WO2009108804A2 - Steroid analogues for neuroprotection - Google Patents
Steroid analogues for neuroprotection Download PDFInfo
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- WO2009108804A2 WO2009108804A2 PCT/US2009/035336 US2009035336W WO2009108804A2 WO 2009108804 A2 WO2009108804 A2 WO 2009108804A2 US 2009035336 W US2009035336 W US 2009035336W WO 2009108804 A2 WO2009108804 A2 WO 2009108804A2
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- WIPO (PCT)
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- amino acid
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- residue
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- MJIBOYFUEIDNPI-HBNMXAOGSA-L zinc 5-[2,3-dihydroxy-5-[(2R,3R,4S,5R,6S)-4,5,6-tris[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxy]-2-[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxymethyl]oxan-3-yl]oxycarbonylphenoxy]carbonyl-3-hydroxybenzene-1,2-diolate Chemical class [Zn++].Oc1cc(cc(O)c1O)C(=O)Oc1cc(cc(O)c1O)C(=O)OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c([O-])c([O-])c2)c1 MJIBOYFUEIDNPI-HBNMXAOGSA-L 0.000 description 1
- 229960003516 zomepirac sodium Drugs 0.000 description 1
- 229940088909 zyloprim Drugs 0.000 description 1
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
- C07J75/005—Preparation of steroids by cyclization of non-steroid compounds
Definitions
- the present invention is in the area of pharmaceutical chemistry and specifically relates to certain steroid analogues, pharmaceutical compositions and methods for neuroprotection in the treatment and prevention of traumatic brain injury and brain injury caused by stroke.
- Traumatic brain injuries result from a blow or jolt to the head or a penetrating head injury that disrupts the function of the brain, with severity ranging from "mild,” i.e., a brief change in mental status or consciousness to "severe,” i.e., an extended period of unconsciousness or amnesia after the injury.
- strokes are a result of diseases that affect the blood vessels that supply blood to the brain.
- a stroke occurs when a blood vessel that brings oxygen and nutrients to the brain either bursts (hemorrhagic stroke) or is clogged by a blood clot or some other mass (ischemic stroke).
- ischemic stroke The majority of strokes are ischemic, however hemorrhagic strokes typically result in more severe injuries.
- a cascade of physiological events leads to neuronal loss including, for example, an inflammatory immune response and excitotoxicity resulting from disrupting the glutamate, acetylcholine, cholinergic, GABA A , and NMDA receptor systems.
- a complex cascade of events leads to the delivery of blood-borne leucocytes to sites of injury to kill potential pathogens and promote tissue repair.
- the powerful inflammatory response has the capacity to cause damage to normal tissue, and dysregulation of the innate, or acquired immune response is involved in different pathologies.
- inflammation is being recognized as a key component of a variety of nervous system disorders. It has long been known that certain diseases such as multiple sclerosis result from inflammation in the central nervous system, but it is only in recent years that it has been suggested that inflammation may significantly contribute to neurodegenerative disoders such as HIV-related dementia, Alzheimer's and prion diseases. It is now known that the resident macrophages of the central nervous system (CNS), the microglia, when activated may secrete molecules that cause neuronal dysfunction, or degeneration.
- CNS central nervous system
- progesterone is a potent neurosteroid that, acutely administered, can dramatically reduce cerebral edema, inflammation, tissue necrosis, and programmed cell death (see Djebaili, M. et al, J. Neurotrauma 2005, 22, 106-118; Pettus, E. H. et al, Brain Res. 2005, 1049, 112-119; Grossman, K. J. et al, Brain Res, 2004, 1008, 29-39; He, J. et al, Exp. Neurol 2004, 189, 404-412; He, J.
- progesterone In vivo data has demonstrated progesterone's neuroprotective effects in injured nervous systems. For example, following a contusion injury, progesterone reduces the severity of post injury cerebral edema. The attenuation of edema by progesterone is accompanied by the sparing of neurons from secondary neuronal death and improvements in cognitive outcome (Roof et al. (1994) Experimental Neurology 129:64-69). Furthermore, following ischemic injury in rats, progesterone has been shown to reduce cell damage and neurological deficit (Jiang et al. (1996) Brain Research 735:101-107).
- PCT Publication WO 02/30409 to Emory University provides methods for conferring a neuroprotective effect on a population of cells in a subject following a traumatic injury to the central nervous system by administration of a progestin or progestin metabolite following a traumatic brain injury.
- PCT Publication WO 06/102644 also to Emory University provides methods for the treatment or the prevention of neuronal damage in the CNS by tapered administration of a progestin or progestin metabolite following a traumatic or ischemic injury to the CNS to avoid withdrawal.
- PCT Publication No. WO/2006/ 102596 to Emory University provides certain methods of treating a subject with a traumatic central nervous system injury, more particularly, a traumatic brain injury that include a therapy comprising a constant or a two-level dosing regime of progesterone.
- progesterone has been shown to be neuroprotective in traumatic brain injury, its efficacy in stroke is less well defined. However, studies have indicated that progesterone may be useful in treating or preventing neurodegeneration following stroke (see Stein, D. (2005) The Case for Progesterone US Ann. N. Y. Acad. ScL. 1052:152-169; Murphy, et al. (2002) Progesterone Administration During Reperfusion, But Not Preischemia Alone, Reduces Injury in Ovariectomized Rats. J. Cereb. Blood Flow & Metab. 22:1181-1188; Murphy, et al. (2000) Progesterone Exacerbates Striatal Stroke Injury in Progesterone- Deficient Female Animals. Stroke 31 : 1173).
- U.S. Patent No. 6,245,757 now expired, to Research Corporation Technologies, Inc. provides a method for the treatment of ischemic damage, such as damage due to stroke or myocardial infarction comprising administering to a mammal afflicted with stroke an effective amount of a neuroprotective steroid in a suitable vehicle.
- progesterone In addition to being a gonadal steroid, progesterone also belongs to a family of autocrine/paracrine hormones called neurosteroids. Neurosteroids are steroids that accumulate in the brain independently of endocrine sources and which can be synthesized from sterol precursors in nervous cells. These neurosteroids can potentiate GABA transmission, modulate the effects of glutamate, enhance the production of myelin, and prevent release of free radicals from activated microglia. Various metabolites of progesterone have also been suggested to have neuroprotective properties.
