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.
• 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.
• Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy and other brain disorders.
• neurosteroids has been hampered by the challenges of selective delivery to specific tissues of the body, such as the brain, as well as undesired metabolism of neurosteroids when delivered orally.
• 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.
• the 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.
• 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.
• lymph or lymphocyte mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune disease, lymph resident infections and transplant rejection.
• enters 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.
• drugs with high lymphatic transport have been highly lipophilic in order to promote physical association with lipoproteins (usually, but not exclusively, log D>5 and solubility in long chain triglyceride of >50 mg/g). Therefore, highly lipophilic analogues of drugs have been envisaged as one way to promote lymphatic drug transport.
• chemical modification of a parent drug can result in a reduction in potency and, in many cases, significant increases in lipophilicity have been correlated with increases in toxicity.
• Lipophilic prodrugs provide a means to temporarily increase lipophilicity and lipoprotein affinity of a pharmaceutical compound, thereby increasing lymphatic targeting. 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.
• the present invention provides a compound of Formula I:
• 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.
• 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:
• 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 such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• 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.
• 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.
• 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.
• triglycerides are assembled into intestinal lipoproteins, primarily chylomicrons. After formation, chylomicrons are exocytosed from enterocytes and subsequently gain preferential access to the intestinal lymphatics. Once within the lymphatic system, 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. Following entry into blood circulation, 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.
• 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 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.
• 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, enhancing 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:
• 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. In some embodiments, 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.
• each of R 1 and R 2 independently is a fatty acid, phosphatide, phospholipid, or analogue thereof, such as those described in detail below.
• each fatty acid independently is a saturated or unsaturated medium-chain or long-chain fatty acid.
• each fatty acid independently has an even number of carbon atoms.
• each fatty acid independently has an odd number of carbon atoms.
• 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 16 -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.
• 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
• P(O) 2 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. In some embodiments, R 3 is an unsaturated, straight, optionally substituted C 1-37 hydrocarbon chain. In some embodiments, R 3 is a saturated, branched, optionally substituted C 1-37 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, branched, optionally substituted C 1-37 hydrocarbon chain. In some embodiments, R 3 is a saturated, straight, optionally substituted C 1-20 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, straight, optionally substituted C 1-20 hydrocarbon chain. In some embodiments, R 3 is a saturated, branched, optionally substituted C 1-20 hydrocarbon chain. In some embodiments, R 3 is an unsaturated, branched, optionally substituted C 1-20 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 16 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 16 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)—.
• 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 C 1-30 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-;
• 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 , 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—,
• C 1-30 e
• L is
• L is
• L is
• L is
• L is
• 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—, —NRC(O)—, —
• 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
• 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—, —NRC(O)O—, —NRC(O)O—, —NRC(O)O—, —OC(O)NR—, —NRC(O)O—, —NRC
• 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 C 1-30 , C 1-25 , C 1-20 , C 3-20 , C 5-20 , or C 7-20 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 3-20 , 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 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 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 -)i-s (i.e., 1-8 polyethylene glycol (PEG) units). In some embodiments, L comprises 1, 2, 3, 4, 5, 6, 7, or 8 PEG units.
• 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-.
• L comprises
• L comprises
• L comprises
• L comprises
• L comprises
• L comprises
• L comprises
• L comprises
• 1 methylene unit of L is replaced with -M-.
• 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.
• a methylene unit of L is replaced with an amino acid.
• the amino acid may be naturally-occurring or non-naturally occurring.
• the amino acid is selected from a non-polar or branched chain amino acid (BCAA).
• 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.
• 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. In some embodiments, -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. In some embodiments, -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, phenyl, an 8-10
• 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. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 is selected from those depicted in Table 1, below.
• 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. In some embodiments, -M- is a carboxyacetal. In some embodiments, -M- is a carboxy(methylacetal). In some embodiments, -M- is an acetal self-immolative group. In some embodiments, -M- is a carboxyacetal self-immolative group. In some embodiments, -M- is a carboxy(methylacetal) self-immolative group.
