drain the small intestine. Instead, these large colloidal structures enter the lymphatic capillaries since the lymphatic endothelium is considerably more permeable than that of the vascular endothelium.
• the prodrug Having been transported via the lymphatic system, the prodrug is cleaved, thereby releasing the parent drug in order to be active at its target site.
• novel lipid-pharmaceutical agent conjugates that facilitate stable transport of the pharmaceutical agent to the intestinal lymph and that readily revert to the parent agent in order to be active.
• the present invention addresses this need and provides other related advantages.
• SUMMARY OF THE INVENTION [0010]
• the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.
• the present invention provides a method of treating a disease, disorder, or condition such as one of those disclosed herein, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• a disease, disorder, or condition such as one of those disclosed herein.
• Compounds of the present invention, and compositions thereof, are useful in promoting transport of a therapeutic agent to the lymphatic system and in subsequently enhancing release of the parent drug, i.e. the therapeutic agent.
• the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R 3 ; each R 3 independently is a saturated or unsaturated, straight or branched, optionally substituted C 1-37 hydrocarbon chain; X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C 1- 6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, - NR(C 1-6 aliphatic)-S-, or -NR(C 1-6 aliphatic)-
• the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed lipid prodrug, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• a disclosed lipid prodrug may exist in the form of a pharmaceutically acceptable salt.
• a reference to a “lipid prodrug” is also a disclosure of “lipid prodrug or a pharmaceutically acceptable salt thereof.” It follows that such a lipid prodrug or pharmaceutically acceptable salt thereof may be used in a pharmaceutical composition and a method of use, such as those disclosed herein.
• One approach to directing drugs into the lymphatic transport system is to employ prodrugs that participate in endogenous pathways that control the absorption, transport (including passive transport), and metabolism of dietary lipids.
• the present invention provides a lipid prodrug comprising a neurosteroid such as a pregnane neurosteroid conjugated to a glycerol-based moiety comprising two fatty acids or other lipids.
• a prodrug mimics a dietary triglyercide, such that it participates in triglyceride processing and metabolism in the GI tract.
• triglycerides Dietary lipids, including triglycerides, follow a particular metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is entirely distinct from that of other nutrients such as proteins and carbohydrates. After ingestion, dietary triglycerides are hydrolyzed by lipases in the lumen to release one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are subsequently absorbed into enterocytes and re-esterified to triglycerides. [0018] Resynthesised triglycerides are assembled into intestinal lipoproteins, primarily chylomicrons.
• chylomicrons are exocytosed from enterocytes and subsequently gain preferential access to the intestinal lymphatics.
• chylomicrons containing packaged triglycerides drain through a series of capillaries, nodes and ducts to join the systemic circulation at the junction of the left subclavian vein and internal jugular vein.
• triglycerides in chylomicrons are preferentially and efficiently taken up by tissues with high expression levels of lipoprotein lipases, such as adipose tissue, the liver, and potentially certain types of tumor tissues.
• Lipid prodrugs are expected to behave similarly to natural triglycerides and to be transported to and through the lymphatic system to reach the systemic circulation without interacting with the liver.
• the lipid prodrugs are cleaved, releasing the neurosteroid such as a pregnane neurosteroid, after the prodrugs have reached the systemic circulation, or after reaching a target tissue.
• the lipid prodrugs release the neurosteroid such as a pregnane neurosteroid by destruction of a self-immolative linker that attaches the neurosteroid to the glyercol-derived group, or by enzymatic cleavage of a linker.
• the pharmacokinetic and pharmacodynamic profiles of the parent neurosteroid may be manipulated to enhance access to the lymph and lymphoid tissues, thereby promoting oral bioavailability via avoidance of first-pass metabolism (and potentially intestinal efflux).
• the disclosed lipid prodrug has improved oral bioavailability, reduced first-pass metabolism, reduced liver toxicity, or improved other pharmacokinetic properties as compared with the parent neurosteroid.
• the disclosed lipid prodrug has increased drug targeting (as compared with the parent therapeutic agent) to sites within the lymph, lymph nodes and lymphoid tissues, and to sites of high lipid utilization and lipoprotein lipase expression such as adipose tissue, liver and some tumors.
• a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood-brain barrier (BBB) via the lymphatic system.
• the present invention provides methods of modulating the delivery, distribution, or other properties of a neurosteroid such as a pregnane neurosteroid.
• the present invention provides a method of delivering a neurosteroid to the systemic circulation of a patient in need thereof, wherein the neurosteroid partially, substantially, or completely bypasses first-pass liver metabolism in the patient, comprising the step of administering to the patient a disclosed lipid prodrug of the neurosteroid.
• the present invention provides a method of modifying a neurosteroid to partially, substantially, or completely bypass first-pass liver metabolism in a patient after administration of the neurosteroid, comprising the step of preparing a disclosed lipid prodrug of the neurosteroid.
• the lipid prodrug is administered orally.
• preparing the lipid prodrug comprises the step of covalently conjugating a neurosteroid to a glycerol-based scaffold comprising two fatty acids or other lipids, thereby providing the lipid prodrug.
• the present invention provides a method of improving oral bioavailability of a neurosteroid, enhacing gut absorption of a neurosteroid, or decreasing metabolism, decomposition, or efflux in the gut of a neurosteroid, comprising the step of preparing a disclosed lipid prodrug of the neurosteroid.
• the present invention provides a method of modifying, e.g., improving, delivery of a neurosteroid to a target tissue, comprising the step of preparing a disclosed lipid prodrug of the neurosteroid.
• the target tissue is the lymph, a lymph node (such as a mesenteric lymph node), adipose tissue, liver, or a tumor, such as a lymph node site of metastasis.
• the target tissue is the brain or CNS.
• Lipid prodrugs that readily convert to parent therapeutic agent after transport via the systemic circulation have reduced free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits in reducing gastrointestinal irritation or toxicity, and/or in increased drug solubility in intestinal bile salt micelles (due to similarities to endogenous monoglycerides).
• Disclosed lipid prodrugs may also in certain embodiments have increased passive membrane permeability (due to greater lipophilicity compared with the parent therapeutic agent).
• the lipid prodrug has greater solubility in lipid formulations or vehicles comprising either lipids alone or mixtures of lipids with surfactants and/or cosolvents, allowing for the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents.
• the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid, or -C(O)R 3 ; each R 3 independently is a saturated or unsaturated, straight or branched, optionally substituted C 1-37 hydrocarbon chain; X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C1- 6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, - NR(C 1-6 aliphatic)-S-, or -NR
• R 1 and R 2 are each independently hydrogen, an acid-labile group, a lipid such as a fatty acid, or -C(O)R 3 .
• R 1 is hydrogen. In some embodiments, R 1 is an acid-labile group. In some embodiments, R 1 is a lipid. In some embodiments, R 1 is a fatty acid. In some embodiments, R 1 is -C(O)R 3 . In some embodiments, R 1 is selected from those depicted in Table 1, below.
• R 2 is hydrogen. In some embodiments, R 2 is an acid-labile group. In some embodiments, R 2 is a lipid.
• R 2 is a fatty acid. In some embodiments, R 2 is -C(O)R 3 . In some embodiments, R 2 is selected from those depicted in Table 1, below. [0028] In some embodiments, each of R 1 and R 2 independently is a fatty acid, phosphatide, phospholipid, or analogue thereof, such as those described in detail below. In some embodiments, each fatty acid independently is a saturated or unsaturated medium-chain or long-chain fatty acid. In some embodiments, each fatty acid independently has an even number of carbon atoms. In some embodiments, each fatty acid independently has an odd number of carbon atoms. In some embodiments, each fatty acid independently has a C 2 -C 40 chain.
• each fatty acid independently has a C 6 -C 20 , C 8 -C 20 , C 10- C 20 , C 10 -C 18 , C 12 -C 18 , C 14 -C 18 , C 16 -C 18 , C 10 - C 16 , C 4- C 10 , or C 6 -C 10 chain.
• each fatty acid independently is a linear C 6 -C 20 fatty acid.
• each fatty acid independently is a linear C 12 -C 18 fatty acid.
• each fatty acid independently is a linear saturated C 6 -C 10 fatty acid.
• each fatty acid independently is selected from oleic acid, palmitic acid, octanoic acid, heptanoic acid, nonanoic acid, EPA, or DHA. In some embodiments, each fatty acid is oleic acid. In some embodiments, each fatty acid is heptanoic acid. In some embodiments, each fatty acid is octanoic acid. In some embodiments, each fatty acid is nonanoic acid.
• R 1 and R 2 are each independently selected from an acid labile group such as tert-butoxycarbonyl (Boc), an amino acid, PEG group, -C(O)OR, -C(O)NR 2 , - CH 2 OR, -C(NR)R, or -P(O) 2 OR.
• R 1 or R 2 is defined as a fatty acid
• R 1 or R 2 is the acyl residue of the fatty acid.
• R 1 is the acyl portion of palmitic acid, i.e. –C(O)C 15 H 31 .
• each R 3 independently is a saturated or unsaturated, straight or branched, optionally substituted C 1-37 hydrocarbon chain.
• R 3 is a saturated, straight, optionally substituted C 1-37 hydrocarbon chain.
• R 3 is an unsaturated, straight, optionally substituted C 1-37 hydrocarbon chain.
• R 3 is a saturated, branched, optionally substituted C 1-37 hydrocarbon chain.
• R 3 is an unsaturated, branched, optionally substituted C 1-37 hydrocarbon chain.
• R 3 is a saturated, straight, optionally substituted C1-20 hydrocarbon chain.
• R 3 is an unsaturated, straight, optionally substituted C 1-20 hydrocarbon chain. In some embodiments, R 3 is a saturated, branched, optionally substituted C1-20 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, branched, optionally substituted C1-20 hydrocarbon chain. In some embodiments, R 3 is selected from those depicted in Table 1, below.
• X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, - O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C 1-6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6 aliphatic)-S-, or -NR(C 1-6 aliphatic)-NR-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the C 1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms.
• X is -O-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -O(C 1-6 aliphatic)-O-. In some embodiments, X is -O(C 1-6 aliphatic)-S-. In some embodiments, X is -O(C 1-6 aliphatic)-NR-. In some embodiments, X is -S(C 1-6 aliphatic)-O-. In some embodiments, X is -S(C 1-6 aliphatic)-S-. In some embodiments, X is -S(C 1-6 aliphatic)-NR-.
• X is -NR(C 1-6 aliphatic)- O-. In some embodiments, X is -NR(C 1-6 aliphatic)-S-. In some embodiments, X is -NR(C 1-6 aliphatic)-NR-. In any of the foregoing embodiments, 0-2 methylene units of the bivalent C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S- and the bivalent C 1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, X is selected from those depicted in Table 1, below.
• Y is absent or is -C(O)-, -C(NR)-, or -C(S)-. [0036] In some embodiments, Y is absent. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-. In some embodiments, Y is selected from those depicted in Table 1, below.
• L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, - NRC(O)O-, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; , wherein either the right-hand side or left-hand side of L is attached to .
• L is a covalent bond.
• L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C 1-30 (e.g., C 3-30 , C 5-30 , C 7-30 , C 3- 25 , C 5-25 , C 7-25 , C 3-20 , C5-20 , or C 7-20 , etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O- , -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(
• L is , , or either the right-hand side or left-hand side of L is attached to . In some embodiments, L is , wherein either the right-hand side or left-hand side of L is attached to , wherein either the right-hand side or left-hand side of L is attached to . In some embodiments, L is , wherein either the right-hand side or left-hand side of L is attached , wherein either the right-hand side or left-hand side of L is attached to .
• L is a covalent bond or a saturated or unsaturated, straight or branched, optionally substituted bivalent C 1-30 (e.g., C 3-30 , C 5-30 , C 7-30 , C 3-25 , C 5-25 , C 7-25 , C 3-20 , C 5- 20 , or C 7-20 , etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NR
• L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C 1-20 (e.g., C 3-20 , C 5-20 , or C 7-20 , etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, - OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or a naturally-occurring amino acid such as , , , , , , , , , , wherein
• L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-16 , C 1-12 ,C 1-10 or C 6-16 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated, straight C 1-20 , C 1-16 , C 1-12 ,C 1-10 or C 1-6 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, - C(O)-, -S(O)-, -S(O) 2 -, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or - NRC(O)O-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated, straight C 1-20 , C 1-16 , C 1-12 , C 1-10 or C 1-6 hydrocarbon chain, wherein 0-6, 0- 4, 0-3, or 0-1 methylene units of L are independently replaced by -O-, -NR-, -S-, -OC(O)-, -C(O)O- , -C(O)-, -S(O)-, -S(O) 2 -, or -C(S)-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated C1-30, C1-25, C1-20, C3-20, C5-20, or C7-20 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 R 4 groups, wherein 0-4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated C 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 R 4 groups, wherein 0-4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated C 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 R 4 groups, wherein 1-2 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated C 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C 7-15 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, or a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by -O-, -OC(O)-, - C(O)O-, or -C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated C 3-30 , C 3-25 , C 3-20 , C 3-15 , C 5-10 , C 5-15 , or C7-15 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, or a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 1-2 methylene units of L are independently replaced by -O-, -OC(O)-, - C(O)O-, or -C(O)-; and 1 methylene unit of L is optionally replaced with -M-.
• L is a bivalent, saturated C 1-25 C 5-25 , C 7-25 , or C 1-20 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, a 3- 6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and 1 methylene unit of L is optionally replaced with -M
• L comprises (-OCH 2 CH 2 -)1-8 (i.e., 1-8 polyethylene glycol (PEG) units). In some embodiments, L comprises 1, 2, 3, 4, 5, 6, 7, or 8 PEG units. [0048] In some embodiments, 0-6 units of L are independently replaced by -O-, -S-, -OC(O)- , -C(O)O-, -C(O)-, or -C(S)-; and 1 methylene unit of L is optionally replaced with -M-. [0049] In some embodiments, L comprises . In some embodiments, L comprises . In some embodiments, L comprises some embodiments, L comprises .
• L comprises . In some embodiments, L comprises . In some embodiments, L comprises In some embodiments, L comprises In some embodiments, 1 methylene unit of L is replaced with -M-. [0051] In some embodiments, 1, 2, 3, or 4 available hydrogen atoms of L are replaced with an R 4 group, i.e., L is optionally substituted with 1, 2, 3, or 4 R 4 groups. [0052] In some embodiments, a methylene unit of L is replaced with an amino acid. The amino acid may be naturally-occurring or non-naturally occurring. In some embodiments, the amino acid is selected from a non-polar or branched chain amino acid (BCAA).
• BCAA non-polar or branched chain amino acid
• the amino acid is selected from valine, isoleucine, leucine, methionine, alanine, proline, glycine, phenylalanine, tyrosine, tryptophan, histidine, asparagine, glutamine, serine threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, cysteine, selenocysteine, or tyrosine.