- the progesterone metabolites allopregnanolone or epipregnanolone are positive modulators of the GABA receptor, increasing the effects of GABA in a manner that is independent of the benzodiazepines (Baulieu, E. E. (1992) Adv. Biochem. Psychopharmacol. 47:1-16; Robel et al. (1995) Crit. Rev. Neurobiol. 9:383-94; Lambert et al. (1995) Trends Pharmacol. ScL 16:295-303; Baulieu, E. E. (1997) Recent Prog. Horm. Res. 52:1-32; Reddy et al. (1996) Psychopharmacology 128:280-92).
- these neurosteroids act as antagonists at the sigma receptor, which can activate the NMDA channel complex (Maurice et al. (1998) Neuroscience 83:413-28; Maurice et al. (1996) J. Neurosci. Res. A ⁇ :lM-A7>; Reddy et al. (1998) Neuroreport 9:3069-73).
- These neurosteroids have also been shown to reduce the stimulation of cholinergic neurons and the subsequent release of acetylcholine by excitability. Numerous studies have shown that the cholinergic neurons of the basal forebrain are sensitive to injury and that excessive release of acetylcholine can be more excitotoxic than glutamate (Lyeth et al. (1992) J. Neurotrauma 9(2):S463-74; Hayes et al. (1992) J. Neurotrauma 9(l):S173-87).
- progesterone itself as a therapeutic suffers from several drawbacks, including most notably its poor solubility and its potential for generating unwanted side effects. Therefore, there is a need for progesterone analogues that exhibit improved solubility and bioavailability for the treatment of ischemic, hemorrhagic or traumatic central nervous injury.
- novel steroid analogues functionalized with polar groups at the C3 and C20 positions that exhibit greater water solubility than the parent compounds and are useful for the prevention and treatment of nervous system damage, in particular due to neurodegenerative reactions to injury or disease.
- the steroid analogues of the invention are derivatized at the 3- and/or 20-positions of the steroid ring with polar amino acid substituents capable of forming water soluble salts.
- the amino acids may be either the naturally occurring or synthetic amino acids in either the D, L configuration or may be a mixture of D and L forms.
- the steroid analogues are derivatized at the 3- and/or 20-positions with a carbohydrate or a substituted acyl group.
- the steroid analogues are optionally substituted with non-hydrogen substituents at the 9-, 1-, 2-, 3-, and 4- positions and may contain double bonds between Cl and C2, C4 and C5 and between C5 and C6.
- Y is O, N or S
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 4 is hydrogen or alkyl; R 4 together with R 3 and X forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms; or R 4 and R 7 together form a double bond;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate, -OR 11 , -NR 11 R 12 ; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 3 together with X and R 4 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R is absent; R 7 is hydrogen or is absent, or R 7 together with R 4 forms a double bond;
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate, -OR 11 , -NR 11 R 12 ; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 8 together with R 9 and Y forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 8 absent;
- R 9 is hydrogen or alkyl; R 9 together with Y and R 8 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms; or R 9 and R 10 together form a double bond;
- R 10 is hydrogen or is absent, or R 10 together with R 9 forms a double bond
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, monophosphate, diphosphate, triphosphate, the residue of an amino acid, a carbohydrate, an optionally substituted ester, or -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid;
- R 12 is hydrogen or alkyl; and the dotted line indicates the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, with certain provisos.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be bonded to the progestin ring by such a group.
- the reactive groups on the amino acid may displace leaving groups formed on the progestin moiety to form a covalent bond.
- Non-limiting examples of amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- the enantiomers of the compounds of Formula I are provided.
- the stereochemical configuration of each asymmetric carbon is opposite that of the natural steroids and analogues of the natural steroids.
- methods of treating or preventing damage resulting from nervous system injury or disease comprising administering a compound of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof in a pharmaceutically acceptable carrier to a patient in need thereof.
- the damage is due to inflammation initiated by a TBI.
- methods of treating or preventing neurodegeneration resulting from ischemic CNS injuries, in particular from ischemic stroke are provided comprising administering a compound of the invention to a patient in need thereof.
- methods of treating or preventing neurodegeneration resulting from hemorrhagic CNS injuries, in particular from hemorrhagic stroke comprising administering a compound of the invention to a patient in need thereof.
- the methods can alleviate the initial damage to the CNS. Therefore, in some embodiments, the compounds are administered to a patient at risk of a CNS injury, in particular to a patient at risk of a stroke.
- the compounds are also effective at reducing or preventing secondary injuries. Therefore, in other embodiments, the compounds are administered to a patient who has suffered a CNS injury within a window of opportunity after the initial insult.
- the initial insult can be either a TBI or a stroke, whether that be an ischemic or hemorrhagic stroke.
- the neural damage occurs from a disease or disorder such as multiple sclerosis or Amyotrophic Lateral Sclerosis (ALS).
- Pharmaceutical compositions, including in combination with additional neuroprotective agents, are also provided.
- Figure 1 shows cerebral edema assay data for selected steroid analogues.
- Figure 2 shows the solubility of selected steroid analogues in phosphate buffered saline.
- Figure 3 shows pharmacokinetic data of steroid analogues P 1-31 and P 1-33 after dosing at
- Figure 4 shows pharmacokinetic data of steroid analogue Pl-131 after dosing at 10 mg/kg.
- Figure 5 shows pharmacokinetic data of steroid analogue Pl-186 after dosing at 10 mg/kg.
- Progesterone is lipid- soluble and essentially water insoluble. Therefore, the intravenous administration of progesterone is difficult in a clinical setting and the dose is limited by the low aqueous solubility of the compound.
- the present invention provides novel steroid analogues that comprise polar groups and exhibit increased aqueous solubility. Also provided are pharmaceutically acceptable salts, esters and prodrugs of the steroid analogues. The compounds, salts, esters and prodrugs provided are useful for the treatment or prevention of central nervous system injury, particularly for the treatment or prevention of damage arising from a traumatic brain injury and the treatment or prevention of injuries occurring from stroke.
- steroid analogues as used herein is intended to encompass analogues of progesterone, analogues of progesterone metabolites or derivatives and other non-progestin steroid compounds.
- the steroid analogues of the invention exhibit increased solubility in aqueous solvents and are capable of forming pharmaceutically acceptable salts that further increase their aqueous solubility.
- pharmaceutical compositions comprising the inventive steroid analogues, pharmaceutically acceptable salts, esters or prodrugs thereof, and methods for the treatment or prevention of CNS injuries, including traumatic brain injury and stroke.
- the present invention relates to steroid analogues that comprise amino acid residues, carbohydrates or other suitable polar groups at the 3- and/or 20-positions of the steroid ring system.
- the improved water solubility of the steroid analogues of the invention can facilitate the administration of the compounds, in particular intravenous administration, which provides the fastest possible exposure of the active agent to the brain or other CNS sites where it is needed, increasing the efficacy of the drug.