• -M- is:
• -M- is selected from one of the following:
• 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. In some embodiments, R 6 is hydrogen or C 1-3 alkyl. In some embodiments, R 6 is hydrogen or methyl.
• each instance of R 6 in the above formulae is the same. In some embodiments, 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, phen
• 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 , —NO 2 , —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 monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C 1-6 aliphatic group is optionally substituted with 1, 2, 3, 4, 5,
• 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.
• R is hydrogen or C 1-4 alkyl.
• R 7 is selected from those depicted in Table 1, below.
• each Z 1 independently is selected from —O—, —NR—, or —S—.
• Z 1 is —O—.
• Z 1 is —NR—.
• Z 1 is —S.
• Z 1 is —NH— or —NMe-.
• 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—. In some embodiments, Z 2 is —NR—. In some embodiments, Z 2 is —S—. In some embodiments, Z 2 is —OC(O)—. In some embodiments, Z 2 is —NRC(O)O—. In some embodiments, 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 . In some embodiments, 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—.
• each Z independently is selected from ⁇ N— or ⁇ C(R 7 )—.
• Z 3 is ⁇ N—.
• Z 3 is ⁇ C(R 7 )—.
• Z 3 is selected from those depicted in Table 1, below.
• each Z 4 independently is selected from —O—, —NR—, —S—, —C(R 6 ) 2 —, or a covalent bond.
• Z 4 is —O—.
• Z 4 is —NR—.
• Z 4 is —S—.
• Z 4 is —C(R 6 ) 2 —.
• Z 4 is a covalent bond.
• Z 4 is selected from those depicted in Table 1, below.
• -M- is selected from one of the following:
• -M- is
• -M- is
• -M- is selected from
• -M- is selected from
• -M- is selected from
• -M- is selected from
• -M- is selected from
• -M- is selected from
• -M- is selected from
• -M- is
• -M- is
• -M- is
• -M- is
• -M- is selected from those depicted in Table 1, below.
• n is 0-18.
• 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. In some embodiments, n is 18.
• 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.
• 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. In some embodiments, 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 ⁇ -tetrahydro
• 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)-20-ethoxy-3 ⁇ -hydroxy-5 ⁇ -pregnan-20-one), Org 20599 (21-chloro-3 ⁇ -hydroxy-20-morpholin-4-yl-5 ⁇ -pregnan-20-one), Org 21465 (20-(2,2-dimethyl-4-morpholinyl)-3 ⁇ -hydroxy-11,20-dioxo-5 ⁇ -pregnan-21-yl methanesulfonate), renanolone (3 ⁇ -hydroxy-5 ⁇ -pregnan-11,20-dione),
• the present invention provides a compound of formula I, wherein is
• the present invention provides a compound of formula I, wherein is
• 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
• 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.
• the present invention provides a compound of formula I,
• the present invention provides a compound of formula I,
• the present invention provides a compound of formula I, wherein is
• R 1 , R 2 , X, Y, and L are as defined above and described in embodiments herein, and wherein each of the A group variables R 1 , R 2a , R 2b , R A , A (or Ring A) and n is as described and defined in US 2020/0024301, the entirety of which is herein incorporated by reference.