• the amino acid is an L-amino acid.
• the amino acid is a D- amino acid. [0053]
• L is selected from those depicted in Table 1, below.
• each -Cy- independently is an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• -Cy- is an optionally substituted 3-6 membered bivalent saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• -Cy- is an optionally substituted 5-membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• -Cy- is an optionally substituted 6-membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is selected from those depicted in Table 1, below.
• each R 4 and R 5 independently is hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with - CN, -OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, pheny
• R 4 is hydrogen. In some embodiments, R 4 is deuterium. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -OR. In some embodiments, R 4 is -NR 2 . In some embodiments, R 4 is -SR. In some embodiments, R 4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is phenyl. In some embodiments, R 4 is an 8-10 membered bicyclic aromatic carbocyclic ring.
• R 4 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 4 is a C 1-6 aliphatic group optionally substituted with -CN, -OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 4 is a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• each R 4 independently is hydrogen, deuterium, halogen, -CN, or C 1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• at least one instance of R 4 is not hydrogen.
• R 4 is C 1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 4 is C 1-4 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl.
• R 4 is tert-butyl. In some embodiments, R 4 is selected from those depicted in Table 1, below. [0061]
• R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -OR. In some embodiments, R 5 is -NR 2 . In some embodiments, R 5 is -SR. In some embodiments, R 5 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is an 8-10 membered bicyclic aromatic carbocyclic ring.
• R 5 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 5 is a C 1-6 aliphatic group optionally substituted with -CN, -OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 5 is a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• each R 5 independently is hydrogen, deuterium, halogen, -CN, or C 1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R 5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered spirocyclic saturated monocyclic carbocyclic ring or 3-6 membered spirocyclic saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• at least one instance of R 5 is not hydrogen.
• R 5 is C 1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R 5 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is n-butyl. In some embodiments, R 5 is isobutyl. In some embodiments, R 5 is tert-butyl. In some embodiments, R 5 is selected from those depicted in Table 1, below.
• -M- is a self-immolative group.
• -M- is an acetal, an o-benzylalcohol, a p-benzylalcohol, a styryl group, a coumarin, or a group that self-immolates via a cyclization reaction.
• -M- is selected from a disulfide, hydrazone, acetal self-immolative group, carboxyacetal self-immolative group, carboxy(methylacetal) self-immolative group, para- hydroxybenzyl carbonyl self-immolative groups, flipped ester self-immolative group, trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self-immolative group.
• -M- is an acetal.
• -M- is a carboxyacetal.
• -M- is a carboxy(methylacetal).
• -M- is an acetal self-immolative group.
• -M- is a carboxyacetal self-immolative group. In some embodiments, -M- is a carboxy(methylacetal) self-immolative group. [0067] In some embodiments, -M- is: , wherein each R 6 independently is selected from hydrogen, deuterium, C 1-10 aliphatic, halogen, or -CN; each R 7 independently is selected from hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10
• -M- is selected from one of the following: , wherein each R 6 independently is selected from hydrogen, deuterium, C 1-5 aliphatic, halogen, or -CN; each R 7 independently is selected from hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -NO2, -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted
• each R 6 independently is selected from hydrogen, deuterium, C 1-5 aliphatic, halogen, or -CN.
• R 6 is hydrogen.
• R 6 is deuterium.
• R 6 is C 1-5 aliphatic.
• R 6 is halogen.
• R 6 is -CN.
• R 6 is hydrogen, C 1-5 alkyl, halogen, or -CN.
• R 6 is hydrogen or C 1-3 alkyl.
• R 6 is hydrogen or methyl.
• each instance of R 6 in the above formulae is the same.
• each R 6 is different. In some embodiments, one R 6 is hydrogen. In some embodiments, one R 6 is C 1-5 aliphatic. In some embodiments, each R 6 is hydrogen. In some embodiments, each R 6 is C 1-5 aliphatic. In some embodiments, R 6 is selected from those depicted in Table 1, below.
• each R 7 independently is selected from hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -NO 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with -CN, -OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membere
• R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is halogen. In some embodiments, R 7 is –CN. In some embodiments, R 7 is –OR. In some embodiments, R 7 is -NR 2 . In some embodiments, R 7 is -NO 2 . In some embodiments, R 7 is –SR. In some embodiments, R 7 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is phenyl. In some embodiments, R 7 is an 8-10 membered bicyclic aromatic carbocyclic ring.
• R 7 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 is or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 7 is or a C 1-6 aliphatic group optionally substituted with -CN, - OR, -NR 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 7 is a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• R 7 is hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -NO2, - SR, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-6 aliphatic group optionally substituted with -CN, -OR, -NR 2 , -SR, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocycl
• R 7 is hydrogen, deuterium, halogen, -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C 1-4 alkyl group optionally substituted with -CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C 1-4 alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• R 7 is hydrogen, halogen, -CN, -OR, or C 1-4 alkyl. [0075] In some embodiments, R is hydrogen or C 1-4 alkyl. [0076] In some embodiments, R 7 is selected from those depicted in Table 1, below. [0077] As defined generally above and described herein, each Z 1 independently is selected from -O-, -NR-, or -S-. In some embodiments, Z 1 is -O-. In some embodiments, Z 1 is -NR-. In some embodiments, Z 1 is -S. In some embodiments, Z 1 is -NH- or -NMe-. [0078] In some embodiments, Z 1 is selected from those depicted in Table 1, below.
• each Z 2 independently is selected from -O-, -NR-, -S-, -OC(O)-, -NRC(O)O-, or -OC(O)NR-.
• Z 2 is -O-.
• Z 2 is -NR-.
• Z 2 is -S-.
• Z 2 is -OC(O)-.
• Z 2 is - NRC(O)O-.
• Z 2 is -OC(O)NR-.
• each Z 2 independently is selected from -O-, -NH-, -NMe-, -S-, -OC(O)-, -NHC(O)O-, -NMeC(O)O-, -OC(O)NH-, or -OC(O)NMe-.
• Z 2 is covalently bound to .
• Z 2 is -O- or -OC(O)O-.
• Z 2 is selected from those depicted in Table 1, below.
• Z 1 is -O- and Z 2 is -O- or -OC(O)O-.
• Z 4 is -C(R 6 ) 2 - . In some embodiments, Z 4 is a covalent bond. [0088] In some embodiments, Z 4 is selected from those depicted in Table 1, below. [0089] In some embodiments, -M- is selected from one of the following: , , , . , , , , , , , , , ,
• -M- is selected from , , , , , , , or .
• -M- is selected from , [0097] In some embodiments, -M- is selected from , , , and . [0098] In some embodiments, -M- is selected from , and . [0099] In some embodiments, -M- is or . [00100] In some embodiments, -M- is . In some embodiments, -M- is . In some embodiments, -M- is [00101] In some embodiments, -M- is selected from those depicted in Table 1, below.
• n is 0-18. [00103] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17.
• n is 18. In some embodiments, n is 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-3, 2- 16, 2-14, 2-12, 2-10, 2-8, 2-6, 3-12, 3-10, 3-8, 3-6, 4-10, 4-8, 4-6, 5-10, 5-8, 5-6, 6-10, 6-8, or 8- 12. [00104] As defined above and described herein, each m independently is 0-6. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.
• each m independently is 0, 1, or 2. In some embodiments, each m independently is 1, 2, 3, or 4.
• a therapeutic agent selected from a naturally-occurring or non naturally-occurring neurosteroid, or an analogue or prodrug thereof.
• exemplary neurosteroids include those described herein.
• Analogues of neurosteroids include deuterated and isotopically-enriched forms of neurosteroids, such as pregnane neurosteroids.
• the analogue is a fatty acid ester derivative of the neurosteroid.
• a neurosteroid bearing two hydroxyl groups may be esterified at one hydroxyl and prepared as a lipid prodrug of Formula I, wherein the lipid prodrug moiety is bound to the other hydroxyl.
• the fatty acid ester comprises a carbon chain of 8-20 carbons.
• the fatty acid is one of those described herein.
• allopregnanolone also known as brexanolone, SAGE-547, 5 ⁇ -pregnan- 3 ⁇ -ol-20-one, 3 ⁇ -hydroxy-5 ⁇ -pregnan-20-one, or 3 ⁇ ,5 ⁇ -t
• alfadolone (3 ⁇ ,21-dihydroxy-5 ⁇ - pregnane-11,20-dione), alfaxolone (3 ⁇ -hydroxy-5 ⁇ -pregnane-11,20-dione), ganaxolone (3 ⁇ - hydroxy-3 ⁇ -methyl-5 ⁇ -pregnan-20-one), hydroxydione (21-hydroxy-5 ⁇ -pregnane-3,20-dione), minaxolone (11 ⁇ -(dimethylamino)-2 ⁇ -ethoxy-3 ⁇ -hydroxy-5 ⁇ -pregnan-20-one), Org 20599 (21- chloro-3 ⁇ -hydroxy-2 ⁇ -morpholin-4-yl-5 ⁇ -pregnan-20-one), Org 21465 (2 ⁇ -(2,2-dimethyl-4- morpholinyl)-3 ⁇ -hydroxy-11,20-dioxo-5 ⁇ -pregnan-21-yl methanesulfonate), renanolone (3 ⁇ - hydroxy-5 ⁇ -
• the present invention provides a compound of formula I, wherein is , to provide a compound of formula II:
• Ring B is selected from phenyl, a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring B is further optionally substituted with 1-2 oxo groups; R 6 is an optionally substituted C 1-6 aliphatic group; R 7a is an optionally substituted C 1-6 aliphatic group; R 7b is hydrogen or an optionally substituted C 1-6 aliphatic group; or R 7a and R 7b are optionally taken together with their intervening carbon atom to form a 4-7 membered saturated or partially unsaturated spirocyclic carbocyclic or heterocyclic ring, having 0-3 heteroatoms, in addition to
• the present invention provides a compound of formula I, wherein is , to provide a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein: R 9 is hydrogen or methyl; R 10 is –OC(O)R; R 11 is hydrogen or methyl; R 12 is alpha or beta hydrogen or methyl; R 13 is –C(O)R; and each of R, R 1 , R 2 , X, Y, and L is as defined above and described in embodiments herein, both singly and in combination. [00113] In some embodiments, the present invention provides a compound of formula I, wherein is , to provide a compound of formula IV:
• R 14 is hydrogen, hydroxyl, -CHO, -CHS, -CHNR,-CH 2 OR, -CH 2 SR, -CH 2 N(R) 2 , – CH 2 N(R)(OR), or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• R 17 is hydrogen, -OH
• the present invention provides a compound of formula I, wherein is , thereby forming a compound of formula VII: VII or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X, Y, and L are as defined above and described in embodiments herein, and wherein each of the group variables R 1 , R 2 , R 3 , R 4 , and R 5 is as described and defined in US 2019/0337975, the entirety of which is herein incorporated by reference.
• alfadolone (3 ⁇ ,21-dihydroxy-5 ⁇ - pregnane-11,20-dione), alfaxolone (3 ⁇ -hydroxy-5 ⁇ -pregnane-11,20-dione), ganaxolone (3 ⁇ - hydroxy-3 ⁇ -methyl-5 ⁇ -pregnan-20-one), hydroxydione (21-hydroxy-5 ⁇ -pregnane-3,20-dione), minaxolone (11 ⁇ -(dimethylamino)-2 ⁇ -ethoxy-3 ⁇ -hydroxy-5 ⁇ -pregnan-20-one), Org 20599 (21- chloro-3 ⁇ -hydroxy-2 ⁇ -morpholin-4-yl-5 ⁇ -pregnan-20-one), Org 21465 (2 ⁇ -(2,2-dimethyl-4- morpholinyl)-3 ⁇ -hydroxy-11,20-dioxo-5 ⁇ -pregnan-21-yl methanesulfonate), renanolone (3 ⁇ - hydroxy-5 ⁇
• the neurosteroid is not selected from pregnanolone, pregnenolone, 3 ⁇ - dihydropregesterone, isopregnanolone, epipregnanolone, or 21-hydroxyallopregnanolone.
• the neurosteroid is a naturally-occurring or non naturally-occurring (e.g., synthetic) inhibitory neurosteroid.
• the neurosteroid is a naturally-occurring inhibitory neurosteroid selected from: 3 ⁇ -Dihydroprogesterone (3 ⁇ -DHP): pregn-4-en-3 ⁇ -ol-20-one, 5 ⁇ -Dihydroprogesterone (5 ⁇ -DHP; allopregnanedione): 5 ⁇ -pregnane-3,20-dione, 5 ⁇ -Dihydroprogesterone (5 ⁇ -DHP; pregnanedione): 5 ⁇ -pregnane-3,20-dione, Allopregnanediol: 5 ⁇ -pregnane-3 ⁇ ,20 ⁇ -diol, Allopregnanolone (brexanolone; SAGE-547): 5 ⁇ -pregnan-3 ⁇ -ol-20-one, Dihydrodeoxycorticosterone (DHDOC): 21-hydroxy-5 ⁇ -pregnan-20-one, Pregnanediol: 5 ⁇ -pregnan-3 ⁇ ,20
• 3 ⁇ -DHP 3 ⁇ -Dihydroprogesterone
• Epipregnanolone 5 ⁇ -pregnan-3 ⁇ -ol-20-one
• Dexamethasone 9 ⁇ -fluoro-11 ⁇ ,17 ⁇ ,21-trihydroxy-16 ⁇ -methylpregna-1,4-diene-3,20-dione or an analogue thereof.
• [00128] is selected from: Pregnenolone (P5): pregn-5-en-3 ⁇ -ol-20-one, Progesterone (P4): pregn-4-ene-3,20-dione, 3 ⁇ -Methoxypregnenolone (MAP-4343): 3 ⁇ -methoxypregn-5-en-20-one, Cyclopregnol (neurosterone): 6 ⁇ -hydroxy-3:5-cyclopregnan-20-one.
• lipid prodrugs shown in Table 1 are in the form of prodrugs.
• a lipid prodrug moiety of the present invention is attached to the therapeutic agent or the active form thereof.
• a provided lipid prodrug moiety is attached at any modifiable oxygen, sulfur, or nitrogen atom of a pregnane neurosteroid.
• allopregnanolone has the following structure: and may be attached to the lipid prodrug moiety e.g., via its hydroxyl (OH) group or at another chemically modifiable position such as the ketone.
• brackets around a therapeutic agent means that the moiety is covalently attached to at any available modifiable nitrogen, oxygen, or sulfur atom.