- the inventive steroid analogs can minimize undesired side effects that are typically accompany acute or prolonged treatment with progesterone, such as sleepiness, reduced arousal and increased blood clotting.
- the compounds of the present invention are steroid analogues that are modified to comprise polar groups and exhibit a greater aqueous solubility than the naturally occurring parent compounds.
- analogues of steroid compounds are provided that are modified at the 3- and/or 20-position of the steroid ring system to incorporate polar groups.
- the ring numbering shown below for the structure of progesterone (PROG) is maintained throughout this document to avoid ambiguity.
- Progesterone Substituents on the steroid analogues that lie below the plane of the paper as drawn are termed in the " ⁇ ” or “alpha” configuration.
- Substituents that lie above the plane of the paper are termed in the " ⁇ ” or “beta” configuration.
- the two methyl groups shown in the progesterone structure below are in the beta configuration.
- steroid analogues such as progesterone, pregnenolone and the like, comprising an amino acid residue, a carbohydrate or other polar group bonded to the 3 -position of the steroid ring system.
- steroid analogues that comprise an amino acid residue, a carbohydrate or other polar group bonded to the 20-position of the ring system are provided.
- steroid analogues comprising amino acid residues and/or carbohydrates or other polar groups at the 3- and at the 20-positions of the ring system are provided.
- the inventive steroid analogues have greater aqueous solubility than the parent compounds and are thus advantageous for administration, in particular in situations in which rapid availability and effective dosing of the compounds are critical.
- the steroid analogues comprise a basic nitrogen group that enables the formation of pharmaceutically acceptable salts and prodrugs.
- the inventive steroid analogues are useful for the treatment or prevention of central nervous system injury, particularly traumatic brain injury and stroke.
- the invention provides a steroid analogue of Formula I:
- Y is O, N or S
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 4 is hydrogen or alkyl;
- R 4 together with R 3 and X forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms; or R 4 and R 7 together form a double bond;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate, -OR 11 , -NR 11 R 12 ; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 3 together with X and R 4 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R is absent;
- R 7 is hydrogen or is absent, or R 7 together with R 4 forms a double bond
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate, -OR 11 , -NR 11 R 12 ; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 8 together with R 9 and Y forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 8 absent;
- R 9 is hydrogen, alkyl; R 9 together with Y and R 8 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 9 and R 10 together form a double bond;
- R 10 is hydrogen or is absent, or R 10 together with R 9 forms a double bond
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, monophosphate, diphosphate, triphosphate, the residue of an amino acid, a carbohydrate, an optionally substituted ester, or -C(O)R', where R' is OR 1 , NR 1 R 2 ,alkyl, aryl, aralkyl, or the residue of an amino acid;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , -NR 11 R 12 or R 3 is absent;
- R 4 is hydrogen or alkyl, or R 4 and R 7 together form a double bond;
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , -NR 11 R 12 , or R 8 is absent;
- R 9 is hydrogen or alkyl, or R 9 and R 10 together form a double bond; and
- R 11 is a residue of an amino acid, a carbohydrate, or an optionally substituted ester.
- compounds of Formula I are provided wherein: R is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , - NR 11 R 12 or R 3 is absent; R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , -NR 11 R 12 or R 8 absent; and R 11 is the residue of an amino acid, a carbohydrate or an optionally substituted ester.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 4 and R 9 are independently hydrogen or methyl.
- X and Y are O. In other embodiments, X is O and Y is N or X is N and Y is O. In other embodiments, both X and Y are N. In certain embodiments in which Y is O, R 9 and R 10 come together to form a double bond.
- one of R 3 and R 8 is a residue of an amino acid.
- the amino acid is a naturally occurring amino acid.
- R 3 is a residue of an amino acid.
- R 8 is a residue of an amino acid.
- both R 3 and R 8 are residues of an amino acid.
- R 3 is a carbohydrate.
- R 8 is a carbohydrate.
- X is O
- R 3 is the residue of an amino acid
- R 7 is absent.
- Y is O, R 8 is the residue of an amino acid, and R 10 is absent;
- X is N; R 7 together with R 4 form a double bond; R 3 is OR 11 or NR 11 R 12 ; and R 11 is the residue of an amino acid or a carbohydrate.
- Y is N; R 10 together with R 9 form a double bond; R 8 is OR 11 or NR 11 R 12 ; and R 11 is the residue of an amino acid or a carbohydrate.
- X is O; R 3 is the residue of a naturally occurring amino acid or a carbohydrate; R 7 is absent; Y is O; R 8 is absent; and R 9 and R 10 together form a double bond.
- X is O; R 3 is the residue of an amino acid; R 7 is absent; Y is N; R 10 together with R 9 form a double bond; R 8 is OR 11 or NR 11 R 12 ; and R 11 is the residue of an amino acid or a carbohydrate.
- X is N; R 7 together with R 4 form a double bond; R 3 is OR 11 or NR 11 R 12 ; R 11 is the residue of an amino acid or a carbohydrate; Y is O; R 8 is the residue of an amino acid; and R 10 is absent.
- X is N; R 7 together with R 4 form a double bond; R 3 is OR 11 or NR 11 R 12 ; Y is N; R 10 together with R 9 form a double bond; R 8 is OR 11 or NR 11 R 12 ; and R 11 is the residue of an amino acid or a carbohydrate.
- X is N, R 7 together with R 4 form a double bond, and R 3 is - C(O)R'.
- Y is N, R 9 and R 10 together form a double bond, and R8 is - C(O)R'.
- X is O and R 3 is monophosphate, diphosphate, triphosphate
- Y is O and R 8 is monophosphate, diphosphate, triphosphate
- X is O; R 3 is the residue of an amino acid; R 7 is absent; R 1 , R 2 , R 4 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- X is O; R 3 is the residue of an amino acid; R 7 is absent; R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen.