• the present invention provides a compound of formula I,
• 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—S—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-2l-yl methanesulfonate), renanolone (3 ⁇ -hydroxy-5 ⁇ -pregnan-11
• the neurosteroid is a naturally-occurring or non naturally-occurring (e.g., synthetic) inhibitory neurosteroid. In some embodiments, the neurosteroid is a naturally-occurring inhibitory neurosteroid selected from:
• a non naturally-occurring (e.g., synthetic) inhibitory neurosteroid selected from:
• Alfadolone 3 ⁇ ,21-dihydroxy-5 ⁇ -pregnane-11,20-dione
• Alfadolone acetate 3 ⁇ ,21-dihydroxy-5 ⁇ -pregnane-11,20-dione 21-acetate
• Alfaxalone 3 ⁇ -hydroxy-5 ⁇ -pregnane-11,20-dione
• EIDD-036 (P4-20-O) 20-(hydroxyimino)pregn-4-en-3-one
• Ganaxolone 3 ⁇ -methyl-5 ⁇ -pregnan-3 ⁇ -ol-20-one
• Hydroxydione 21-hydroxy-5 ⁇ -pregnane-3,20-dione
• Minaxolone 11 ⁇ -(dimethylamino)-2 ⁇ -ethoxy-5 ⁇ -pregnan-3 ⁇ -ol-20-one
• ORG-20599 21-chloro-2 ⁇ -morpholin-4-yl-5 ⁇ -pregnan-3 ⁇ -ol-20-one
• ORG-21465 2 ⁇ -(
• SAGE-217 (Zuranolone): 3 ⁇ -hydroxy-3 ⁇ -methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5 ⁇ -pregnan-20-one, or a proneurosteroid, such as:
• Progesterone carboxymethyloxime P4-3-CMO
• a naturally-occurring excitatory neurosteroid selected from:
• 3 ⁇ -Dihydroprogesterone pregn-4-en-3 ⁇ -ol-20-one
• Epipregnanolone 5 ⁇ -pregnan-3 ⁇ -ol-20-one
• Isopregnanolone (sepranolone): 5 ⁇ -pregnan-3 ⁇ -ol-20-one
• Pregnenolone sulfate P5: pregn—S—en-3 ⁇ -ol-20-one 3 ⁇ -sulfate
• Pregnenolone pregn—S—en-3 ⁇ -ol-20-one.
• Dexamethasone 9 ⁇ -fluoro-11 ⁇ ,17 ⁇ ,21-trihydroxy-16 ⁇ -methylpregna-1,4-diene-3,20-dione or an analogue thereof.
• PDD Pregnadienedione
• Pregnenolone (P5) pregn—S—en-3 ⁇ -ol-20-one
• Progesterone (P4) pregn-4-ene-3,20-dione
• 3 ⁇ -Methoxypregnenolone (MAP-4343) 3 ⁇ -methoxypregn—S—en-20-one
• Cyclopregnol (neurosterone) 60-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:
• 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
• the present invention provides a compound of Formula I-a:
• the present invention provides a compound of Formula I-b:
• the present invention provides a compound of Formula I-c:
• the present invention provides a compound of Formula I-d:
• 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:
• each of R 1 , R 2 , R 4 , R, 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:
• the present invention provides a compound of Formula I-g:
• the present invention provides a compound of Formula I-h:
• 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:
• 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:
• 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:
• 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:
• 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:
• 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:
• 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-a or XIII-b:
• 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:
• 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 XIV:
• L is N
• L is N
• L is N
• L is N
• L is N
• L is N
• 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.
• each m independently is 0, 1, 2, or 3; or each m independently is 0 or 1.
• each m is 0.
• each m is 1.
• each m is 0 or 1 and n is 2-12.
• -M- is
• -M- is
• -M- is
• -M- is
• -M- is
• -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
• -M- is
• -M- is
• the right-hand side of the above embodiments of -M- is attached to such as at an available O atom of .
• 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 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 C 1-3 alkyl, for example, methyl.
• -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 C 1-3 alkyl, for example, methyl. In some embodiments, -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. In some embodiments, -M- is not present and at least one of R 4 or R 5 is not hydrogen. In some embodiments, -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. In some embodiments, -M- is not 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.
• each R 4 and R 5 independently is selected from C 1-6 alkyl, such as C 1-3 alkyl, for example, methyl, optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.
• L is N
• each of R 1 and R 2 is heptanoic acid. In some embodiments of Formula XV, each of R 1 and R 2 is octanoic acid. In some embodiments of Formula XV, 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:
• 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.
• 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).
• a fatty acid phosphatide, phospholipid, or analogue thereof
• phosphatidylcholine e.g., phosphatidylcholine, lecithin, phosphatidylethanolamine, cephalin, or phosphatidylserine or analogue or portion thereof, such as a partially hydrolyzed portion thereof
• other lipid-processing mimetic e.
• the fatty acid is a short-chain, medium-chain, or long-chain fatty acid. In some embodiments, 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. In some embodiments, the lipid, e.g., fatty acid, has a C 2 -C 60 chain. In some embodiments, the lipid, e.g., fatty acid, has a C 2 -C 28 chain.