• available modifiable nitrogen, oxygen, or sulfur atoms in the following therapeutic agent compound structures are depicted below, wherein each wavy bond defines the point of attachment t , r
• the present invention provides a compound of Formula I-a: I-a or a pharmaceutically acceptable salt thereof, wherein each of L, R 1 , R 2 , and X is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-b: or a pharmaceutically acceptable salt thereof, wherein each of L and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-c: I-c or a pharmaceutically acceptable salt thereof, wherein each of L, R 1 , R 2 , and X is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-d: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , X, M, and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-e: I-e or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , X, M, and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-f: I-f or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , X, n, and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-g: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , X, M, and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula I-h: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , M, and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula VIII-a, VIII-b, VIII-c, VIII-d, VIII-e, VIII-f, or VIII-g: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , M, and is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula IX-a or IX-b: IX-b or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , and M is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula IX-c or IX-d: IX-c or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , and M is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula X: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , X, and M is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula XI: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , and M is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula XII-a, XII-b, XII-c, XII-d, XII-e, XII-f, or XII-g:
• the present invention provides a compound of Formula XIII-a or XIII-b: XIII-b or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4 , R 5 , and -M- is as defined above and described in embodiments herein, both singly and in combination.
• the present invention provides a compound of Formula XIII-c or XIII-d:
• each of R 1 , R 2 , R 4 , R 5 , and M is as defined above and described in embodiments herein, both singly and in combination.
• R 1 , R 2 , R 4 , R 5 , and M is as defined above and described in embodiments herein, both singly and in combination.
• each of R 1 , R 2 , R 4 , R 5 , and M is as defined above and described in embodiments herein, both singly and in combination.
• each 0-4 and 1-18 range is varied independently of the others.
• the present invention provides a compound of Formula XIV: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen or -C(O)R 3 ; each R 3 independently is a saturated or unsaturated, straight or branched, optionally substituted C 1-37 hydrocarbon chain; X is -O-; Y is -C(O)-; L is a saturated or unsaturated, straight or branched, optionally substituted bivalent C 3-20 hydrocarbon chain, wherein 0-2 methylene units of L are independently replaced by -Cy-, -O-, -N(R)- -S-, -OC(O)-, -C(O)O-, or -C(O)-; and wherein 1 methylene unit of L is optionally replaced with -M-; or right-hand side of L is attached to ; each -
• L is or . In some embodiments, L . In some embodiments, L is . In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; or 0-12, 0-10, 0-8, or 0-6; or 1-12, 1-10, 1-8, or 1-6; or 2-12, 2-10, 2-8, or 2-6; or 0-4. In some embodiments, each m independently is 0, 1, 2, or 3; or each m independently is 0 or 1. In some embodiments, each m is 0. In some embodiments, each m is 1. In some embodiments, each m is 0 or 1 and n is 2-12. , r embodiments, -M- is .
• the right-hand side of the above embodiments of -M- is attached to , such as at an available O atom of .
• -M- is some embodiments, the right-hand side of the above embodiments of -M- is attached to , such as at an available O atom
• one instance of R 4 is hydrogen and one instance of R 5 is hydrogen.
• each R 4 and R 5 independently is hydrogen, deuterium, halogen, -CN, or C 1-6 aliphatic optionally substituted with -OR or 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• one instance of R 4 or R 5 is C 1-6 alkyl, such as C 1-3 alkyl, for example, methyl. In some embodiments, two instances of R 4 and R 5 are each independently C 1-6 alkyl, such as C1-3 alkyl, for example, methyl. [00165] In some embodiments, -M- is present. In some embodiments, -M- is present and at least one of R 4 or R 5 is not hydrogen. In some embodiments, -M- is present and at least one of R 4 or R 5 is C 1-6 alkyl, such as C1-3 alkyl, for example, methyl.
• -M- is present and at least two instances of R 4 and R 5 are independently C 1-6 alkyl, such as C 1-3 alkyl, for example, methyl.
• -M- is not present.
• -M- is not present and at least one of R 4 or R 5 is not hydrogen.
• -M- is not present and at least one of R 4 or R 5 is C 1-6 alkyl, such as C 1-3 alkyl, for example, methyl.
• -M- is not present and at least two instances of R 4 and R 5 are independently C 1-6 alkyl, such as C1-3 alkyl, for example, methyl.
• R 4 two instances of R 4 , two instances of R 5 , or one instance of R 4 and one instance of R 5 are present; and each R 4 and R 5 independently is selected from C 1-6 alkyl, such as C1-3 alkyl, for example, methyl, optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• C 1-6 alkyl such as C1-3 alkyl, for example, methyl, optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• L is or , wherein either the right-hand side or left-hand side of L is attached to ; and -M- is: , wherein each R 6 independently is selected from hydrogen, deuterium, C1-10 aliphatic, halogen, or -CN; each R 7 independently is selected from hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -NO 2 , -SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from
• each of R 1 and R 2 independently is a fatty acid; each R 4 independently is hydrogen, deuterium, halogen, -CN, or a C 1-6 aliphatic group optionally substituted with halogen, -CN, -OR, -NR 2 , or -SR; and [00171]
• each of R 1 and R 2 is heptanoic acid.
• each of R 1 and R 2 is octanoic acid.
• each of R 1 and R 2 is nonanoic acid.
• each R 4 is hydrogen. In some embodiments of Formula XV, each R 4 is methyl.
• the present invention provides a lipid prodrug compound shown in Table 1: Table 1: Exemplary Compounds
• the present invention provides a compound as depicted in Table 1, above, wherein one or both of the fatty acids depicted above (at the R 1 and R 2 positions of the Formulae depicted herein) independently are replaced with another fatty acid.
• Lipids Including Fatty Acids, Phospholipids, Lipid-Processing Mimetics, and Mixtures Thereof, for Use in Disclosed Lipid Prodrugs
• Lipid prodrugs according to the present disclosure mimic the lipid-processing that takes place in the human body.
• a variety of lipids are suitable for use in lipid prodrugs of the present disclosure.
• the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof (e.g., phosphatidylcholine, lecithin, phosphatidylethanolamine, cephalin, or phosphatidylserine or analogue or portion thereof, such as a partially hydrolyzed portion thereof), or other lipid-processing mimetic (e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing).
• the fatty acid is a short-chain, medium-chain, or long-chain fatty acid.
• the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is a monounsaturated fatty acid. In some embodiments, the fatty acid is a polyunsaturated fatty acid, such as an ⁇ -3 (omega-3) or ⁇ - 6 (omega-6) fatty acid.
• the lipid, e.g., fatty acid has a C2-C60 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2-C28 chain. In some embodiments, the lipid, e.g., fatty acid, has a C 2 -C 40 chain.
• the lipid e.g., fatty acid
• the lipid, e.g., fatty acid has a C4-C40 chain.
• the lipid e.g., fatty acid
• the lipid has a C4-C40, C2-C38, C2-C36, C2-C34, C2-C32, C2-C30, C4- C 30 , C 2 -C 28 , C 4 -C 28 , C 2 -C 26 , C 4 -C 26 , C 2 -C 24 , C 4 -C 24 , C 6 -C 24 , C 8 -C 24 , C 10 -C 24 , C 2 -C 22 , C 4 -C 22 , C 6 - C 22 , C 8 -C 22 , C 10 -C 22 , C 2 -C 20 , C 4 -C 20 , C 6 -C 20 , C 8 -C 20 , C 10 -C 20 , C 2 -C 18 , C 4 -C 18 , C 6 -C 18 , C 8 -C 18 , C 10 - C 18 , C 12 -
• the lipid e.g., fatty acid
• the lipid has a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C13, C14, C15, C 16 , C17, C 18 , C19, C 20 , C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54, C 55 , C 56 , C 57 , C 58 , C 59 , or C 60 chain.
• the lipid prodrug comprises two fatty acids, each of which independently is selected from a fatty acid having a chain with any one of the foregoing ranges or numbers of carbon atoms.
• one of the fatty acids independently is a fatty acid with a C6-C21 chain and one independently is a fatty acid with a C 12 - C36 chain.
• each fatty acid independently has a chain of 11, 12, 13, 14, 15, 16, or 17 carbon atoms.
• the lipid prodrug comprises two lipids.
• the two lipids, e.g., fatty acids, taken together have 6-80 carbon atoms (an equivalent carbon number (ECN) of 6-80).
• the lipids e.g., fatty acids
• the lipids have an ECN of 6-80, 8-80, 10-80, 12-80, 14-80, 16-80, 18-80, 20-80, 22-80, 24-80, 26-80, 28-80, 30-80, 4-76, 6-76, 8- 76, 10-76, 12-76, 14-76, 16-76, 18-76, 20-76, 22-76, 24-76, 26-76, 28-76, 30-76, 6-72, 8-72, 10- 72, 12-72, 14-72, 16-72, 18-72, 20-72, 22-72, 24-72, 26-72, 28-72, 30-72, 6-68, 8-68, 10-68, 12- 68, 14-68, 16-68, 18-68, 20-68, 22-68, 24-68, 26-68, 28-68, 30-68, 6-64, 8-64, 10-64, 12-64, 14- 64, 16-64, 18-64, 20-64, 22-64, 24-64, 26
• Suitable fatty acids include saturated straight-chain fatty acids, saturated branched fatty acids, unsaturated fatty acids, hydroxy fatty acids, and polycarboxylic acids. In some embodiments, such fatty acids have up to 32 carbon atoms.
• Examples of useful saturated straight-chain fatty acids include those having an even number of carbon atoms, such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid and n-dotriacontanoic acid, and those having an odd number of carbon atoms, such as propionic acid, n-valeric acid, enanthic acid, pelargonic acid, hendecanoic acid, tridecanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, heneicosanoic acid, tricosanoic acid, pentacosanoic acid, and heptacosanoic acid.
• saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, isolauric acid, 11-methyldodecanoic acid, isomyristic acid, 13-methyl-tetradecanoic acid, isopalmitic acid, 15-methyl-hexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachic acid, 19-methyl-eicosanoic acid, ⁇ -ethyl- hexanoic acid, ⁇ -hexyldecanoic acid, ⁇ -heptylundecanoic acid, 2-decyltetradecanoic acid, 2- undecyltetradecanoic acid, 2-decylpentadecanoic acid, 2-undecylpentadecanoic acid, and Fine oxocol 1800 acid (product of Nissan Chemical Industries, Ltd.).
• Suitable saturated odd-carbon branched fatty acids include anteiso fatty acids terminating with an isobutyl group, such as 6- methyl-octanoic acid, 8-methyl-decanoic acid, 10-methyl-dodecanoic acid, 12-methyl- tetradecanoic acid, 14-methyl-hexadecanoic acid, 16-methyl-octadecanoic acid, 18-methyl- eicosanoic acid, 20-methyl-docosanoic acid, 22-methyl-tetracosanoic acid, 24-methyl- hexacosanoic acid, and 26-methyloctacosanoic acid.
• an isobutyl group such as 6- methyl-octanoic acid, 8-methyl-decanoic acid, 10-methyl-dodecanoic acid, 12-methyl- tetradecanoic acid, 14-methyl-hexadecanoic acid, 16-methyl-octadecanoic
• Suitable unsaturated fatty acids include 4-decenoic acid, caproleic acid, 4- dodecenoic acid, 5-dodecenoic acid, lauroleic acid, 4-tetradecenoic acid, 5-tetradecenoic acid, 9- tetradecenoic acid, palmitoleic acid, 6-octadecenoic acid, oleic acid, 9-octadecenoic acid, 11- octadecenoic acid, 9-eicosenoic acid, cis-11-eicosenoic acid, cetoleic acid, 13-docosenoic acid, 15-tetracosenoic acid, 17-hexacosenoic acid, 6,9,12,15-hexadecatetraenoic acid, linoleic acid, linolenic acid, ⁇ -eleostearic acid, ⁇ -eleostearic acid, punicic acid, 6,9,12
• Suitable hydroxy fatty acids include ⁇ -hydroxylauric acid, ⁇ - hydroxymyristic acid, ⁇ -hydroxypalmitic acid, ⁇ -hydroxystearic acid, ⁇ -hydroxylauric acid, ⁇ - hydroxyarachic acid, 9-hydroxy-12-octadecenoic acid, ricinoleic acid, ⁇ -hydroxybehenic acid, 9- hydroxy-trans-10,12-octadecadienic acid, kamolenic acid, ipurolic acid, 9,10- dihydroxystearic acid, 12-hydroxystearic acid and the like.
• polycarboxylic acids examples include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, D,L- malic acid, and the like.
• each fatty acid independently is selected from Propionic acid, Butyric acid, Valeric acid, Caproic acid, Enanthic acid, Caprylic acid, Pelargonic acid, Capric acid, Undecylic acid, Lauric acid, Tridecylic acid, Myristic acid, Pentadecylic acid, Palmitic acid, Margaric acid, Stearic acid, Nonadecylic acid, arachidic acid, Heneicosylic acid, Behenic acid, Tricosylic acid, Lignoceric acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, Psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.
• each fatty acid independently is selected from ⁇ -linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linoleic acid, dihomo-gamma-linoleic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, herring acid, docosahexaenoic acid, or tetracosanolpentaenoic acid, or another monounsaturated or polyunsaturated fatty acid.
• one or both of the fatty acids is an essential fatty acid.
• the therapeutic benefits of disclosed lipid prodrugs may be increased by including such fatty acids in the lipid prodrug.
• the essential fatty acid is an n-6 or n-3 essential fatty acid selected from the group consisting of linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, docosapentaenoic n-6 acid, alpha-linolenic acid, stearidonic acid, the 20:4n-3 acid, eicosapentaenoic acid, docosapentaenoic n-3 acid, or docosahexaenoic acid.
• each fatty acid independently is selected from all-cis-7,10,13- hexadecatrienoic acid, ⁇ -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid, or lipoic acid.
• the fatty acid is selected from eicosapentaenoic acid, docosahexaenoic acid, or lipoic acid.
• fatty acids include all-cis-7,10,13-hexadecatrienoic acid, ⁇ -linolenic acid (ALA or all-cis- 9,12,15-octadecatrienoic acid), stearidonic acid (STD or all-cis-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA or all-cis-8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA, clupanodonic acid or all-cis-7,10,13,16,19
• the fatty acid is a medium-chain fatty acid such as lipoic acid.
• Fatty acid chains differ greatly in the length of their chains and may be categorized aaccording to chain length, e.g., as short to very long.
• Short-chain fatty acids are fatty acids having about five or less carbons (e.g., butyric acid).
• each of the fatty acids independently is a SCFA.
• one of the fatty acids independently is a SCFA.
• Medium-chain fatty acids include fatty acids having about 6-12 carbons, which can form medium-chain triglycerides.
• each of the fatty acids independently is a MCFA. In some embodiments, one of the fatty acids independently is a MCFA.
• Long-chain fatty acids include fatty acids having about 13-21 carbons. In some embodiments, each of the fatty acids independently is a LCFA. In some embodiments, one of the fatty acids independently is a LCFA.
• Very long chain fatty acids include fatty acids having about 22 or more carbons, such as 22-60, 22-50, or 22-40 carbons. In some embodiments, each of the fatty acids independently is a VLCFA. In some embodiments, one of the fatty acids independently is a VLCFA.
• one of the fatty acids independently is a MCFA and one independently is a LCFA.