- Y is O; R 8 is the residue of an amino acid; R 10 is absent; R 1 , R 2 , R 4 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- Y is O; R 8 is the residue of an amino acid; R 10 is absent; R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In another embodiment, the dotted line between Cl and C2 represents a double bond.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be boded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- Non- limiting examples of amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-conf ⁇ guration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- a progesterone or steroid analogue Formula II is provided:
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, monophosphate, diphosphate, triphosphate, a carbohydrate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or R 3 together with the oxygen and R 4 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms;
- R 4 is hydrogen or alkyl, or R 4 together with R 3 and the oxygen atom forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms;
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate, -OR 11 , -NR 11 R 12 ; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 8 together with R 9 and Y forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 8 is absent;
- R 9 is hydrogen or alkyl; R 9 together with Y and R 8 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms; or R 9 and R 10 together form a double bond;
- R 10 is hydrogen or absent, or R 10 together with R 9 form a double bond
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, monophosphate, diphosphate, triphosphate, the residue of an amino acid, a carbohydrate, optionally substituted acyl, or -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 , or the residue of an amino acid;
- R 12 is hydrogen or alkyl; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that neither R 3 nor YR 8 R 10 represent an ester of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid; and with the proviso that when Y is N, R 8 does not represent aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid or a carbohydrate
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , -NR 11 R 12 or R 8 is absent
- R 11 is the residue of an amino acid, a carbohydrate or optionally substituted acyl.
- Y is O. In other embodiments, Y is N. In certain embodiments in which Y is O, R 9 and R 10 come together to form a double bond.
- one of R 3 and R 8 is a residue of an amino acid. In particular embodiments, the amino acid is a naturally occurring amino acid. In certain embodiments, R 3 is a residue of an amino acid. In certain other embodiments, R 8 is a residue of an amino acid. In yet further embodiments, both R 3 and R 8 are residues of an amino acid.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 4 and R 9 are independently hydrogen or methyl.
- Y is O; R 8 is the residue of an amino acid; and R 10 is absent.
- Y is N; R 10 together with R 9 form a double bond; R 8 is OR 11 ; and R 11 is the residue of an amino acid or a carbohydrate.
- Y is N; R 10 together with R 9 form a double bond; R 8 is -NR 11 R 12 ; R 11 is the residue of an amino acid or a carbohydrate; and R 12 is hydrogen.
- R 3 is the residue of a naturally occurring amino acid or a carbohydrate;
- R 4 is hydrogen;
- Y is O;
- R 10 together with R 9 form a double bond; and
- R 8 is absent.
- R 3 is a carbohydrate; R 4 is hydrogen; Y is O; R 10 together with R 9 form a double bond; and R 8 is absent.
- R 3 is the residue of a naturally occurring amino acid or a carbohydrate;
- R 4 is hydrogen;
- Y is O;
- R 8 and R 9 are hydrogen; and
- R 10 is absent.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl. In still another embodiment, R 1 and R 2 are independently hydroxyl or halogen. In another embodiment of Formula II, R 1 is alkyl; and R 2 and R 5 are hydrogen. In another embodiment, of Formula II, R 2 is alkyl; and R 1 and R 5 are hydrogen. In still another embodiment, of Formula II, R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 3 is the residue of a naturally occurring amino acid;
- R 4 is hydrogen;
- Y is O;
- R 8 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 3 is the residue of a naturally occurring amino acid;
- R 4 is alkyl;
- Y is O;
- R 8 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- OR 3 is in the alpha configuration. In still another embodiment, OR 3 is in the beta configuration.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 3 represents a naturally occurring ⁇ -amino acid in the L-configuration. In another embodiment, R 3 is a residue of L-valine. In other embodiments, R 3 represents an amino acid residue with the D-configuration or R 3 represents a non-natural amino acid. In other embodiments, R 3 represents the residue of a ⁇ ⁇ or ⁇ amino acid.
- R 3 represents an ester of an amino acid.
- R 3 represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be boded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- Non-limiting examples of amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid and arginine.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-conf ⁇ guration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- a progesterone analogue of Formula III is provided:
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate, -OR 11 , -NR 11 R 12 ; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 3 together with X and R 4 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 3 is absent;
- R 4 is hydrogen or alkyl; R 4 together with R 3 and X forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms; or R 4 together with R 7 form a double bond;
- R 7 is hydrogen or is absent, or R 7 together with R 4 forms a double bond
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, monophosphate, diphosphate, triphosphate, a carbohydrate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or R 8 together with R 9 and the oxygen atom forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms,;
- R 9 is hydrogen, alkyl, or R 9 together with the oxygen atom and R 8 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms,;
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, the residue of an amino acid, a carbohydrate, optionally substituted acyl, or -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 , or the residue of an amino acid;
- R 12 is hydrogen or alkyl; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that neither XR 3 R 7 nor R 8 represent an ester of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , -NR 11 R 12 or R 3 is absent;
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, or a carbohydrate;
- R 11 is the residue of an amino acid, a carbohydrate or optionally substituted acyl.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 4 and R 9 are independently hydrogen or methyl.
- X is O. In other embodiments, X is N. In certain embodiments in which X is O, R 3 and R 4 come together to form a double bond.
- one of R 3 and R 8 is a residue of an amino acid. In particular embodiments, the amino acid is a naturally occurring amino acid. In certain embodiments, R 3 is a residue of an amino acid. In certain other embodiments, R 8 is a residue of an amino acid. In yet further embodiments, both R 3 and R 8 are residues of an amino acid.
- R 3 is a carbohydrate. In another embodiment, R 8 is a carbohydrate.
- X is O; R 3 is the residue of an amino acid or a carbohydrate; and R 7 is absent.
- X is N; R 4 together with R 7 form a double bond; R 3 is OR 11 ; and R 11 is the residue of an amino acid or a carbohydrate.
- X is N; R 4 together with R 7 form a double bond; R 3 is -NR 11 R 12 ; R 11 is the residue of an amino acid or a carbohydrate; and R 12 is hydrogen.
- R 8 is the residue of a naturally occurring amino acid; R 9 is hydrogen; X is O; R 4 together with R 7 form a double bond; and R 3 is absent.
- R 8 is a carbohydrate; R 9 is hydrogen; X is O; R 4 together with R 7 form a double bond; and R 3 is absent.
- R 8 is the residue of a naturally occurring amino acid or a carbohydrate; R 9 is hydrogen; X is O; R 3 and R 4 are hydrogen; and R 7 is absent.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 8 is the residue of a naturally occurring amino acid; R 9 is hydrogen; X is O; R 4 together with R 7 form a double bond; R 3 is absent; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is the residue of a naturally occurring amino acid; R 9 is alkyl; X is O; R 4 together with R 7 form a double bond; R 3 is absent; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- -XR 3 R 7 is in the alpha configuration. In still another embodiment, -XR 3 R 7 is in the beta configuration.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 8 represents a naturally occurring ⁇ -amino acid in the L-configuration. In another embodiment, R 8 is a residue of L-valine. In another embodiment, R 8 represents an amino acid residue with the D-configuration. In another embodiment, R 8 represents a non-natural amino acid. In other embodiments, R 8 represents the residue of a ⁇ ⁇ or ⁇ amino acid.