• the lipid, e.g., fatty acid has a C 2 -C 40 chain. In some embodiments, the lipid, e.g., fatty acid, has a C 2 -C 12 or C 4 -C 12 chain. In some embodiments, the lipid, e.g., fatty acid, has a C 4 -C 40 chain.
• the lipid e.g., fatty acid
• the lipid e.g., fatty acid
• the lipid has a C 2 , C 3 , C 4 , C 5 , C 1-6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , C 50 , C 51 , C 52 , C 53 , C 54 , C 55 , C 56 , C 57 , C 58 , C
• 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 C 6 -C 21 chain and one independently is a fatty acid with a C 12 -C 36 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 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, 18-68, 18-68,
• 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 examples 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 acid, 18-methyl-
• 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, 6,9,12,15-oc
• Suitable hydroxy fatty acids include ⁇ -hydroxylauric acid, ⁇ -hydroxymyristic acid, ⁇ -hydroxypalmitic acid, ⁇ -hydroxystearic acid, o-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.
• 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-docosapentaenoic acid), docosahexaenoic acid (DHA or all-cis-4,7,10,13,16,19-doc
• Fatty acid chains differ greatly in the length of their chains and may be categorized according 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.
• one of the fatty acids independently is a MCFA.
• Long-chain fatty acids include fatty acids having about 13-21 carbons.
• each of the fatty acids independently is a LCFA.
• one of the fatty acids independently is a LCFA.
• VLCFA Very long chain fatty acids
• each of the fatty acids independently is a VLCFA.
• one of the fatty acids independently is a VLCFA.
• one of the fatty acids independently is a MCFA and one independently is a LCFA.
• a variety of therapeutic agents may be covalently conjugated to the lymphatic system-directing lipids, e.g., triglyceride scaffolds, described herein.
• the present invention 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.
• GABA Gamma aminobutyric acid
• GR GABA receptor-chloride ionophore complex
• Certain 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.
• the antidepressant effect of allopregnane is well-established in animal models (e.g., Frye, C. A. & Walf, A. A. Horm Behav 41(3): 306-15 (2002)) and low levels of allopregnanolone are associated with various depressive-mood disorders (e.g., Anreen, L. et al.
• 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).
• 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
• neurosteroid e.g., allopreganolone prodrugs that have improved bioavailability and circumvent first pass metabolism by the liver.
• 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. Neurobiol.
• 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.
• a pregnane neurosteroid such as allopregnanolone
• the present invention provides a method of treating a GABA A -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, Parkinson's disease, or Alzheimer's disease.
• PTSD post-traumatic stress disorder
• PMDD premenstrual dysphoric disorder
• SAD seasonal affective disorder
• social anxiety memory loss
• Niemann-Pick disease type C or an associated neurological or physical symptom epilepsy
• the status epilepticus is super-refractory status epilepticus (SRSE), a severe form of uncontrolled seizures.
• SRSE super-refractory status epilepticus
• 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.
• 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.
• ALLO Allopregnanolone
• 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. In some embodiments, 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.
• 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.
• 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 lipof
• 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.
• the term “about,” when referring to a numerical value or range of a parameter such as mass, weight, volume, time, concentration, biological activity, c Log P, 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 refers 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.
• treatment may be administered in the absence of symptoms.
• 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.
• glycolide 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.
• the carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2 being in the middle and sn-1 and sn-3 being the ends of the glycerol.
• Naturally occurring oils and fats consist largely of triglycerides wherein the 3 fatty acyl residues may or may not be identical.
• long chain triglycerides or “LCT” means both a simple and mixed triglyceride containing fatty acids with more than 12 carbon atoms (long chain fatty acids, “LCFA”)
• MCT medium chain triglycerides
• ECN equivalent carbon number
• tripalmitin tripalmitic glycerol
• ECN acyl chain lengths of 8, 16 and 16; 10, 14 and 16; 8, 14 and 18, etc.
• 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.
• therapeutic 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.