• Therapeutic Agents and Exemplary Associated Diseases [00194]
• a variety of therapeutic agents may be covalently conjugated to the lymphatic system-directing lipids, e.g., triglyceride scaffolds, described herein.
• the present invention by conjugating a therapeutic agent to a lymphatic system- directing lipid, provides enhanced desirable properties of the therapeutic agent such as improving oral bioavailability, minimizing destruction of the agent in the gut, avoiding liver first-pass effect, improving therapeutic agent delivery to a target tissue, or increasing the solubility and stability of the therapeutic agents, including the solubility and stability of the agents in vivo.
• the present invention provides a compound of formula I, wherein the therapeutic agent is a pregnane neurosteroid or an analogue or prodrug thereof.
• neurotransmitters regulate the conductance of ions across neuronal membranes.
• GABA Gamma aminobutyric acid
• GR GABA receptor-chloride ionophore complex
• endogenous steroids such as the A-ring reduced metabolites of progesterone, act as selective allosteric modulators of the GR complex without classical steroid hormone activity.
• pregnane neurosteroids such as allopregnanolone (3 ⁇ -hydroxy-5 ⁇ -pregnane-20-one) and allotetrahydrodeoxycorticosterone (5 ⁇ ,3 ⁇ -THDOC), act as potent positive allosteric modulators of GR and produce anxiolytic (Bitran, D. et al. J. Neuroendocrinol 7(3): 171-7 (1995)), anti-conflict (Perche, F. et al. Aggress Behav 27(2): 130-8 (2001)), antiseizure (Frye, C.A. Brain Res. 643(1-2): 194-203 (1995)), and antinociceptive (Wiebe, J.P.
• pregnane neurosteroids act as potent positive allosteric modulators of GR and produce anxiolytic (Bitran, D. et al. J. Neuroendocrinol 7(3): 171-7 (1995)), anti-conflict (Perche
• pregnane neurosteroid treatment has been shown to have positive effects in various neurological conditions (e.g., Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Niemann-Pick Type C, fragile X-associate tremor/ataxia syndrome (FXTAS), diabetic neuropathy, status epilepticus (including benzodiazepine resistant), and traumatic brain injury (Irwin, R.W. et al. Front. Cell. Neurosci.8:203. doi: 10.3389/fncel.2014.00203).
• neurosteroids are susceptible to metabolism and have poor bioavailability (Rupprecht, R. Psychoneuroendocrinology, 28(2): 139-68 (2003)).
• a disclosed lipid prodrug comprises a therapeutic agent selected from neuroactive steroids, such as allopregnanolone, pregnanolone, pregnenolone, 3 ⁇ - dihydroprogesterone, isopregnanolone, epipregnanolone, and 21-hydroxyallopregnanolone, or others disclosed herein.
• the neuroactive steroid is selected from allopregnanolone or 21-hydroxyallopregnanolone.
• the compounds disclosed herein can be used to treat a variety of diseases, or one or more symptom(s) thereof, including, for example, post-partum depression (Osborne, L.M. et al. Psychoneuroendocrinology 79: 116-21 (2017)), depression (Almeida, F. B. et al. Neurobiology of Stress 12 (2020) 100218; Melón, L. et al. Front. Endocrinol.9:703. (2016); Almeida, F. B. et al. Physiology & Behavior 194 (2016) 246–251), anxiety (Schüle, C. et al. Prog.
• a neurological disease or condition e.g., post-partum depression, depression, anxiety, Niemann-Pick disease, Status Epilecticus, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Niemann-Pick Type C, fragile X-associate tremor/ataxia syndrome, diabetic neuropathy, seizures, or traumatic brain injury, comprising administering to a subject in need thereof a compound of the present invention.
• a neurological disease or condition e.g., post-partum depression, depression, anxiety, Niemann-Pick disease, Status Epilecticus, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Niemann-Pick Type C, fragile X-associate tremor/ataxia syndrome, diabetic neuropathy, seizures, or traumatic brain injury.
• the present invention provides a method of treating or preventing a disease, disorder, or condition in which an increased level of a pregnane neurosteroid, such as allopregnanolone, is beneficial, or a disease, disorder, or condition caused by a deficiency in a pregnane neurosteroid, such as an allopregnanolone deficiency, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
• the present invention provides a method of treating a GABAA- related disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
• the present invention provides a method of treating a disease, disorder, or condition caused by deficient activation of GABA A , comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug.
• the disease, disorder, or condition is selected from post-partum depression, depression, major depressive disorder, bipolar disorder, a mood disorder, anxiety, post- traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety, memory loss, poor stress tolerance, Niemann-Pick disease type C or an associated neurological or physical symptom, epilepsy, essential tremor, epileptiform disorders, NMDA hypofunction, migraines, status epilepticus, a sleep disorder such as insomnia, Fragile X Syndrome, depression induced by another medication (such as finasteride or another 5 alpha reductase inhibitor), PCDH19 female pediatric epilepsy, sexual dysfunction,
• the status epilepticus is super-refractory status epilepticus (SRSE), a severe form of uncontrolled seizures.
• the disease, disorder, or condition is depression induced by another medication (such as finasteride or another 5 alpha reductase inhibitor).
• the depression induced by another medication is postfinasteride syndrome.
• the disease, disorder, or condition is selected from post-partum depression, depression, major depressive disorder, bipolar disorder, Niemann-Pick disease type C, epilepsy, essential tremor, epileptiform disorders, NMDA hypofunction, status epilepticus, Parkinson’s disease, or Alzheimer’s disease.
• the status epilepticus is super- refractory status epilepticus (SRSE), a severe form of uncontrolled seizures.
• SRSE super- refractory status epilepticus
• the present invention provides a method of treating a depressive mood disorder (e.g., major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, disruptive mood dysregulation disorder, depression related to medical illness, postpartum depression) and/or anxiety disorder (e.g., panic disorder and post-traumatic stress disorder) comprising administering to a subject in need thereof a disclosed lipid prodrug.
• a depressive mood disorder e.g., major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, disruptive mood dysregulation disorder, depression related to medical illness, postpartum depression
• anxiety disorder e.g., panic disorder and post-traumatic stress disorder
• the present invention provides a method of treating multiple sclerosis, traumatic brain injury, ischemia, stroke, peripheral neuropathy, neuropathic pain, spinal cord trauma, or a non-REM sleep disorder associated with Alzheimer’s Disease (AD) or Parkinson’s Disease (PD), comprising administering to a subject in need thereof a disclosed lipid prodrug.
• AD Alzheimer’s Disease
• PD Parkinson’s Disease
• the present invention provides a method of reducing neuroinflammation in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the subject has AD or PD. See, e.g., Canelif Yilmaz, et al., Frontiers in Neuroendocrinology, https://doi.org/10.1016/j.yfrne.2019.100788, which is hereby incorporated by reference in its entirety. [00209] Allopregnanolone (ALLO; Brexanolone; SAGE-547) is currently being investigated as treatment for postpartum depression (NCT2614547; Kanes, S. et al. Lancet 390(10093): 480-9 (2017)).
• the present invention provides a method of treating Fragile X syndrome or Fragile X-associated syndrome in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug. In some embodiments, the present invention provides a method of treating Fragile X syndrome in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug. In some embodiments, the present invention provides a method of treating Fragile X-associated syndrome in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the present invention provides a method of treating Fragile X-associated tremor/ataxia syndrome in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the present invention provides a method of treating epilepsy and related epileptic disorders in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the epileptic disorder is acute repetitive seizures.
• the epileptic disorder is treatment referactive seizures.
• the epileptic disorder is status epilepticus.
• the epileptic disorder is a convulsive state including, but not limited to, status epilepticus, epileptic seizures or spasms.
• Specific types of epileptic seizures include, but are not limited to, tonic-clonic (Grand Mal) seizure, partial (Focal) seizure, catamenial seizure, acute repetitive seizure, psychomotor (complex partial) seizure, absence (Petit Mal) seizure, and myoclonic seizure.
• the present invention provides a method of treating a demyelinating disease in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the demyelinating disease is selected from multiple sclerosis, neuromyelitis optica, optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy and adrenomyeloneuropathy, Guillain-Barre syndrome, anti-myelin associated glycoprotein peripheral neurophathy, Charcot-Marie-Tooth disease, progressive inflammatory neuropathy, chronic inflammatory demyelinating polyneuropathy, and amyotrophic lateral sclerosis (ALS).
• the demyelinating disease is multiple sclerosis.
• the multiple sclerosis is relapsing remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis.
• RRMS multiple sclerosis
• the present invention provides a method of treating a lysosomal storage disorder in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the lysosomal storage disorder is selected from Farber disease, Krabbe disease, Fabry disease, Schindler disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, Sandhoff disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, sulfatidosis, metachromatic leukodystrophy, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, phosphotransferase deficiency, mucolipidin 1 deficiency, neuronal ceroid lipofuscinoses, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, fucosidosis, cystinosis, py
• the present invention provides a method of treating a nervous system disorder in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the nervous system disorder is Angelman syndrome, Rett syndrome, Dravet syndrome, Lennox-Gastaut syndrome, or catamenial epilepsy.
• the nervous system disorder is Angelman syndrome, Rett syndrome, or Dravet syndrome.
• the nervous system disorder is Lennox-Gastaut syndrome or catamenial epilepsy.
• the present invention provides a method of treating a sleep disorder in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the sleep disorder is secondary to rheumatoid arthritis.
• the sleep disorder is obstructive sleep apnea, insomnia, or restless legs syndrome.
• the present invention provides a method of treating hepatic encephalopathy in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the present invention provides a method of treating chronic pain in a subject, comprising administering to a subject in need thereof a disclosed lipid prodrug.
• the therapeutic agent is ganaxolone or allopregnanolone. 2. Definitions [00219] While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the presently-disclosed subject matter.
• the term “about,” when referring to a numerical value or range of a parameter such as mass, weight, volume, time, concentration, biological activity, cLogP, or percentage, is meant to encompass variations of, e.g., ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified value or range.
• treatment “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
• treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
• lipid refers to natural and non-natural hydrophobic and/or lipophilic fats, oils, polymers, hydrocarbons, and other such materials.
• suitable lipids when incorporated into a lipid prodrug, are processed or metabolized similarly to triglyercides in the GI tract or mimic such processing or metabolism.
• glycoceride refers to an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids or other lipids and is also known as an acylglycerol.
• a “monoglyceride” is produced; if two positions are esterified, a “diglyceride” is produced; and if all three positions of the glycerol are esterified with fatty acid a “triglyceride” or “triacylglycerol” is produced.
• a glyceride is called “simple” if all esterified positions contain the same fatty acid; or “mixed” if different fatty acids are involved.
• Naturally occurring oils and fats consist largely of triglycerides wherein the 3 fatty acyl residues may or may not be identical.
• long chain triglycerides means both a simple and mixed triglyceride containing fatty acids with more than 12 carbon atoms (long chain fatty acids, “LCFA”)
• long chain fatty acids “LCFA”
• MCT medium chain triglycerides
• ECN equivalent carbon number
• tripalmitin tripalmitic glycerol
• tripalmitic glycerol which is a simple triglyceride containing 3 acyl radicals of 16 carbon atoms
• Naturally occurring oils are frequently “mixed” with respect to specific fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone.
• triacylglycerols with ECNs of 24-30 typically contain predominately medium chain fatty acids, while triacylglycerols with ECNs of greater than 43 typically contain predominantly long chain fatty acids.
• Triacylglycerols having an ECNs of 32-42 typically contain one or two MCFA in combination with one or two LCFAs to “fill” the triglyceride.
• Triacylglycerols with ECNs in the range of greater than 30 to less than 48 typically represent mixed triacylglycerol species that are absent from or are present in significantly lower concentrations in physical mixtures.
• the fatty acids that occur in foods usually contain an even number of carbon atoms in an unbranched chain, e.g., lauric or dodecanoic acid.
• self-immolative group refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond.
• self-immolative groups include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative groups, carboxyacetal self-immolative groups, carboxy(methylacetal) self-immolative groups, para-hydroxybenzyl carbonyl self-immolative groups, flipped ester self-immolative groups, and trimethyl lock, or 2- hydroxyphenyl carbamate (2-HPC) self-immolative groups.
• a number of other suitable self- immolative groups are known in the art as described, for example, in C. A. Blencowe et al., Polym. Chem. 2011, 2, 773-790 and F. Kratz et al., ChemMedChem.
• the term “therapeutic agent,” “active pharmaceutical agent,” “active agent,” or “pharmaceutical agent” includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g., of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system.
• Pharmaceutical agent includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g., of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system.
• Lipid prodrug compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
• aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
• aliphatic groups contain 1-6 aliphatic carbon atoms.
• aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
• “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
• the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
• heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc.
• a bicyclic group has 7- 12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
• a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
• a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
• a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
• Exemplary bicyclic rings include: [00230]
• Exemplary bridged bicyclics include: [00231]
• the term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
• lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
• lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
• heteroatom means one or more of boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• unsaturated as used herein, means that a moiety has one or more units of unsaturation.
• bivalent C1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
• alkylene refers to a bivalent alkyl group.
• An “alkylene chain” is a polymethylene group, i.e., –(CH 2 )n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• alkenylene refers to a bivalent alkenyl group.
• a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• halogen means F, Cl, Br, or I.
• aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
• aryl may be used interchangeably with the term “aryl ring.”
• aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
• aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
• heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
• heteroaryl group may be mono– or bicyclic.
• heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
• heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
• heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
• a heterocyclyl group may be mono– or bicyclic.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
• partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
• compounds of the invention may contain “optionally substituted” moieties.
• substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
• an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• R * is C 1–6 aliphatic
• R * is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or – NO 2
• each R ⁇ independently is selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
• An optional substituent on a substitutable nitrogen independently is –R ⁇ , –NR ⁇ 2, – C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2, –C(S)NR ⁇ 2, – C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ independently is hydrogen, C 1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubsti
• the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group (or other basic group) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. 3.
• lymphatic-directing lipid prodrugs as well as pharmaceutically acceptable compositions comprising a disclosed lipid prodrug, and a pharmaceutically acceptable excipient, diluent, or carrier, are useful for treating a variety of diseases, disorders or conditions. Such diseases, disorders, or conditions include those described herein.
• diseases, disorders, or conditions include those described herein.
• therapeutic agents described herein are known to be associated with treatment of one or more diseases, disorders, or conditions.
• the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof comprising administering to said patient a disclosed lipid prodrug.
• lipid prodrugs are useful for the stable transport of pharmaceutical agents to the intestinal lymph and release of the pharmaceutical agents in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver, or in the systemic circulation.
• Disclosed lipid prodrugs are particularity useful for the transport and release of pharmaceutical agents that benefit from avoidance of first pass metabolism, for example, therapeutic agents that exhibit greater than about 50% first pass metabolism when administered orally.