- R 8 represents an ester of an amino acid. In another embodiment, R 8 represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- R 3 represents an ester of an amino acid.
- R represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be boded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-conf ⁇ guration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- a compound of Formula III with the stereochemical configuration of Formula IHb is provided: nib wherein the definition of variables X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are as defined in Formula III above.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 3 is an -OR 11 , -NR 11 R 12 , monophosphate, diphosphate, triphosphate, a carbohydrate, or -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid;
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , -NR 11 R 12 , monophosphate, diphosphate, triphosphate, -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or R 8 together with R 9 and Y forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 8 is absent;
- R 9 is hydrogen or alkyl; R 9 together with Y and R 8 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 9 and R 10 together form a double bond;
- R 10 is hydrogen or absent, or R 10 together with R 9 form a double bond
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, the residue of an amino acid, a carbohydrate monophosphate, diphosphate, triphosphate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or an optionally substituted ester;
- R 12 is hydrogen or alkyl; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that YR 8 R 10 does not represent an ester of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid; and with the proviso that when Y is N, R 8 does not represent aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 3 is an -OR 11 , -NR 11 R 12 , or a carbohydrate
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, -OR 11 , - NR 11 R 12 , or R 8 is absent
- R 11 is the residue of an amino acid, a carbohydrate or an optionally substituted ester
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 9 is hydrogen or methyl.
- Y is O. In other embodiments, Y is N. In certain embodiments in which Y is O, and R 8 and R 10 come together to form a double bond. In certain other embodiments, one of R 3 and R 8 is a residue of an amino acid. In particular embodiments, the amino acid is a naturally occurring amino acid. In certain embodiments, R 3 is a residue of an amino acid. In certain other embodiments, R 8 is a residue of an amino acid. In yet further embodiments, both R 3 and R 8 are residues of an amino acid.
- R 3 is a carbohydrate.
- R 8 is a carbohydrate.
- Y is O; R 8 is the residue of an amino acid; and R 10 is absent.
- Y is N; R 10 together with R 9 form a double bond; R 8 is OR 11 ; and R 11 is the residue of an amino acid or a carbohydrate.
- Y is N; R 10 together with R 9 form a double bond; R 8 is -NR 11 R 12 ; R 11 is the residue of an amino acid or a carbohydrate; and R 12 is hydrogen.
- R 3 is -OR 11 and R 11 is the residue of a naturally occurring amino acid or a carbohydrate; Y is O; R 10 together with R 9 form a double bond; and R 8 is absent.
- R 3 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid;
- R 12 is hydrogen;
- Y is O;
- R 10 together with R 9 form a double bond; and
- R 8 is absent.
- R 3 is a carbohydrate; Y is O; R 10 together with R 9 form a double bond; and R 8 is absent.
- R 3 is -OR 11 and R 11 is the residue of a naturally occurring amino acid or a carbohydrate; Y is O; R 8 and R 9 are hydrogen; and R 10 is absent.
- R 3 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid;
- R 12 is hydrogen;
- Y is O;
- R 8 and R 9 are hydrogen; and
- R 10 is absent.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 3 is -OR 11 and R 11 is the residue of a naturally occurring amino acid; Y is O; R 10 together with R 9 form a double bond; R 8 is absent; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 3 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid;
- R 12 is hydrogen;
- Y is O;
- R 8 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 is a single bond and the dotted line between C5 and C6 is a single bond.
- the dotted line between C4 and C5 is a single bond and the dotted line between C5 and C6 is a double bond.
- the dotted line between C4 and C5 is a double bond and the dotted line between C5 and C6 is a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 3 comprises a residue of a naturally occurring ⁇ - amino acid in the L-configuration. In another embodiment, R 3 comprises a residue of L- valine. In another embodiment, R comprises an amino acid residue with the D- configuration. In another embodiment, R 3 comprises a non-natural amino acid. In other embodiments, R comprises the residue of a ⁇ ⁇ or ⁇ amino acid.
- R 3 represents an ester of an amino acid.
- R represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be boded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-conf ⁇ guration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- a progesterone or steroid analogue of Formula V is provided:
- V or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is O, N or S;
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid a carbohydrate; -OR 11 ; -NR 11 R 12 , monophosphate, diphosphate, triphosphate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; R 3 together with X and R 4 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R is absent;
- R 4 is hydrogen or alkyl; R 4 together with R 3 and X forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms, or R 4 together with R 7 form a double bond;
- R 8 is -OR 11 , -NR 11 R 12 , monophosphate, diphosphate, triphosphate, a carbohydrate, - C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid;
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, the residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 , or the residue of an amino acid; or an optionally substituted ester;
- R 12 is hydrogen or alkyl; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that XR 3 R 7 does not represent an ester of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid; and with the proviso that R 8 does not represent aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid a carbohydrate; -OR 11 ; -NR 11 R 12 , or R 3 is absent; R 8 is -OR 11 , - NR 11 R 12 or a carbohydrate; R 11 is the residue of an amino acid, a carbohydrate or an optionally substituted ester.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 4 is hydrogen or methyl.
- X is O. In other embodiments, X is N. In certain embodiments in which X is O, R 3 and R 4 come together to form a double bond. In certain embodiments, one of R 3 and R 8 is a residue of an amino acid. In particular embodiments, the amino acid is a naturally occurring amino acid. In certain embodiments, R is a residue of an amino acid. In certain other embodiments, R 8 is a residue of an amino acid. In yet further embodiments, both R 3 and R 8 are residues of an amino acid.
- R 3 is a carbohydrate.
- R 8 is a carbohydrate.
- X is O; R 3 is the residue of an amino acid or a carbohydrate; and R 7 is absent.
- X is N; R 4 together with R 7 form a double bond; R 3 is OR 11 ; and R 11 is the residue of an amino acid or a carbohydrate.
- X is N; R 4 together with R 7 form a double bond; R 3 is -NR 11 R 12 ; R 11 is the residue of an amino acid or a carbohydrate; and R 12 is hydrogen.
- R 8 is -OR 11 ;
- R 11 is the residue of a naturally occurring amino acid or a carbohydrate;
- X is O;
- R 3 is absent.
- R 8 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid;
- R 12 is hydrogen;
- X is O;
- R 4 together with R 7 form a double bond; and
- R 3 is absent.
- R 8 is -OR 11 ;
- R 11 is a carbohydrate;
- X is O;
- R 4 together with R 7 form a double bond; and
- R 3 is absent.