• the chemical elements are identified in accordance with the Periodic Table of the Elements, Handbook of Chemistry and Physics, 98 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
• 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 C 3 -C 6 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.
• 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.
• the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
• 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.
• the term “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:
• Exemplary bridged bicyclics include:
• lower alkyl refers to a C 1-4 straight or branched alkyl group.
• exemplary 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 means that a moiety has one or more units of unsaturation.
• bivalent C 1-8 (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 )—, 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 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 whether preceded by the term “optionally” or not, 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.
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; —(CH 2 ) 0-4 R ⁇ ; —(CH 2 ) 0-4 OR ⁇ ; —O(CH 2 ) 0-4 R ⁇ , —O—(CH 2 ) 0-4 C(O)OR ⁇ ; —(CH 2 ) 0-4 CH(OR ⁇ ) 2 ; —(CH 2 ) 0-4 SR ⁇ ; —(CH 2 ) 0-4 Ph, which may be substituted with R ⁇ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R ⁇ ; —CH ⁇ CHPh, which may be substituted with R ⁇ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R ⁇ ; —NO 2 ; —CN; —N 3 ;
• Each R ⁇ independently is hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, —CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R ⁇ selected from ⁇ O and ⁇ S; or each R ⁇ is optionally substituted with a monovalent substituent independently selected from halogen, —(CH 2 ) 0-2 R ⁇ , -(haloR ⁇ ), —(CH
• 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; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from ⁇ O, ⁇ S, ⁇ NNR* 2 , ⁇ NNHC(O)R*, ⁇ NNHC(O)OR*, ⁇ NNHS(O) 2 R*, ⁇ NR*, ⁇ NOR*, —O(C(R* 2 )) 2 -3 O—, or —S(C(R*2)) 2-3 S—, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is —O(CR* 2
• 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 ⁇ , —NH 2 , —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 unsubstit
• 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, pamoate,
• 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 13C- 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.
• Disclosed 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.
• 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. In some embodiments, 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
• 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.
• the present invention provides a composition
• 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.
• pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated.
• Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the disclosed 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-polyoxyprop
• 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.
• 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.
• Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• 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.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
• compositions may be administered in the form of suppositories for rectal administration.
• suppositories 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.
• suitable non-irritating excipient 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. In other embodiments, 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.
• the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
• 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.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• 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.
• the rate of compound release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
• 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.
• 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 alcohol and gly
• 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. Examples of embedding compositions that can be used 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.
• 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.
• buffering agents 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. 11 (Supp 2), S93-S98, 2000; Pouton, C. W., Eur. J. Pharm. Sci. 29 278-287, 2006).
• LFCS lipid formulation classification system
• 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.
• 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.
• hydrophilic surfactants and co-solvents e.g., PEG, propylene glycol and diethylene glycol monoethyl ether
• 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. In some embodiments, the lipid vehicle consists essentially of one or more surfactants/co-surfactants/co-emulsifiers, and/or solvents/co-solvents.
• 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., MaisineTM35-1).
• 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).
• Mixtures of fatty acids (“structured glycerides”) adapted for enhancing the absorption and transport of lipid soluble compounds are disclosed in, e.g., U.S. Pat. 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 C 8-22 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 and polyoxyl
• 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.
• 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
• Many different approaches may be used to achieve these ends including the use of high melting point lipids that disperse/erode slowly in the GI tract, or polymers that form a matrix that slowly erodes.
• formulations may take the form of large monolithic dose forms or may be present as micro or nano-particulate matrices as described in, for example, in Mishra, Handbook of Encapsulation and Controlled Release, CRC Press, Boca Raton, (2016) ISBN 978-1-4822-3234-9, Wilson and Crowley Controlled Release in Oral Drug Delivery, Springer, NY, ISBN 978-1-4614-1004-1 (2011) or Wise, Handbook of Pharmaceutical Controlled Release Technology, Marcel Dekker, NY, ISBN 0-82467-0369-3 (2000).
• 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)
• 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 gastrointestinal tract or enterocyte.
• the enzyme inhibitor inhibits pancreatic lipases, examples of which include, but are not limited to, Alli® (orlistat).