• the therapeutic agent exhibits greater than about 60% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 70%, 80%, or 90% first pass metabolism when administered orally.
• Therapeutic agents that may benefit from the stable transport to the intestinal lymph and release in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver, or in the systemic circulation include, but are not limited to, therapeutic agents listed herein such as allopregnanolone, pregnanolone, pregnenolone, 3 ⁇ - dihydroprogesterone, isopregnanolone, epipregnanolone, ganaxolone, or 21- hydroxyallopregnanolone.
• the presently disclosed lipid prodrugs are also useful for the targeted release of the therapeutic agent within the lymphatic system, for example, in the lymph, lymphocytes and lymphoid tissues, as well as in tissues with high lipase activity such as adipose tissue, certain cancers, or the liver.
• the therapeutic agent exhibits poor lymphatic transport when administered orally.
• the therapeutic exhibits less than 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.2%, 0.15%, or 0.1% when administered orally.
• the present invention provides for improved lymphatic transport of such therapeutic agents.
• a disclosed lipid prodrug exhibits at least 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% lymphatic transport when administered orally. In some embodiments, a disclosed lipid prodrug exhibits about 1-50%, 5-40%, 10-30%, 15-25%, or about 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1% lymphatic transport when administered orally, as measured by either w/w% of the lipid prodrug administered or w/w% of the therapeutic agent in its lipid prodrug form vs. the unmodified therapeutic agent.
• a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood-brain barrier (BBB) via the lymphatic system.
• the present invention provides a method of treating or preventing a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a disclosed lipid prodrug that comprises a pregnane neurosteroid therapeutic.
• the present invention provides a pharmaceutical composition comprising a disclosed lipid prodrug formulated substantially as described in one of the Examples below or another exemplary formulation herein.
• such a pharmaceutical composition provides a pharmacokinetic result upon administration to a subject as described in Tables B, C, D, or E below.
• Pharmaceutically Acceptable Compositions [00261]
• the present invention provides a composition comprising a lipid prodrug of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the amount of lipid prodrug in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an “effective amount”).
• a composition of the present disclosure is formulated for oral administration to a patient.
• compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene
• compositions of the present invention may be administered orally, parenterally, enterally, intracisternally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the composition is administered orally, intraperitoneally, or intravenously.
• the composition is a transmucosal formulation.
• the composition is injected directly into the lymphatic system.
• Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or di-glycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
• carriers commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, may also be added.
• useful diluents include lactose and dried corn starch.
• compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
• the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food.
• the pharmaceutically acceptable composition is administered with food.
• a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
• the dosage form may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
• Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
• the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin.
• the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• the lipid prodrug is formulated as an orally administerable, lipid-based formulation.
• Lipid-based formulations for oral delivery are known in the art and may include, for example, substantially non-aqueous vehicles which typically contain one or more lipid components.
• the lipid vehicles and resulting lipid formulations may be usefully classified as described below according to their shared common features according to the lipid formulation classification system (LFCS) (Pouton, C.W., Eur. J. Pharm. Sci.
• Lipid vehicles, and the resulting lipid formulations may contain oil/lipids and/or surfactants, optionally with co-solvents.
• Type I formulations include oils or lipids which require digestion, such as mono, di and tri-glycerides and combinations thereof.
• Type II formulations are water-insoluble self emulsifying drug delivery systems (SEDDS) which contain lipids and oils used in Type I formulations, with additional water insoluble surfactants.
• SEDDS water-insoluble self emulsifying drug delivery systems
• Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) which contain lipids and oils used in Type I formulations, with additional water-soluble surfactants and/or co-solvents (Type IIIa) or a greater proportion of water-soluble components (Type IIIb).
• Type IV formulations contain predominantly hydrophilic surfactants and co-solvents (e.g., PEG, propylene glycol and diethylene glycol monoethyl ether) and are useful for drugs which are poorly water soluble but not lipophilic. Any such lipid formulation (Type I- IV) is contemplated herein for use with a disclosed lipid prodrug or pharmaceutical composition thereof.
• the lipid vehicle contains one or more oils or lipids, without additional surfactants, co-surfactants or co-emulsifiers, or co-solvents, i.e. it consists essentially of one or more oils or lipids. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants, optionally together with one or more co- solvents. In some embodiments, the lipid vehicle contains a mixture of oil/lipid, surfactant and co-solvent.
• the lipid vehicle consists essentially of one or more surfactants/co-surfactants/co-emulsifiers, and/or solvents/co-solvents.
• oils or lipids which may be used in the present invention include almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut oil, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric glycerides, fractionated triglycerides, glyceryl tricaprate, gly
• Examples of mono and diglycerides which may be used in such formulations include glycerol mono- and diesters having fatty acid chains from 8 to 40 carbon atoms, including hydrolysed coconut oils (e.g., Capmul® MCM), hydrolysed corn oil (e.g., MaisineTM35-l).
• hydrolysed coconut oils e.g., Capmul® MCM
• hydrolysed corn oil e.g., MaisineTM35-l
• the monoglycerides and diglycerides are mono-or di- saturated fatty acid esters of glycerol having fatty acid chains of 8 to 18 carbon chain length (e.g., glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate and glyceryl dicaprate).
• glyceryl monostearate glyceryl distearate
• glyceryl monocaprylate glyceryl dicaprylate
• glyceryl monocaprate and glyceryl dicaprate glyceryl dicaprate
• Mixtures of fatty acids (“structured glycerides”) adapted for enhancing the absorption and transport of lipid soluble compounds are disclosed in, e.g., U.S. Patent No.6,013,665, which is hereby incorporated by reference.
• Suitable surfactants for use in the lipid formulations include propylene glycol mono- and di-esters of C8-22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, sugar fatty acid esters, such as, but not limited to, sucrose palmitate, sucrose laurate, and sucrose stearate; sorbitan fatty acid esters such as, but not limited to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan fatty acid esters such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene mono- and di-fatty acid esters including, but not limited to, polyoxyl 40 stearate
• a co-emulsifier, or co-surfactant may be used in the formulation.
• a suitable co- emulsifier or co-surfactant may be a phosphoglyceride; a phospholipid, for example lecithin, or a free fatty acid that is liquid at room temperature, for example, iso-stearic acid, oleic acid, linoelic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid, and caproic acid.
• Suitable solvents/co-solvents include ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and glycerol.
• a polymer may also be used in the formulation to inhibit drug precipitation or to alter the rate of drug release. A range of polymers have been shown to impart these properties and are well known to those skilled in the art.
• Suitable polymers include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetyl succinate, other cellulose-derived polymers such as methylcellulose; poly(meth)acrylates, such as the Eudragit series of polymers, including Eudragit E100, polyvinylpyrrolidone, or others as described in, e.g., Warren et al., Mol. Pharmaceutics 2013, 10, 2823-2848. [00287] Formulations may be chosen specifically to provide for sustained release of the active in the gastrointestinal (GI) tract in order to control the rate of absorption.
• GI gastrointestinal
• Formulations may also contain materials commonly known to those skilled in the art to be included in lipid-based formulations, including antioxidants, for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
• antioxidants for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluene
• solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).
• the lipid prodrug may be co-administered orally with an enzyme inhibitor to increase stability of the prodrug in
• the enzyme inhibitor will inhibit cellular lipase enzymes such as monoacylglycerol lipase, an example of which includes, but is not limited to, JZL184 (4-nitrophenyl-4-[bis(l,3-benzodioxol-5- yl)(hydroxy)methyl]piperidine-l-carboxylate).
• monoacylglycerol lipase an example of which includes, but is not limited to, JZL184 (4-nitrophenyl-4-[bis(l,3-benzodioxol-5- yl)(hydroxy)methyl]piperidine-l-carboxylate).
• JZL184 4-nitrophenyl-4-[bis(l,3-benzodioxol-5- yl)(hydroxy)methyl]piperidine-l-carboxylate.
• the lipid prodrug or pharmaceutically acceptable composition thereof can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of the lipid prodrug or composition and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
• a disclosed lipid prodrug or composition can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient’s status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
• Such additional agents may be administered separately from a provided lipid prodrug or composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a disclosed lipid prodrug in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another. [00293] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present disclosure. For example, a disclosed lipid prodrug may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
• the present disclosure provides a single unit dosage form comprising a disclosed lipid prodrug, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the additional agent is formulated in a separate composition from the lipid prodrug.
• the amount of both a disclosed lipid prodrug and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
• compositions of this invention should be formulated so that a dosage of between about 0.01–500 mg/kg body weight/day of a disclosed lipid prodrug can be administered.
• compositions which comprise an additional therapeutic agent that additional therapeutic agent and the disclosed lipid prodrug may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of between about 0.01 ⁇ g/kg to 100 mg/kg body weight/day of the additional therapeutic agent can be administered.
• the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
• the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
• agents with which the lipid prodrugs of this invention may be combined include, without limitation: treatments for Alzheimer’s Disease such as Aricept ® and Exelon ® ; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as L- DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex ® and Rebif ® ), Copaxone ® , and mitoxantrone; treatments for asthma such as albuterol and Singulair ® ; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclopho
• combination therapies of the present invention include a monoclonal antibody or a siRNA therapeutic.
• the present invention provides a method of treating an inflammatory disease, disorder or condition such as a neuroinflammatory disease or Alzheimer’s disease, by administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents.
• Such additional therapeutic agents may be small molecules or a biologic and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ri
• the present invention provides a method of treating a depressive mood disorder (e.g., major depressive disorder, bipolar disorder, seasonal affective disorder (SAD), cyclothymic disorder, premenstrual dysphoric disorder, persistent depressive disorder, disruptive mood dysregulation disorder, depression related to medical illness, postpartum depression) and/or anxiety disorder (e.g., panic disorder and post-traumatic stress disorder) comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), fluvoxamine (Luvox®/Luvox CR®), paroxetine (Paxil®/Paxil CR®), sertraline (Zoloft®), desvenlafaxine (Pristiq®), duloxetine (Cymbalta®), venlafaxine (Effexor®/Effexor XR
• the present invention provides a method of treating Alzheimer’s disease comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from donepezil (Aricept ® ), rivastigmine (Exelon ® ), galantamine (Razadyne ® ), tacrine (Cognex ® ), and memantine (Namenda ® ).
• the disclosed lipid prodrugs and compositions, and any co-administered additional therapeutic agents, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease, disorder, or condition such as an inflammatory disorder, a neurodegenerative or neurological disorder, or schizophrenia.
• a disease, disorder, or condition such as an inflammatory disorder, a neurodegenerative or neurological disorder, or schizophrenia.
• the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
• Disclosed lipid prodrugs are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• the expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.
• lipid prodrug or composition thereof any co-administered additional therapeutic agents will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific lipid prodrug employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific lipid prodrug or composition; the duration of the treatment; drugs used in combination or coincidental with the specific lipid prodrug or composition employed, and like factors well known in the medical arts.
• a dose is selected to account for lymphatic uptake, metabolism, and release of the parent drug allopregnanolone (allo). For example, if a given dose of lipid prodrug is absorbed more efficiently than an equivalent oral or intravenous dose of allopregnanolone, the dose of lipid prodrug is decreased by an appropriate amount to result in the desired plasma or lymphatic system concentration of allopregnanolone.
• the dose is selected such that an orally-administered dose of lipid prodrug provides, upon lymphatic uptake in the patient, metabolism, and release of the parent drug allopregnanolone, a desired, effective concentration, e.g., a plasma or lymphatic system concentration, of allopregnanolone to treat a disease, disorder, or condition, such as those disclosed herein.
• a desired, effective concentration e.g., a plasma or lymphatic system concentration
• the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.01 mg/kg to about 100 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.1 mg/kg to about 25 mg/kg.
• the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.5 mg/kg to about 15 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 1 mg/kg to about 10 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 2 mg/kg to about 7.5 mg/kg. In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 3.0 mg/kg to about 7.0 mg/kg.
• the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg/kg.
• the dose is about 1 mg to about 5 g of lipid prodrug or a pharmaceutically acceptable salt thereof.
• the dose is about 10 mg to about 2.5 g of lipid prodrug or a pharmaceutically acceptable salt thereof.
• the dose is about 100 mg to about 2.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 250 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 500 mg to about 1.0 g of lipid prodrug or a pharmaceutically acceptable salt thereof. [00306] In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide a particular dose of allopregnanolone when the prodrug is administered orally.
• the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 0.01 mg/kg to about 100 mg/kg of allopregnanolone, 0.1 mg/kg to about 25 mg/kg, about 0.5 mg/kg to about 15 mg/kg, about 1 mg/kg to about 10 mg/kg, about 2 mg/kg to about 7.5 mg/kg, about 3.0 mg/kg to about 7.0 mg/kg of allopregnanolone.
• the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.5, 1.7, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg/kg of allopregnanolone when the prodrug is administered orally. [00307] In some embodiments, the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is calculated to provide about 5 mg to about 3 g of allopregnanolone when the prodrug is administered orally.
• the dose is calculated to provide about 50 mg to about 2.5 g of allopregnanolone, or about 100 mg to about 1.5 g, or about 250 mg to about 1.0 g of allopregnanolone. 4. Methods of Making Lipid Prodrugs General Methods for Making Lipid Prodrugs [00308]
• the lipid prodrug compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
• the therapeutic agents comprised in disclosed lipid prodrugs may be purchased commercially or prepared by organic synthesis, semi- synthesis, fermentation (e.g., with viral vectors), and like methods known in the art.
• protecting groups as defined below can be used to manipulate therapeutic agents in preparation for conjugation to the remainder of the lipid prodrug structure, for example, to prevent undesired side reactions from taking place.
• LG includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
• oxygen protecting group includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc.
• Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference.
• suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates.
• Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl.
• silyl ethers examples include trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
• Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
• Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
• arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
• Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5 th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference.
• Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
• Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
• a two-step oxidation process (for example, PCC, then KMnO 4 ) can then be used to transform alcohol vii into the desired acid-TG iv via the intermediate aldehyde viii.
• Scheme 4 Synthesis of compounds of formula x wherein -M- is an acetal self-immolative (ASI) group.
• ASI acetal self-immolative
• the alcohol-bearing parent molecule must be functionalized and activated prior to conjugation with acid-triglyceride iii as outlined above in Scheme 4.
• Int-1 (220 g, 388 mmol) was dissolved in a solution of THF (3000 mL) and water (200 mL) at 0 oC. Sodium borohydride (22 g, 579 mmol) was added portion wise. After addition, the mixture was filtered to afford a cake, which was dried to afford compound Int-2 (1,3-DG) (177 g, 311 mmol, 80% yield) as a white solid.
• n-Butyllithium (n-BuLi, 1.6 M in hexanes, 765 ⁇ L, 1.23 mmol) was added slowly to a solution of TMS-acetylene (198 ⁇ L, 1.40 mmol) in THF (1.5 mL) at –78 °C and the mixture stirred at –78 °C for five minutes then warmed to rt and stirred for a further 15 minutes.