- R 8 is -OR 11 ;
- R 11 is the residue of a naturally occurring amino acid or a carbohydrate;
- X is O;
- R 3 and R 4 are hydrogen; and
- R 7 is absent.
- R 8 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid or a carbohydrate;
- R 12 is hydrogen;
- X is O;
- R 3 and R 4 are hydrogen; and
- R 7 is absent.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 8 is -OR 11 ;
- R 11 is the residue of a naturally occurring amino acid;
- X is O;
- R 3 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid;
- R 12 is hydrogen;
- X is O;
- R 4 together with R 7 form a double bond;
- R 3 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is -OR 11 ;
- R 11 is the residue of a naturally occurring amino acid;
- X is O;
- R 3 and R 4 are hydrogen;
- R 7 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid;
- R 12 is hydrogen;
- X is O;
- R 3 and R 4 are hydrogen;
- R 7 is absent; and
- R 1 , R 2 , R 5 and R 6 are hydrogen; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 is a single bond and the dotted line between C5 and C6 is a single bond.
- the dotted line between C4 and C5 is a single bond and the dotted line between C5 and C6 is a double bond.
- the dotted line between C4 and C5 is a double bond and the dotted line between C5 and C6 is a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- -XR 3 R 7 is in the alpha configuration. In still another embodiment, -XR 3 R 7 is in the beta configuration.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 8 comprises a naturally occurring ⁇ -amino acid in the L-configuration. In another embodiment, R 8 comprises a residue of L-valine. In another embodiment, R 8 comprises an amino acid residue with the D-configuration. In another embodiment, R 8 comprises a non-natural amino acid. In other embodiments, R 8 comprises the residue of a ⁇ ⁇ or ⁇ amino acid.
- R 3 represents an ester of an amino acid.
- R represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be boded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-conf ⁇ guration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or R 3 together with the oxygen and R 4 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms;
- R 4 is hydrogen, alkyl or R 4 together with R 3 and the oxygen forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that neither R 3 does not represent an ester of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 3 is hydrogen, optionally substituted acyl, a residue of an amino acid or a carbohydrate.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 4 is hydrogen or methyl.
- R is the residue of a naturally occurring amino acid; and R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen.
- R is the residue of a naturally occurring amino acid or a carbohydrate;
- R 4 is alkyl; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 1 is alkyl; and R 2 , R 4 and R 5 are hydrogen.
- R 1 and R 4 are alkyl; and R 2 and R 5 are hydrogen.
- R 3 is a carbohydrate; and R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen.
- R is -C(O)R', where R' is alkyl, aryl, aralkyl, or the residue of an amino acid; and R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- OR 3 is in the alpha configuration. In still another embodiment, OR 3 is in the beta configuration.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration.
- R 3 represents a naturally occurring ⁇ -amino acid in the L-configuration.
- R is a residue of L-valine.
- R represents an amino acid residue with the D-configuration.
- R represents a non-natural amino acid.
- R represents the residue of a ⁇ ⁇ or ⁇ amino acid.
- R 3 represents an ester of an amino acid.
- R 3 represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be bonded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-configuration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 3 is -OR 11 , -NR 11 R 12 , monophosphate, diphosphate, triphosphate, a carbohydrate, or -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid;;
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, the residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate; -C(O)R', where R' is OR 1 , NR 1 R 2 , alkyl, aryl, aralkyl, or the residue of an amino acid; or an optionally substituted ester;
- R 12 is hydrogen or alkyl; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond.
- R 3 is -OR 11 , -NR 11 R 12 , or a carbohydrate; and R 11 is the residue of an amino acid, a carbohydrate, or an optionally substituted ester.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 3 is -OR 11 and R 11 is the residue of a naturally occurring amino acid; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 3 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid or a carbohydrate;
- R 12 is hydrogen; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 3 OR 11 , R 11 is a carbohydrate; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 3 is -C(O)R', where R' is alkyl, aryl, aralkyl, or the residue of an amino acid; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 3 comprises a naturally occurring ⁇ -amino acid in the L-configuration. In another embodiment, R 3 comprises a residue of L-valine. In another embodiment, R 3 comprises an amino acid residue with the D-configuration. In another embodiment, R comprises a non-natural amino acid. In other embodiments, R comprises the residue of a ⁇ ⁇ or ⁇ amino acid.
- R represents an ester of an amino acid.
- R represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- a residue of an amino acid is connected to the steroid ring system at the carboxyl group of the amino acid.
- a residue of an amino acid is connected to the steroid at the amino acid side chain.
- amino acids that contain side chains with functional groups that are capable of forming a bond with a hydroxy or a ketone group may be boded to the steroid ring by such a group.
- the reactive groups on the amino acid side chains may displace leaving groups formed on the steroid moiety to form a covalent bond.
- amino acids with reactive groups in the side chain include lysine, cysteine, serine, tyrosine, aspartic acid, arginine and the like.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- amino acid(s) in any of the embodiments of the invention described herein may be naturally occurring or synthetic amino acids and may be in the D or L stereoisomeric form or may exist as a D, L mixture.
- the 20 naturally occurring ⁇ -amino acids in the L-conf ⁇ guration are encompassed by the invention as well as ⁇ -amino acids in the D- configuration.
- Synthetic amino acids in either stereoisomeric form are also encompassed.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid, a carbohydrate, monophosphate, diphosphate, triphosphate; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or , R 8 together with R 9 and the oxygen forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms,;
- R 9 is hydrogen, alkyl, or R 9 together with the oxygen and R 8 forms an optionally substituted 5-6 membered heterocyclic or heteroaryl ring containing 1-4 nitrogen, oxygen or sulfur atoms,; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that R 8 does not represent an ester of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid; and with the proviso that when Y is N, R 8 does not represent aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2- (hydroxyethylamino)-propionic acid.
- R 8 is hydrogen, optionally substituted acyl, a residue of an amino acid or a carbohydrate.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 9 is hydrogen or methyl.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 8 is the residue of a naturally occurring amino acid; and R 1 , R 2 , R 5 , R 6 and R 9 are hydrogen.
- R 8 is the residue of a naturally occurring amino acid or a carbohydrate;
- R 9 is alkyl; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 1 is alkyl; and R 2 , R 5 and R 9 are hydrogen.
- R 1 and R 9 are alkyl; and R 2 and R 5 are hydrogen.
- R 8 is a carbohydrate; and R 1 , R 2 , R 5 , R 6 and R 9 are hydrogen.