• 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(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate).
• a provided lipid prodrug, or pharmaceutically acceptable composition thereof may be administered to a patient in need thereof in combination with one or more additional therapeutic agents and/or therapeutic processes.
• 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.
• 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.
• the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present disclosure.
• 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.
• 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, cyclophosphamide, and sulfasalazin
• 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.
• 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 (Aral)
• 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®), miln
• 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®).
• a disclosed lipid prodrug 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.
• subject or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
• 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. In some embodiments, 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.
• the dose of lipid prodrug or a pharmaceutically acceptable salt thereof is about 3.0 mg/kg to about 7.0 mg/kg. In some embodiments, 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. In some embodiments, the dose is about 10 mg to about 2.5 g of lipid prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, 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.
• 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. In some embodiments, 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.
• 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. In some embodiments, 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.
• 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 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.
• 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.
• 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.
• compounds of the present invention may be synthesized via one of the following routes:
• Diacid chlorides i which are readily available from the corresponding malonic acids, can be reacted with a diglyceride such as ii in the presence of pyridine or another appropriate base to give acid-triglyceride (acid-TG) iii-a (see Scheme 1).
• acid-TG acid-triglyceride
• Formula iii-a is shown with C 15 H 31 fatty acid side chains, but other fatty acids (such as those described above) can be substituted in this and other Formulas described below.
• acid-TG iii-b can be generated by ring-opening with diglyceride ii in the presence of pyridine or another appropriate base (Scheme 2).
• This method works best when R 4 and R 5 of acid anhydride i-a are identical, e.g. both Me, but will result in a regioisomeric mixture of acid-TG products iv when R 4 and R 5 differ from each other. Consequently, other methods, such as that outlined in Scheme 3, can advantageously be employed in this circumstance.
• acetal self-immolative group can be used where an additional carboxy group is included.
• Reaction of the parent drug with a chloroalkyl chloroformate gives chloroalkyl carbonates (shown) or carbamates xi (see Scheme 5).
• Displacement of the halide leaving group is then accomplished by treatment with the carboxylate derived from acid-TG iv-c in an appropriate solvent such as refluxing toluene to afford the target compound xii.
• the acid-triglyceride iv is typically functionalized with the TML moiety prior to conjugation with a pharmaceutical agent as outlined in Scheme 6. Coupling of acid-TG iv with TML phenol xiii under standard conditions gives triglyceride xiv, which can be deprotected under acidic conditions (10-camphorsulfonic acid) to give alcohol xv.
• TML trimethyl lock
• Int-1 (220 g, 388 mmol) was dissolved in a solution of THF (3000 mL) and water (200 mL) at 0° C. 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.
• Int-7 (68 g, 86.5 mmol) and palladium on carbon (3 g) were suspended in THE (400 mL). The mixture was hydrogenated under hydrogen atmosphere at 30° C. for 16 h, then filtered and concentrated to dryness. The residue was further purified by trituration with hexane to afford Int-4 (C5 ⁇ Me-acid-2-TG) (51 g, 73.2 mmol, 84% yield) as a white solid.
• Int-12 (65 g, 77 mmol) and palladium on carbon (3 g) were suspended in THE (400 mL). The mixture was hydrogenated under hydrogen atmosphere at 30° C. for 16 h, then it was filtered and the filtrate concentrated to dryness and then further purified by trituration with hexane to afford Int-9 (C10-acid-2-TG) (50 g, 66.4 mmol, 86% yield) as a white solid.
• Int-13 prepared according to: Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465-1469.
• Int-14 prepared according to: Chowdhury, R.; Ghosh, S. K. Org. Lett. 2009, 11, 3270-3273.
• 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 THE (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 THE (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 THE (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). The combined organic extracts were washed with brine (20 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• 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 THE (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-269 and Int-270 were prepared from Int-235:
• 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 THE (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.
• the reaction was re-cooled to ⁇ 50° C., a solution of bromide Int-39 (525 mg, 1.60 mmol) and DMPU (1.06 mL, 8.82 mmol) in THE (6 mL) was added dropwise and the mixture stirred at ⁇ 50° C.