• the reaction was re-cooled to –50 °C, a solution of bromide Int-14 (90.0 mg, 0.350 mmol) in THF (1 mL) was added dropwise and the mixture stirred at –50 °C for 15 minutes and then at room temperature for 17 hours.
• Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 201 ⁇ L, 0.201 mmol) was added dropwise to a 7:2 mixture of silylalkyne Int-15 and alkyne Int-16 (55.6 mg combined, 0.215 mmol) in THF (1 mL) at 0 °C and the mixture stirred at room temperature for one hour.
• the reaction was diluted with water (5 mL) and sat. aq. NH 4 Cl (3 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 10 mL).
• Int-17 prepared according to: Kim, H.-O. et al. Synlett 1998, 1059-1060. [00353] A suspension of PdCl 2 (PPh 3 ) 2 (16.8 mg, 0.0240 mmol) in DMF (1.5 mL) was degassed using N2 gas for five minutes, and then CuI (9.1 mg, 0.0480 mmol), Et3N (66.8 ⁇ L, 0.480 mmol) and a degassed solution of alkyne Int-16 (48.5 mg, 0.240 mmol) and enol triflate Int-17 (94.3 mg, 0.360 mmol) in DMF (2 mL) were added.
• PdCl 2 (PPh 3 ) 2 (16.8 mg, 0.0240 mmol) in DMF (1.5 mL) was degassed using N2 gas for five minutes, and then CuI (9.1 mg, 0.0480 mmol), Et3N (66.8 ⁇ L, 0.480 mmol) and
• Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 98.3 ⁇ L, 98.3 ⁇ mol) was added to a solution of TBDPS ether Int-22 (39.0 mg, 39.3 ⁇ mol) in THF (2.5 mL) at 0 °C and the mixture stirred at room temperature for three hours. The reaction was diluted with water (10 mL), extracted with ethyl acetate (3 ⁇ 15 mL), and the organic extracts washed with brine (30 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• TBDPS ether Int-22 39.0 mg, 39.3 ⁇ mol
• Int-25 prepared according to: Gossauer, A.; Kuhne, G. Liebigs. Ann. Chem. 1977, 664-686. [00361] A solution of ylide Int-25 (8.1 mg, 19.0 ⁇ mol) in toluene (0.4 mL) was added to aldehyde Int-24 (11.0 mg, 14.6 ⁇ mol) in toluene (0.6 mL) and the mixture heated at reflux for four hours. The reaction was cooled to rt and concentrated under reduced pressure to give the crude product.
• n-Butyllithium (n-BuLi, 1.6 M in hexanes, 4.01 mL, 6.42 mmol) was added slowly to a solution of TMS-acetylene (1.02 mL, 7.22 mmol) in THF (9 mL) at –78 °C and the mixture stirred at –78 °C for five minutes then warmed to room temperature and stirred for a further 15 minutes.
• Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 1.61 mL, 1.61 mmol) was added dropwise to silylalkyne Int-40 (463 mg, 1.34 mmol) in THF (12 mL) at 0 °C and the mixture stirred at room temperature for 40 minutes.
• the reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product.
• a suspension of PdCl2(PPh3) 2 (32.2 mg, 0.0459 mmol) in DMF (4 mL) was degassed using a stream of N 2 gas for five minutes, and then CuI (35.0 mg, 0.184 mmol), Et 3 N (256 ⁇ L, 1.84 mmol) and a degassed solution of alkyne Int-41 (250 mg, 0.918 mmol) and enol triflate Int- 17 (313 mg, 1.19 mmol) in DMF (6 mL) were added.
• the mixture was degassed using a stream of N 2 for a further five minutes and then heated at 70 °C for one hour.
• TBDPS ether Int-46 (65.7 mg, 0.0619 mmol) in THF (3 mL) at 0 °C and the mixture stirred at room temperature for 19 hours.
• the reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 15 mL). The combined organic extracts were washed with sat. aq. NaHCO 3 and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product.
• C8 ⁇ Me-acid-2-TG-oleate (Int-178): [00398] Using the Pd-coupling, hydrogenation, EDC-coupling, and TBAF deprotection procedures described for the synthesis of Int-49, compound Int-177 (C8 ⁇ Me-OH-2-TG-oleate) was prepared from 1-(tert-butyldiphenylsilyloxy)-pent-4-yne, benzyl (Z)-3-(((trifluoromethyl) sulfonyl)oxy)but-2-enoate (Int-198; prepared similarly to Int-17), and Int-112.
• C10 ⁇ Me-acid-2-TG-oleate (Int-187): [00401] Compounds Int-185 and Int-186 were prepared from 1-benzyloxy-pentan-5-ol and Int-112 according to the procedures described for the synthesis of Int-43 and Int-47. Oxidation of Int-186 to Int-187 was conducted using the Jones’ reagent according to the procedure described for preparation of Int-178.
• C15 ⁇ Me-acid-2-TG-oleate (Int-233): [00406] Compound Int-232 was prepared from Int-45 and Int-112 according to the procedures described for the conversion of Int-45 to Int-47. Oxidation of Int-232 to Int-233 was conducted using the Jones’ reagent according to the procedure described for preparation of Int-178. [00407] C15 ⁇ Me-OH-2-TG-oleate (Int-232) MS (ESI, +ve) m/z: 893.17 (M+18).
• C12 ⁇ Me-acid-2-TG (Int-247): [00415] Compound Int-247 was prepared by oxidation of Int-121 using PCC and KMnO 4 according to the procedures described for preparation of Int-110 from Int-108.
• n-Butyllithium (n-BuLi, 2.0 M in cyclohexane, 18.1 mL, 36.3 mmol) was added slowly to a solution of TMS-acetylene (5.7 mL, 41.5 mmol) in THF (45 mL) at –78 oC and the mixture stirred at –78 °C for five minutes then warmed to room temperature and stirred for a further 15 minutes.
• Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 9.7 mL, 9.70 mmol) was added dropwise to silylalkyne Int-52 (3.05 g, 9.62 mmol) in THF (40 mL) at 0 ⁇ C and the mixture stirred at room temperature for one hour. The reaction was diluted with water (25 mL) and the organic solvent removed under reduced pressure. The resulting solution was diluted with brine (100 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 50 mL).
• Int-17 was prepared as described above. [00423] A suspension of PdCl 2 (PPh 3 ) 2 (605 mg, 0.862 mmol) in DMF (40 mL) was degassed using N2 gas for five minutes, and then CuI (335 mg, 1.76 mmol), Et3N (2.40 mL, 17.2 mmol) and a degassed solution of alkyne Int-53 (2.11 g, 8.62 mmol) and enol triflate Int-17 (3.40 g, 13.00 mmol) in DMF (50 mL) were added. The mixture was degassed using a stream of N 2 for a further five minutes and then heated at 70 °C for one hour.
• Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 574 ⁇ L, 0.574 mmol) and acetic acid (32.8 ⁇ L, 0.574 mmol) were added to a solution of TBDPS ether Int-58 (395 mg, 0.383 mmol) in THF (15 mL) at 0 °C and the mixture stirred at room temperature for 17 hours. The reaction was concentrated under reduced pressure and the residue diluted with ethyl acetate (30 mL), washed with water (2 ⁇ 20 mL) and brine (30 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• TBDPS ether Int-58 395 mg, 0.383 mmol
• Int-25 was prepared as described above. [00431] A solution of ylide Int-25 (270 mg, 0.637 mmol) in toluene (10 mL) was added to aldehyde Int-60 (262 mg, 0.331 mmol) in toluene (8 mL) and the mixture heated at reflux for 20 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 15% ethyl acetate/hexanes) gave ⁇ , ⁇ -unsaturated benzyl ester Int-61 (273 mg, 88%) as a yellow oil.
• Ph-C3-phenol-2-TG (Int-67): Scheme 21. Synthesis of Int-67. [00458] DBU (108 ⁇ L, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 ⁇ L, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour.
• TBDPSCl t-butyldiphenylsilyl chloride
• the reaction mixture was cooled to room temperature, diluted with cold water (300 mL), and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The resulting material was purified by column chromatography using silica gel (100-200 mesh). Desired product eluted at 10% ethyl acetate/ hexane as a mobile phase. Pure fractions were concentrated under vacuum to afford Int- 195 (21.0 g, 43.3 %).
• the reaction mixture was diluted with water (60 mL), and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The resulting oil was purified by column chromatography using silica gel (100-200 mesh). Desired product eluted at 2% ethyl acetate/ hexane as a mobile phase. Pure fractions were concentrated under vacuum to afford Int-199 (3.0 g, 35 %).
• Alcohol Int-68 (commercially available; 90.0 mg, 0.499 mmol) was added in a single portion to a suspension of t-BuOK (84.1 mg, 0.749 mmol) in THF (2 mL) and the mixture stirred at room temperature for one hour.
• a solution of bromide Int-69 (190 mg, 0.699 mmol) in THF (1 mL) and TBAI (36.9 mg, 0.100 mmol) were then added and the resulting mixture heated at reflux for 20 hours.
• Int-74 is a known compound that may be prepared as described in Charette, A. B. et al. J. Am. Chem. Soc.2001, 123, 11829-11830.
• Alcohol Int-68 (commercially available; 135 mg, 0.749 mmol) was added in a single portion to a suspension of t-BuOK (118 mg, 1.05 mmol) in THF (2.5 mL) and the mixture stirred at RT for one hour.
• a solution of bromide Int-74 (273 mg, 1.12 mmol) in THF (2 mL) was then added and the resulting mixture heated at reflux for 26 hours.
• 1,8-dibromooctane (2.75 g, 10.13 mmol) was added and the reaction mixture was stirred and allowed to warm from -78 oC to room temperature over 3h. The reaction was monitored by TLC for completeness. An additional identical batch starting with 1.5 g propionic acid was prepared and the two batches combined before workup. The combined reaction mixture was diluted with water (100 mL) and acidified with 1N HCl (25 ml) and extracted with ethyl acetate (3 x 100 ml), and the combined organic layer was dried over Na 2 SO 4 and evaporated to give crude compound. The title compound was purified by combi flash purification, eluting with 10% ethyl acetate/hexane as the mobile phase.
• Int-80 (2.44 g, 9.49 mmol) was added at room temperature and stirred for 2h. The reaction was monitored by TLC until completion, after which the reaction mixture was filtered through celite and washed with DCM (45 ml), then evaporated to give the crude product, which was purified by combi flash purification, eluting with 7% ethyl acetate/hexane. After evaporation, Int-81 (C12a'aMe-acid-2-TG) (1.7 g, 44.3%) was obtained as an off-white solid.
• Iodotriglyceride Int-95 Scheme 27. Synthesis of Int-95.
• Int-93 is a known compound prepared from cycloheptanone as shown above (see Kai, K. et al. Tetrahedron 2008, 64, 6760-6769).
• TMSCl chlorotrimethylsilane
• TMSCl chlorotrimethylsilane
• Int-105 [00497] Int-99: [00498] A suspension of 1,16-hexanediol (200 mg, 0.774 mmol) in DMF (2 mL) was added a suspensiom of NaH (34.1 mg, 60% w/w dispersion in mineral oil, washed twice with dry petrol, 8.51 mmol) in DMF (1 mL) at 0 °C and the mixture stirred at 0 °C for 10 minutes and then at rt for 30 minutes. TBDPSCl (221 ⁇ L, 0.851 mmol) was added and the mixture stirred at rt for 17 hours.
• Int-100 [00500] Pyridinium chlorochromate (PCC, 106 mg, 0.491 mmol) and Celite (100 mg) were added to alcohol Int-99 (122 mg, 0.246 mmol) in CH 2 Cl 2 (6 mL) at 0 °C and the mixture stirred at 0 °C for 10 minutes and then at rt for 1.5 hours. The reaction was filtered through a short pad of silica gel, eluting with 50% ethyl acetate/hexanes (80 mL), and the filtrate concentrated under reduced pressure to give crude aldehyde Int-100 (121 mg, quant.) as a yellow oil that was immediately used without purification.
• PCC Pyridinium chlorochromate
• Celite 100 mg
• Int-101 [00502] Ylide methyl 2-(triphenyl- ⁇ 5 -phosphaneylidene)acetate (205 mg, 0.614 mmol) was added to crude aldehyde Int-100 (121 mg, 0.246 mmol) in toluene (6 mL) and the mixture heated at reflux for one hour. The reaction was cooled to rt and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate/hexanes) gave alpha,beta-unsaturated methyl ester Int-101 (100 mg, 74%, 6:1 mixture of E/Z isomers) as a yellow oil.
• Int-102 [00504] A solution of alkene Int-101 (99.0 mg, 0.180 mmol) in ethyl acetate (5 mL) in a two- neck flask was evacuated and flushed with N2 gas three times each, then palladium on carbon (10% w/w, 28.7 mg, 0.0270 mmol) was added and the resulting suspension re-evacuated and flushed with N 2 three times. The flask was fitted with a H 2 balloon, evacuated and flushed with H 2 three times and the reaction mixture stirred at rt under 1 atm of H2 for one hour.
• Int-103 [00506] A solution of potassium hydroxide (2.0 M, 530 ⁇ L, 1.06 mmol) was added to ester Int- 102 (26.0 mg.0.0854 mmol) in ethanol (3 mL) and the mixture heated at 70 °C for 50 minutes. The reaction was acidified to pH 3 by addition of 1 M HCl and diluted with ethyl acetate (40 mL). The organic phase was washed with water (2 ⁇ 30 mL) and brine (30 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• potassium hydroxide 2.0 M, 530 ⁇ L, 1.06 mmol
• Int-104 [00508] DMAP (10.2 mg, 0.0839 mmol), EDC•HCl (40.2 mg, 0.210 mmol) and 1,3-diglyceride Int-2 (52.5 mg, 0.0923 mmol) were added to a solution of acid Int-103 (45.2 mg, 0.0839 mmol) in CH 2 Cl 2 (4 mL) and the mixture stirred at RT for 22 hours. The reaction was diluted with CH 2 Cl 2 (10 mL), silica gel was added and the mixture concentrated under reduced pressure.
• Int-105 Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 154 ⁇ L, 0.154 mmol) and acetic acid (8.8 ⁇ L, 0.154 mmol) were added to a solution of TBDPS ether Int-104 (84.0 mg, 0.0771 mmol) in THF (3 mL) at 0 °C and the mixture stirred at 0 °C for 15 minutes and then at rt for seven hours. The reaction was diluted with ethyl acetate (40 mL), washed with water (30 mL) and brine (2 x 30 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• TBDPS ether Int-104 84.0 mg, 0.0771 mmol
• Int-110 (TML(CO2H)-C4-2-TG): Scheme 30. Synthesis of Int-110.
• Int-106 prepared according to: Amsberry, K. L. et al. Pharm Res.1991, 8, 455-461.