- R 8 is -C(O)R', where R' is alkyl, aryl, aralkyl, or the residue of an amino acid; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 8 is the residue of a naturally occurring ⁇ - amino acid in the L-configuration. In another embodiment, R 8 is a residue of L-valine. In another embodiment, R 8 is an amino acid residue with the D-configuration. In another embodiment, R 8 represents a residue of a non-natural amino acid. In other embodiments, R 8 represents the residue of a ⁇ ⁇ or ⁇ amino acid.
- R 8 represents an ester of an amino acid. In another embodiment, R 8 represents an ester of an amino acid residue where the ester bond is formed with a carboxylate group on the side chain of the amino acid.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate;
- R 8 is -OR 11 , -NR 11 R 12 , -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid; or a carbohydrate;
- R 11 is hydrogen, optionally substituted alkyl, hydroxyalkyl, aminoalkyl, the residue of an amino acid, a carbohydrate or an optionally substituted ester; -C(O)R', where R' is alkyl, aryl, aralkyl, OR 1 , NR 1 R 2 or the residue of an amino acid;
- R 12 is hydrogen or alkyl; and the dotted lines indicate the presence of either a single bond or a double bond, wherein the valences of a single bond are completed by hydrogens, provided that if the dotted line between C4 and C5 or between C5 and C6 represents a double bond then the other dotted line between C4 and C5 or between C5 and C6 represents a single bond; and with the proviso that R 8 does not represent aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 is alkyl; and R 2 and R 5 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- R 3 is -OR 11 and R 11 is the residue of a naturally occurring amino acid; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is -NR 11 R 12 ;
- R 11 is the residue of a naturally occurring amino acid or a carbohydrate;
- R 12 is hydrogen; and
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is a carbohydrate; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 8 is -C(O)R', where R' is alkyl, aryl, aralkyl, or the residue of an amino acid; and R 1 , R 2 , R 5 and R 6 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R 8 comprises a naturally occurring ⁇ -amino acid in the L-configuration. In another embodiment, R 8 comprises a residue of L-valine. In another embodiment, R 8 comprises an amino acid residue with the D-configuration. In another embodiment, R 8 comprises a non-natural amino acid. In other embodiments, R 8 comprises the residue of a ⁇ ⁇ or ⁇ amino acid.
- R is the side chain of a naturally occurring amino acid
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate; and with the proviso that R does not represent the side chain of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)-propionic acid.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 2 is alkyl; and R 1 and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, and the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R comprises the side chain of a naturally occurring ⁇ -amino acid in the L-configuration.
- R comprises a residue of L- alanine, L-leucine, L-isoleucine, L-proline, L-proline, L-phenylalanine, L-tryptophan, L- lysine, or L-valine.
- R comprises an amino acid residue with the D- configuration.
- R is the side chain of a naturally occurring amino acid
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen, hydroxyl cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heterocyclic, heteroaryl, amino, thiol, alkoxy, sulfide, nitro, cyano, azide, sulfonyl, acyl, carboxyl, an ester, an amide, carbamate, carbonate, an amino acid residue or a carbohydrate; and with the proviso that R does not represent the side chain of aspartic acid, glutamic acid, gamma amino butyric acid or ⁇ -2-(hydroxyethylamino)- propionic acid.
- R 1 , R 2 , R 5 and R 6 are independently hydrogen, alkyl, halogen or hydroxyl.
- R 1 , R 2 , R 5 and R 6 are independently methyl, ethyl or propyl.
- R 1 , R 2 , R 5 and R 6 are independently thiomethyl, hydroxymethyl or cyano.
- R 1 , R 2 , R 5 and R 6 are independently vinyl or ethynyl.
- R 1 , R 2 , R 5 and R 6 are independently fluoro, bromo, chloro or iodo.
- R 6 is alkyl or fluoro.
- R 1 , R 2 and R 5 are independently hydrogen or alkyl.
- R 1 and R 2 are hydroxyl.
- R 1 and R 2 are independently hydroxyl or halogen.
- R 1 , R 2 , R 5 and R 6 are hydrogen.
- R 1 is alkyl; and R 2 , and R 5 are hydrogen.
- R 5 is alkyl; and R 1 and R 2 are hydrogen.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between C4 and C5 represents a single bond and the dotted line between C5 and C6 represents a double bond.
- the dotted line between C4 and C5 represents a double bond and the dotted line between C5 and C6 represents a single bond.
- the dotted line between Cl and C2 represents a single bond. In still another embodiment, the dotted line between Cl and C2 represents a double bond.
- the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, and the hydrogen at the C5 bridgehead carbon is in the alpha configuration. In another embodiment, and the dotted lines between C4 and C5 and between C5 and C6 represent a single bond, the hydrogen at the C5 bridgehead carbon is in the beta configuration
- R comprises the side chain of a naturally occurring ⁇ -amino acid in the L-configuration.
- R comprises a residue of L- alanine, L-leucine, L-isoleucine, L-proline, L-proline, L-phenylalanine, L-tryptophan, L- lysine, or L-valine.
- R comprises an amino acid residue with the D- configuration.
- R 1 , R 2 , R 5 , and R 6 are as defined in Formula I; and R 13 and R 14 are hydrogen, optionally substituted alkyl, carboxy, sulfonyl, sulfonic acid, sulfonamide, an ester, and amide, hydroxyalkyl, aminoalkyl, the residue of an amino acid, or a carbohydrate.
- R 1 , R 2 , R 5 , and R 6 are as defined in Formula I; and R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, carboxy, sulfonyl, sulfonic acid, sulfonamide, an ester, and amide, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, the residue of an amino acid, or a carbohydrate.
- variables R 1 , R 2 , R 5 , and R 6 are as defined in Formula I; and R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, carboxy, sulfonyl, sulfonic acid, sulfonamide, an ester, and amide, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, the residue of an amino acid, or a carbohydrate.
- R 1 , R 2 , R 5 , and R 6 are as defined in Formula I; and R 13 and R 14 are hydrogen, optionally substituted alkyl, carboxy, sulfonyl, sulfonic acid, sulfonamide, an ester, and amide, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, the residue of an amino acid, or a carbohydrate.
- the invention provides the steroid analogues having the Formulas presented in Table 1 below, or a pharmaceutically acceptable salts, esters or prodrugs thereof,
- the present invention includes all possible stereochemical configurations of the compounds.
- the stereochemistry of the compounds of the invention will retain the natural stereochemistry of the natural steroid.
- the stereochemistry at C8, C9, ClO, C13, C14 and C17 will retain the stereochemistry of the natural steroid compounds.
- the compounds of the invention include compounds with variable configurations at C- 3 and C-5 of the steroid ring system.