• 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 THE (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 (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• a suspension of PdCl 2 (PPh 3 ) 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.
• Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 186 ⁇ L, 0.186 mmol) and acetic acid (10.6 ⁇ L, 0.186 mmol) were added dropwise to 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 (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• 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.
• Int-185 and Int-186 were prepared from 1-benzyloxy-pentan—S—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.
• 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.
• 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.
• Int-50 prepared according to: Subba Reddy, B. V. et al. Helv. Chim. Acta. 2013, 96, 1983-1990.
• Int-51 known compound that may be prepared as disclosed in Takagi, Y. et al. Tetrahedron: Asymm. 2004,15, 2591-2594).
• 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 THE (45 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.
• the reaction was re-cooled to ⁇ 78° C., a solution of bromide Int-51 (3.10 g, 10.4 mmol) and DMPU (6.3 mL, 51.8 mmol) in THE (30 mL) was added slowly and the mixture stirred at -78° C.
• 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).
• the combined organic extracts were washed with brine (3 ⁇ 50 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.
• Int-17 was prepared as described above.
• 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 THE (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.
• Int-211 was prepared from dec-9-yn-1-ol and TBDPSCl using the procedure for preparation of Int-56, above.
• Int-213 was prepared from Int-212 by analogy to the procedure for preparation of Int-59, above.
• Int-214 was prepared from Int-213 by analogy to the procedure for preparation of Int-60, above.
• Int-214 (19 g, 58.2 mmol) in toluene (190 mL) at room temperature under nitrogen atmosphere was added Int-215 (68.19 g, 174.8 mmol; prepared from triphenyl phosphine and t-butyl 2-bromopropanoate).
• Int-215 (68.19 g, 174.8 mmol; prepared from triphenyl phosphine and t-butyl 2-bromopropanoate).
• the resulting reaction mixture was heated at 90° C. for 2 hours.
• the reaction mixture was cooled to room temperature and concentrated under reduced pressure.
• the resulting oil was purified by column chromatography using silica gel (100-200 mesh), with product eluting at 2-4% EtOAc in hexane, to afford Int-216 (15.0 g, 58.9%).
• compounds Int-222, Int-223, and Int-224 were prepared from Int-112 and tert-butyldimethyl(tridec-12-yn-1-yloxy)silane, which was prepared from dodecan-1,12-diol by mono-TBS protection (with TBSCl, imidazole, and DMAP in a mixture of DCM and DMF) followed by PCC oxidation and Ohira reagent homologation (by analogy to the procedures for synthesizing Int-197 from Int-195).
• the reaction mixture was cooled to room temperature, diluted with cold water (300 mL), and extracted with ethyl acetate (3 ⁇ 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 ⁇ 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%).
• Int-69 is a known compound that may be prepared as described in, e.g., Sang-sup, J. et al. Tetrahedron: Asymmetry 1997, 8, 1187-1192).
• 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 THE (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.
• the reaction was cooled to room temperature and diluted with ethyl acetate (10 mL), quenched with water (15 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 20 mL).
• 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 THE (2.5 mL) and the mixture stirred at RT for one hour.
• the reaction was cooled to room temperature and diluted with ethyl acetate (10 mL), quenched with water (20 mL) and the aqueous phase extracted with ethyl acetate (3 ⁇ 25 mL).
• 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
• acetonitrile 1.5 mL
• the reaction was cooled to RT, diluted with ethyl acetate and water (10 mL each), and extracted with ethyl acetate (3 ⁇ 15 ml).
• TBDPSCl (221 ⁇ L, 0.851 mmol) was added and the mixture stirred at rt for 17 hours.
• 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 THE (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 ⁇ 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-106 prepared according to: Amsberry, K. L. et al. Pharm Res. 1991, 8, 455-461.
• Int-122 was also prepared using similar methods:
• Int-45 was prepared as described above and coupled with Int-115 using EDC and DMAP similarly to methods described above to provide Int-124.
• 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 THE (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. NaHCO 3 and brine (30 mL each), dried (MgSO 4 ) and concentrated under reduced pressure to give the crude product.

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