• DMAP (18.3 mg, 0.149 mmol
• EDC•HCl (71.6 mg, 0.374 mmol) were added to a solution of Int-28 (100 mg, 0.149 mmol) and phenol Int-106 (53.0 mg, 0.164 mmol) in CH 2 Cl 2 (4 mL) and the mixture stirred at room temperature for 19 hours.
• reaction was filtered through a short pad of silica gel, eluting with 50% ethyl acetate/hexanes (50 mL), and the filtrate concentrated under reduced pressure to give crude aldehyde Int-109 (59.8 mg, quant.) as a yellow oil that was used without purification.
• TML-C8 ⁇ Me-acid-2-TG-oleate (Int-267): [00522] Using similar methods as described for the synthesis of alcohol Int-108, compound Int-266 was prepared from Int-106 and Int-178.
• TML-C8 ⁇ ' ⁇ Me-acid-2-TG-oleate (Int-268): [00525] Using similar methods as described for the synthesis of Int-267, compound Int-268 was prepared from Int-106 and Int-176.
• reaction mixture was concentrated under reduced pressure yielding a crude sticky material, which was purified by column chromatography using silica gel (100-200 mesh). Pure compound was eluted at 15% ethyl acetate and hexane as the mobile phase. Pure fractions were concentrated under reduced pressure to afford pure Int-113 (2.95 g, 75.8%) as a viscous liquid.
• Int-125 [00539] Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 243 ⁇ L, 0.243 mmol) and AcOH (13.9 L, 0.243 mmol) were added dropwise to TBDPS ether Int-124 (58.7 mg, 0.0809 mmol) in THF (4 mL) at 0 ⁇ C and the mixture stirred at rt for 19 hours. The reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 15 mL). The combined organic extracts were washed with sat. aq.
• TBAF Tetrabutylammonium fluoride
• chloromethyl chlorosulfate (0.062 ml, 0.618 mmol) was added dropwise at rt and stirred vigorously at rt for 18 h.
• the reaction was monitored by TLC, and after completion of reaction, the reaction mixture was diluted with DCM (25 ml). The organic phase was separated and the aqueous phase extracted with DCM (2 x 50 ml). Combined organic layers were washed with water (50 ml), brine (50 mL), dried over sodium sulphate, filtered and concentrated at reduced pressure to get crude material.
• Int-155 was prepared: [00551] Tetra-n-butyl ammonium hydrogen sulfate (24 mg, 0.072 mmol) and potassium bicarbonate (286 mg, 2.86 mmol) in distilled water (10 ml) was added to a stirred solution of acid linker Int-4 (0.5 g, 0.72 mmol) and tetra-n-butyl ammonium hydrogen sulfate (24 mg, 0.072 mmol) in dichloromethane (10 ml) at rt and stir for 0.5 h.
• chloromethyl chlorosulfate (0.092 ml, 0.89 mmol) was dropwise added at room temperature and stirred vigorously at rt for 18h.
• the reaction was monitored by TLC, after completion of reaction; reaction mixture was diluted with DCM (5 ml). The organic phase was separated and the aqueous phase was extracted with DCM (2 x 5 ml). The combined organic layers were washed with water (10 ml), brine (10 mL), dried over sodium sulfate, filtered and concentrated at reduced pressure to get crude material. Crude material was purified by column chromatography over silica, compound eluted at 15% ethyl acetate/hexane as a mobile phase.
• the resulting acid chloride was dissolved in DCM (20 ml), then ZrCl 4 (0.33 g, 1.45 mmol) in DCM (10 mL) was added dropwise to the reaction mixture at 0 oC and stirred at 0 oC for 10 minutes. Then paraldehyde (0.383 g, 2.90 mmol) was added and the reaction mixture was stirred at 0 oC for 0.5 h and RT for 1 h. The reaction mixture was diluted with DCM (50 mL) and water (50 mL). The organic layer was washed with water (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product.
• the resulting acid chloride was dissolved in DCM (20 ml), then ZrCl 4 (0.33 g, 1.45 mmol) in DCM (10 mL) was added dropwise to the reaction mixture at 0 oC and stirred at 0 oC for 10 minutes. Then paraldehyde (0.383 g, 2.90 mmol) was added and the reaction mixture was stirred at 0 oC for 0.5 h and RT for 1 h. The reaction mixture was diluted with DCM (50 mL) and water (50 mL). The organic layer was washed with water (25 mL) and brine (25 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to give the crude product.
• C10 ⁇ Me-acid-2-TG (Int-151) Scheme 40. Synthesis of Int-151.
• Intermediate C10 ⁇ Me-acid-2-TG (Int-151) was prepared from octane-1,8-diol as shown in Scheme 40, using methods described above.
• C12 ⁇ Me-acid-2-TG (Int-167): [00571] Intermediate C12 ⁇ Me-acid-2-TG (Int-167) was prepared using the procedures shown in Scheme 40, using decane-1,10-diol in place of octane-1,8-diol.
• Int-140 PHB-C12 ⁇ ' ⁇ Me-bromide-2-TG (Int-140): [00591] Using similar methods, Int-140 was prepared from 4-(((tert- butyldimethylsilyl)oxy)methyl)phenol (a known compound that may be prepared as described in, e.g., Smith, J. H. et al. Angew. Chem. Int.
• DMPHB-C10 ⁇ Me-bromide-2-TG (Int-147): [00599] Using similar methods as described for the synthesis of Int-135, compound Int-147 was prepared from Int-132 and Int-30: [00600] 4-(Dimethylamino)pyridine (DMAP, 6.9 mg, 0.0563 mmol) and EDC•HCl (21.6 mg, 0.113 mmol) were added to a solution of acid-TG Int-30 (45.3 mg, 0.0591 mmol) and phenol Int- 132 (15.0 mg, 0.0563 mmol) in CH 2 Cl 2 (3 mL) and the mixture stirred at room temperature for three days.
• DMAP Dimethylamino)pyridine
• EDC•HCl (21.6 mg, 0.113 mmol)
• FSI5-C5bMe-acid-2-TG (Int-162): [00610] Using similar methods as described for the synthesis of Int-160, compound Int-162 was prepared from Int-158 and Int-4: [00611] To a solution of Int-4 (0.50 g, 0.71 mmol) in DMF (5 mL) was added Na 2 CO 3 (0.45 g, 4.31 mmol) followed by TBAI (0.130 g, 0.35 mmol) and Int-158 (0.21 g, 0.71 mmol) at room temperature, and then the reaction mixture was stirred at 100 °C for 18 h.
• CDMPHB-(OPNP)-C10 ⁇ Me-2-TG-oleate (Int-206): Scheme 48. Synthesis of Int-206. [00690] Pyridine (0.52 mg, 6.63 mmol) was added dropwise to a stirred solution of Int-189 (2.4 g, 2.21 mmol) and 4-nitrophenylchloroformate (1.33 g, 6.63 mmol) in DCM (20 mL) at 0 o C. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated then diluted with water (50 mL).
• 1,3-DG-acetate (Int-284): [00739] To a solution of 1,3-dihydroxypropan-2-one (5.0 g, 55.5 mmol) and acetic anhydride (11.33 g, 111.07 mmol) in acetone (50ml) was added pyridine (9.66g, 122.18 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution evaporated under vacuum, redissolved in DCM (50 ml) and washed with 1N HCl (50 ml), water (50ml).
• reaction was monitored by TLC, after completion of reactions, reaction mixture was cooled to RT, diluted with DM water (100 ml) and extracted with ethyl acetate (3 x 100 ml), and combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford crude oil. Purification was done by column chromatography using silica gel (100-200 mesh). Pure product was eluted at 15% ethyl acetate/ hexane as a mobile phase.
• reaction mixture was stirred at RT for 2 days under 20 kg/Cm 2 (285 psi) H2 pressure (in an autoclave), after completion of reaction, the reaction mixture was filtered through a pad of celite, and washed with ethyl acetate (240 ml). The filtrate was concentrated under reduced pressure to afford crude. Purification was done by column chromatography using silica gel (100-200 mesh). Pure compound was eluted at 15% ethyl acetate in hexane to get pure Int-287 (4.0 g, 96.38%) as colourless oil.
• reaction was monitored by TLC. After completion of reaction, reaction mixture was distilled out to get crude material; Purification was done by column chromatography using silica gel (100-200 mesh). Pure product was eluted at 2-3 % ethyl acetate/ hexane as a mobile phase. Pure fractions were concentrated in the rota vapour to get pure Int-292 (0.40 g, 33.3%) as a colourless oil. [00750] A solution of Int-292 (0.40 g) in DCM (10 ml) was added TFA (0.8 ml, 2V) 0 0 C and reaction mixture was stirred at RT for 16 h. Reaction was monitored by TLC.
• reaction mixture was distilled out, diluted with water (50 ml) and extracted with Ethyl acetate (3 x 50 ml). Combined organic layer was dried over Na 2 SO 4 , evaporated under reduced pressure to get crude; Purification was done by column chromatography using silica gel (100-200 mesh). Pure product was eluted at 6-7 % ethyl acetate: hexane as a mobile phase. Pure fractions were concentrated in the rota vapour to get pure Int-293 (0.200 g, 54.05%) as a colourless oil.
• DMOPHB-alcohol-C10bMe-2-TG-oleate (Int-297): Scheme 55: Synthesis of Int-297 [00755] 4-(Dimethylamino)pyridine (DMAP, 447 mg, 3.66 mmol) and N-(3- dimethylaminopropyl)-N ⁇ -ethyl-carbodiimide (EDC•HCl, 935 mg, 4.88 mmol) were added to a solution of acid Int-187 (2.00 g, 2.44 mmol) and 4-hydroxy-3,5-dimethoxybenzaldehyde (445 mg, 2.44 mmol) in CH 2 Cl 2 (30 mL) and the mixture stirred at room temperature overnight.
• DMAP Dimethylamino)pyridine
• EDC•HCl N-(3- dimethylaminopropyl)-N ⁇ -ethyl-carbodiimide
• Int-301 was purified by column chromatography using 12-15% Ethyl acetate and hexane as eluent to get pure Int-301 (279 mg yield 96%) as a colourless liquid: MASS (ESI, +ve) m/z: 780.37 (MH+18).
• Example 2 Synthesis of Exemplary Compounds Synthesis of IAL-CDMPHB-C5bMe-2-TG-oleate: 1-(4-((((((3S,5S,8R,9S,10S,13S,14S,17S)- 17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3- yl)oxy)carbonyl)oxy)methyl)-2,6-dimethylphenyl) 5-(1,3-bis(oleoyloxy)propan-2-yl) 3- methylpentanedioate I-20.
• Step 1 (3S,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro- 1H-cyclopenta[a]phenanthren-3-yl (4-nitrophenyl) carbonate 2.2
• 4-Nitrophenyl chloroformate 151 mg, 0.75 mmol was added to a mixture of pyridine (95 ⁇ L, 1.18 mmol) and iso-allopregnanolone (150 mg, 0.47 mmol) in CH 2 Cl 2 (5.0 mL). The resulting mixture was stirred at room temperature for 90 minutes before being concentrated in vacuo.
• Step 2 1-(1,3-bis(oleoyloxy)propan-2-yl) 5-(4-formyl-2,6-dimethylphenyl) 3- methylpentanedioate
• DMAP 4-(Dimethylamino)pyridine
• EDC N-(3- dimethylaminopropyl)-N ⁇ -ethyl-carbodiimide
• 307 mg, 1.60 mmol were added to a solution of the Int-210 (600 mg, 0.80 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (120 mg, 0.80 mmol) in CH 2 Cl 2 (40 mL) and the mixture stirred at room temperature overnight.
• reaction was concentrated to near dryness and purified by normal phase flash column chromatography (Biotage Isolera, 40 g, Silicycle siliasep cartridge) using n-heptane and EtOAc (gradient: 1:0 to 7:3) to give the desired compound (555 mg, 79%) as a colourless oil.
• Step 3 1-(1,3-bis(oleoyloxy)propan-2-yl) 5-(4-(hydroxymethyl)-2,6- dimethylphenyl) 3-methylpentanedioate
• Sodium borohydride NaBH 4 , 24 mg, 0.62 mmol
• MeOH MeOH
• THF THF
• Step 4 1-(4-((((((((3S,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13- dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)oxy)methyl)-2,6- dimethylphenyl) 5-(1,3-bis(oleoyloxy)propan-2-yl) 3-methylpentanedioate I-20 [00779] Potassium carbonate (K 2 CO 3 , 122 mg, 0.88 mmol) was added to a mixture of 1-(1,3- bis(oleoyloxy)propan-2-yl) 5-(4-(hydroxymethyl)-2,6-dimethylphenyl) 3-methylpentanedioate (130 mg, 0.15 mmol) in N,N-dimethylformamide (3.0 mL) at 0 °C.
• Step 1 Preparation of Compound 2.3
• 1-Chloroethyl chloroformate (67.8 ⁇ L, 0.628 mmol) and pyridine (95.2 ⁇ L, 1.18 mmol) were added to allopregnanolone (125 mg, 0.393 mmol) in CH 2 Cl 2 (5 mL) at 0 °C and the mixture stirred at 0 °C for 30 minutes and then at rt for two hours.
• Step 2 ALL-CMSI-C10b'bMe-2-TG-oleate I-1
• Cesium carbonate (Cs 2 CO 3 , 43.4 mg, 133 ⁇ mol) and tetra-n-butylammonium iodide (TBAI, 8.2 mg, 22.2 ⁇ mol) were added to a suspension of Int-172 (37.0 mg, 44.4 ⁇ mol) and compound 2.3 (18.9 mg, 44.4 ⁇ mol) in DMF (2 mL) and the mixture heated at 60 °C for 1.5 hours.
• reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 300 ml), then the combined organic layers were dried over Na 2 SO 4 .
• the mixture was filtered and the filtrate concentrated under vacuum to get the crude product, which was purified by column chromatography using silica gel (100-200 mesh). Pure compound was eluted at 20% ethyl acetate and hexane as a mobile phase. The pure fraction was concentrated under vacuum to obtain the desired ALL-CMSI-C5bMe-TG-Oleate I-2 (8.5g, 48%) as a viscous oil.
• Step 1 Synthesis of 5-(benzyloxy)-3-methyl-5-oxopentanoic acid [00795] To a solution of compound 4-methyldihydro-2H-pyran-2,6(3H)-dione (3.0 g, 23.428 mmol) and DMAP (1.42 g, 11.71 mmol) in DCM (60 ml) was added benzyl alcohol (1.26 g, 11.71 mmol), then the reaction mixture was stirred at room temperature for 18 h at 0°C.
• Step 2 Synthesis of Compound 2.6 [00797] To a solution of 5-(benzyloxy)-3-methyl-5-oxopentanoic acid (3.34 g, 78.58 mmol) in toluene (30ml) was added Cs2CO3 (5.12 g, 157.17 mmol). The reaction was stirred at room temperature for 15 min and then compound 2.3 (1.85 g, 78.75 mmol) (pre dissolved in 30 ml Toluene) and TBAI (2.87 g, 7.783 mmol) were added at room temperature. The reaction mixture was stirred at 90°C for 2h.
• reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 200 ml), combined organic layer dried over Na2SO4, distilled under vacuum to get crude compound, which was purified by column chromatography using silica gel (100-200 mesh). Pure compound was eluted at 15 % ethyl acetate and hexane as a mobile phase then pure fraction was conc. in the rota vapour to get pure compound 2.6 (3.0 g, 61.22%) as viscous oil.
• Step 3 Synthesis of Compound 2.7 [00799] To a solution of compound 2.6 (3.0 g, 4.80 mmol) in ethyl acetate (100 ml) was added palladium on carbon (10% w/w, 3.0 g) and the resulting suspension was evacuated and flushed with N2 three times. The reaction mixture was then stirred at room temperature for 18 h under 20 kg H 2 pressure. After completion of the reaction, the reaction mixture was filtered through a celite bed, and washed with ethyl acetate (200 ml). The filtrate was concentrated under reduced pressure to afford crude compound 2.7 (1.6 g, 72%) as a colourless oil which was used in the next step without purification.
• Step 4 Synthesis of I-2 [00801] To a stirred solution of compound 2.7 (1.0 g, 1.87 mmol) and Int-112 (0.69 g 1.12 mmol) in DCM (20 ml) was added EDC•HCl (0.89 g, 4.67 mmol) and DMAP (0.28 g, 1.87 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC.
• reaction mixture was concentrated under vacuum to get crude material which was purified by column chromatography purification using 5% ethyl acetate and n-Hexane as eluent to yield pure I-2 (1.05 g, 49.9%) as yellowish viscous liquid.
• Step 1 Compound 3 [00804] To a solution of of allopreganolone (200 mg, 0.62 mmol) in DCM (3 ml) was added EDC.HCl (300 mg, 1.57 mmol) and DMAP (38 mg, 0.31 ⁇ mmol) and stirred at rt for 15 min, then 5-bromopentanoic acid (220 mg, 1.13 mmol) was added at room temperature and stirred at rt for 16 h. The reaction was monitored by TLC, and after completion of reaction, the reaction mixture was diluted with water (10 ml) and extracted with DCM (3 x 10 ml). The combined organic layer was dried over Na 2 SO 4, and concentrated to get crude material.
• Step 2 ALL-FSI5-C12a’aMe-TG I-5
• DBU 0.75 g, 0.49 mmol
• compound 3 0.118 g, 0.24 mmol
• TBAI 0.045 g, 0.12 mmol
• reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3 x 10 ml), combined organic layer dried over Na2SO4, then distilled under vacuum to get crude compound, which was purified by combi flash purification, compound was eluted at 5% ethyl acetate and hexane as a mobile phase then the pure fraction was concentrated to get pure compound ALL-FSI5-C12a’aMe-TG I-5 (65 mg, 21.74%) as viscous oil.
• ALL-C10-2-TG I-7 (30 mg, 11.3%) as viscous liquid.
• Step 1 Compound 4 [00811] A mixture of allopregnanolone (250 mg, 0.785 mmol), acetic acid (0.35 mL, 5.54 mmol), acetic anhydride (1.12 mL, 10.0 mmol) and DMSO (1.72 mL, 20.1 mmol) was stirred at rt for three days and 19 hours. The reaction was diluted with ethyl acetate (50 mL) and the organic layer washed with sat. aq.
• Step 2 ALL-ASI-C5bMe-2-TG-oleate I-9
• Sulfuryl chloride (6.0 ⁇ L, 74.0 ⁇ mol) was added to a solution of compound 4 (20.0 mg, 52.8 ⁇ mol) in CH 2 Cl 2 (2 mL) at 0 °C and the reaction was stirred at 0 °C for 30 minutes. The reaction was concentrated under reduced pressure, dissolved in toluene (3 ⁇ 5 mL) and re- concentrated under reduced pressure.
• ALL-ASI-C10b’bMe-2-TG-oleate I-32 was synthesized using the procedure provided above for I-9, replacing Int-210 with Int-172. Purification by silica gel chromatography (3% ethyl acetate/toluene) gave ALL-ASI-C10b’bMe-2-TG-oleate I-32 (15.7 mg, 34%) as a colourless oil.
• ALL-ASI-C12b’bMe-2-TG-oleate I-34 was synthesized using the procedure provided above for I-9, replacing Int-210 with Int-174. Purification by silica gel chromatography (3% ethyl acetate/toluene) gave ALL-ASI-C12b’bMe-2-TG-oleate I-34 (23.5 mg, 50%) as a colourless oil.
• ALL-ASI-C6-2-TG-oleate I-40 was synthesized using the procedure provided above for I-9, replacing Int-210 with C6-acid-TG-oleate (Int-276).
• C6-acid-TG-oleate was prepared from Int-112 and adipoyl chloride using the procedures depicted in Scheme 10. Purification by silica gel chromatography (8% to 9% ethyl acetate/hexanes) gave ALL-ASI-C6-2-TG-oleate I-40 (31.6 mg, 74%) as a colourless oil.
• ALL-ASI-C8-2-TG-oleate I-41 was synthesized using the procedure provided above for I-9, replacing Int-210 with Int-277. Purification by silica gel chromatography (8% to 9% ethyl acetate/hexanes) gave ALL-ASI-C8-2-TG-oleate I-41 (35.0 mg, 80%) as a colourless oil.
• ALL-ASI-C8bMe-2-TG-oleate I-42 was synthesized using the procedure provided above for I-9, replacing Int-210 with Int-178. Purification by silica gel chromatography (8% to 9% ethyl acetate/hexanes) gave ALL-ASI-C8bMe-2-TG-oleate I-42 (24.0 mg, 54%) as a colourless oil.
• ALL-ASI-C8b’bMe-2-TG-oleate I-13 was synthesized using the procedure provided above for I-9, replacing Int-210 with Int-176. Purification by silica gel chromatography (8% to 9% ethyl acetate/hexanes) gave ALL-ASI-C8b’bMe-2-TG-oleate I-13 (47.5 mg, 79%) as a colourless oil.
• Step 1 Preparation of Compound 2.4 [00821] Chloromethyl chloroformate (22.3 ⁇ L, 0.251 mmol) and pyridine (38.1 ⁇ L, 0.471 mmol) were added to allopregnanolone (50.0 mg, 0.157 mmol) in CH 2 Cl 2 (2 mL) at 0 °C and the mixture stirred at 0 °C for 30 minutes and then at rt for one hour.
• Step 2 ALL-CASI-C8-2-TG-oleate I-29
• Cs2CO3 (36.5 mg, 112 ⁇ mol) and TBAI (6.9 mg, 18.7 ⁇ mol) were added to a solution of C8-acid-TG-oleate (Int-277) (29.0 mg, 37.3 ⁇ mol, prepared from Int-112 and oxalyl chloride using the procedures depicted in Scheme 10) and compound 2.4 (15.3 mg, 39.4 ⁇ mol) in DMF (2 mL) and the mixture was heated at 70 °C for two hours.
• ALL-CASI-C8b’bMe-2-TG-oleate I-30 was synthesized using the procedure provided above for I-29, replacing C8-acid-TG-oleate with Int-176. The product was purified by silica gel chromatography (8% to 9% ethyl acetate/hexanes) to give ALL-CASI-C8b’bMe-2-TG-oleate I- 30 (35.8 mg, 87%) as a colourless oil.
• ALL-CASI-C5bMe-2-TG-oleate I-39 was synthesized using the procedure provided above for I-29, replacing C8-acid-TG-oleate with Int-210. The product was purified by silica gel chromatography (9% to 10% ethyl acetate/hexanes) to give ALL-CASI-C5bMe-2-TG-oleate I-39 (27.6 mg, 62%) as a colourless oil.
• Step 2 ALL-CDMPHB-C5bMe-2-TG-oleate I-10
• Potassium carbonate (13.7 mg, 99.3 ⁇ mol) was added to a solution of compound 2.5 (12.0 mg, 24.8 ⁇ mol) and Int-279 (24.1 mg, 27.3 ⁇ mol) in DMF (1.5 mL) and the mixture heated at 70 oC for two days and two hours.
• the reaction was cooled to rt, diluted with ethyl acetate (20 mL), washed with sat. aq. NaHCO3 (3 ⁇ 20 mL) and brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product.
• reaction mixture was diluted with DM water (5 ml) and extracted with DCM (3 x 10 ml), and the combined organic layer was dried over sodium sulphate and concentrated under vaccuum to get crude material. Purification was done by column chromatography using 100-200 mesh silica gel, and pure compound was eluted at 10% ethyl acetate/hexane to yield ALL-TML-C8bMe-2-TG oleate I-12 (100 mg, 15.37%).
• Allopregnanolone (0.157 g, 0.495 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC, and after 16h the reaction was completed.
• the reaction mixture was diluted with DM water (30 ml) and extracted with DCM (3 x 25 ml), and the combined organic layer was dried over sodium sulphate and concentrated under vacuum to get crude material. Purification was done by column chromatography using 100-200 mesh silica gel, and pure compound was eluted at 8% ethyl acetate/hexane to get ALL-TML-C8b'bMe-2-TG oleate I-14 (100 mg, 15.41%).
• ALL-CMSI-C6-2-TG-oleate I-43 was synthesized using the procedure provided above for I-35, replacing Int-174 with Int-276. The product was purified by silica gel chromatography (9% to 10% ethyl acetate/hexanes) to give ALL-CMSI-C6-2-TG-oleate I-43 (24.6 mg, 52%) as a colourless oil.
• ALL-CMSI-C8-2-TG-oleate I-44 was synthesized using the procedure provided above for I-35, replacing Int-174 with Int-277. The product was purified by silica gel chromatography (9% to 10% ethyl acetate/hexanes) to give ALL-CMSI-C8-2-TG-oleate I-44 (34.5 mg, 74%) as a colourless oil.
• ALL-CMSI-C8bMe-2-TG-oleate I-45 was synthesized using the procedure provided above for I-35, replacing Int-174 with Int-178. The product was purified by silica gel chromatography (8% to 10% ethyl acetate/hexanes) to give ALL-CMSI-C8bMe-2-TG-oleate I-45 (48.5 mg, 88%) as a colourless oil.
• Step 1 Compound 5.1 [00838] To a solution of 4-methyldihydro-2H-pyran-2,6(3H)-dione (1.5 g, 11.718 mmol) in DCM (20 ml) was added DMAP (1.42 g, 11.718 mmol). The reaction mixture was stirred at room temperature for 10 min, then (2,4-dimethoxyphenyl)methanol (0.98 g, 5.859 mmol) was added. The reaction mixture was stirred at room temperature for an additional 16 h.
• reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with DCM (3 x 20 ml). The organic layer was washed with 1 N HCl (20 ml). The combined organic layer was dried over Na2SO4 and evaporated under vacuum to get crude compound 5.1 as a colorless liquid (1.9 g, quantitative yield), which was directly used in the next step.
• Step 2 Compound 5.2 [00840] To a solution of compound 2.3 (2.15 g, 5.067 mmol; produced as shown in the synthesis of I-1) in toluene (5 ml) was added Cs2CO3 (3.29 g, 10.134 mmol) and stirred at room temperature for 15 min then compound 5.1 (1.5 g, 5.067 mmol) (pre dissolved in 10 ml Toluene) and TBAI (0.934 g, 25.33 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C for 2 h. The reaction was monitored by TLC.
• reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3 x 10 ml), and the combined organic layer was dried over Na 2 SO 4, The reaction mixture was reduced under vacuum to get crude compound 5.2, which was purified by column chromatography using silica gel (100-200 mesh). Pure compound was eluted at 12% ethyl acetate and hexane as a mobile phase then pure fraction was under vacuum to get pure compound 5.2 (1.9 g, 55.96%).
• Step 3 ALL-CMSI-C5bMe-acid
• reaction mixture was diluted with DM water (3 ml) and extracted with DCM (3 x 3 ml), and the combined organic layer was dried over sodium sulphate and concentrated under vacuum to get crude material. Purification was done by column chromatography using 100-200 mesh silica gel. Pure compound was eluted at 4% Ethyl acetate/DCM to get ALL-CMSI-C5bMe-2-TG-octanoate I-36 (90 mg, 22.35%).
• ALL-CMSI-C5bMe-2-TG-butyrate I-37 was synthesized using the procedure provided above for I-36, replacing Int-192 with Int-115.
• ALL-CMSI-C5bMe-2-TG-acetate I-38 was synthesized using the procedure provided above for I-36, replacing Int-192 with Int-284.
• reaction mixture was stirred at 90 0 C for 2h. The reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml), combined organic layer dried over sodium sulphate and distilled under vacuum to get crude compound, which was purified by column chromatography using silica gel (100-200 mesh). Pure compound was eluted at 3-5% ethyl acetate and hexane as a mobile phase then pure fraction was conc.
• ALL-CASI-C5bMe-2-TG-octanoate I-47 was synthesized using the procedure provided above for I-29, replacing C8-acid-TG-oleate with Int-299.
• ALL-CASI-C5-2-TG-oleate I-50 was synthesized using the procedure provided above for I-29, replacing C8-acid-TG-oleate with Int-300.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Steroid Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)

Priority Applications (11)

Applications Claiming Priority (6)

Related Child Applications (1)

Publications (1)

Family

ID=77199623

Family Applications (1)

Country Status (9)

Cited By (4)

Families Citing this family (4)

Citations (3)

Family Cites Families (59)

• 2021
  • 2021-02-05 IL IL295362A patent/IL295362A/en unknown
  • 2021-02-05 EP EP21750039.6A patent/EP4100017A4/en active Pending
  • 2021-02-05 AU AU2021217172A patent/AU2021217172A1/en active Pending
  • 2021-02-05 JP JP2022547958A patent/JP7810970B2/ja active Active
  • 2021-02-05 US US17/169,371 patent/US20210268115A1/en not_active Abandoned
  • 2021-02-05 IL IL326763A patent/IL326763A/en unknown
  • 2021-02-05 WO PCT/US2021/016955 patent/WO2021159021A1/en not_active Ceased
  • 2021-02-05 CA CA3166908A patent/CA3166908A1/en active Pending
  • 2021-02-05 KR KR1020227030392A patent/KR20220149534A/ko active Pending
  • 2021-02-05 CN CN202180025754.0A patent/CN115348864A/zh active Pending
• 2022
  • 2022-08-04 US US17/881,458 patent/US20220395513A1/en not_active Abandoned
• 2023
  • 2023-06-26 US US18/341,519 patent/US11975073B2/en active Active
• 2024
  • 2024-01-10 US US18/409,546 patent/US20240245788A1/en active Pending

Patent Citations (3)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events