- the configuration of C-3 is alpha.
- the configuration of C-3 is beta.
- the configuration of C-5 is alpha, and in other embodiments the configuration at C-5 is beta. All possible combinations of stereochemical configurations at C-3 and C-5 are embraced by the invention.
- the stereochemistry of the compounds of the invention will retain the natural stereochemistry of progesterone at the bridgehead carbon atoms C-8, C-9,C- 14 and C-17.
- the stereochemistry of the quaternary carbons C-IO and C-13 will also retain the stereochemistry of the progesterone, unless indicated otherwise.
- the compounds of the invention include compounds with variable configurations at C-3 and C-5 of the steroid ring system.
- the configuration of C-3 is alpha.
- the configuration of C-3 is beta.
- the configuration of C-5 is alpha, and in other embodiments the configuration at C-5 is beta. All possible combinations of stereochemical configurations at C-3 and C-5 are embraced by the invention.
- the pure E- or Z- isomers of the carbonyl- derivatives of the steroid compounds such as oximes derivatives and the like, are provided.
- the invention provides mixtures of E- and Z-isomers of the carbonyl derivatives of the neuroprotective compounds.
- the present invention also encompasses all possible stereochemical configurations of asymmetric substituents, such as amino acids. As described above, the naturally occurring a- amino acids in L, D, and D,L configurations are encompassed. Furthermore, all possible stereochemical configurations of non-natural synthetic amino acids are encompassed by the invention.
- isolated enantiomer refers to a composition that includes at least approximately 95% to 100%, or more preferably, over 97% of a single enantiomer of that compound.
- the term “substantially free of or “substantially in the absence of refers to a composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that compound.
- Ci_5 alkyl independently includes Ci-alkyl, C 2 - alkyl, Cs-alkyl, C 4 -alkyl, C 5 -alkyl.
- alkyl as used herein unless otherwise specified, is intended to have its customary meaning in the art and includes optionally substituted saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbons.
- Alkyl typically is C 1-16 alkyl but can also be lower alkyl, including C 1-10 or Ci_5 alkyl.
- alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexylisohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2, 2-dimethylbutyl and 2,3-dimethylbutyl.
- the alkyl group is a cyclic group, it is typically between C 3-12 or between C3_8 and can include one or more cycles.
- the alkyl group can be optionally substituted with one or more moieties.
- substituents include alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thiol, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in
- protected refers to a group that is added to an oxygen, nitrogen, sulfur or phosphorus atom to prevent its further reaction or for other purposes.
- oxygen and nitrogen protecting groups are known to those skilled in the art or organic synthesis. Suitable protecting groups are described, for example, in Greene, et al., "Protective Groups in Organic Synthesis,” John Wiley and Sons, 4 th edition, 2007.
- aryl as used herein, is intended to have its customary meaning in the art and includes, for example, phenyl, biphenyl, and naphthyl and the like. The aryl group can be optionally substituted.
- Non-limiting examples of substituents include hydroxyl, amino, amido, alkylamino, dialkylamino, haloalkyl, arylamino, alkoxy, aryloxy, halo, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, fulfinyl, fulfamonyl, ester, sulfate, phosphonic acid, phosphate, phosphonyl, phosphinyl, phosphoryl, phosphonate, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate or carboxyl, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, 4 th edition, 2007.
- alkyl refers to an optionally substituted aryl group as defined above linked to the molecule through an alkyl group as defined above.
- alkaryl or alkylaryl refers to an alkyl group as defined above linked to the molecule through an aryl group as defined above.
- the alkyl group can be optionally substituted as describe above and the aryl group can be optionally substituted as described above or with any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis,” John Wiley and Sons, 4 th edition, 2007.
- aryl phenyl; naphthyl; phenylmethyl; phenylethyl; 3,4,5-trihydroxyphenyl; 3,4,5- trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-chlorophenyl; 4-methylphenyl; 3,5-di- tertiarybutyl- 4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-l -naphthyl; 2-methyl-l- naphthylmethyl; 2-naphthylmethyl; 4-chlorophenylmethyl; 4-tertiarybutylphenyl; 4- tertiarybutylphenylmethyl and the like.
- halo or halogen
- chloro, bromo, iodo and fluoro as used herein includes chloro, bromo, iodo and fluoro.
- heteroatom refers to oxygen, sulfur, nitrogen or phosphorus.
- alkylamino or arylamino refers to an amino group that has one or two alkyl or aryl substituents, respectively.
- alkoxy refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above.
- acyl refers to moiety of the Formula -C(O)R', wherein R' is alkyl, aryl, alkaryl, aralkyl, heteroaromatic, heterocyclic, alkoxyalkyl including methoxymethyl, arylalkyl including benzyl, aryloxyalkyl, such as phenoxymethyl, aryl including optionally substituted phenyl.
- a "leaving group” means a functional group that is cleaved from the molecule to which it is attached under appropriate conditions.
- heteroaryl or “heteroaromatic,” as used herein are intended to have their customary meaning in the art, and include an aromatic group that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
- heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen or phosphorus in the ring.
- heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, or imidazo
- the heteroaromatic group can be optionally substituted as described above for aryl.
- the heterocyclic group can be optionally substituted with one or more moieties.
- suitable substituents include alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional
- the heteroaromatic can be partially or totally hydrogenated as desired.
- dihydropyridine can be used in place of pyridine.
- Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired.
- Suitable protecting groups are well known to those skilled in the art, and include, but are not limited to, 9-fluorenylmethoxycarbonyl (Fmoc), benzyl, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl, benzoyl, and propionyl, methanesulfonyl, and p-toluenesulfonyl.
- Fmoc 9-fluorenylmethoxycarbonyl
- benzyl trimethylsilyl, dimethylhexylsilyl
- amino acid includes naturally occurring and synthetic ⁇ , ⁇ ⁇ or ⁇ amino acids.
- the naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.
- residue of an amino acid is intended to mean that an amino acid is bonded to the compound at any substitutable position, including for example, through an ester bond to the carboxyl group of the amino acid. Other substitutable positions include the amino group or the sidechain of the amino acid.
- side chain of a naturally occurring amino acid refers to the side chains of the 20 naturally occurring amino acids, including hydrogen (i.e. the sidechain of glycine).
- the side chains of the naturally occurring amino acids are shown below:
- the amino acid is in the L-configuration.
- the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ -alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ -isoleuccinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ - glycinyl, ⁇ -serinyl,
- amino acid When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of ⁇ , ⁇ ⁇ or ⁇ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the D and L-conf ⁇ gurations.
- thio refers to a sulfur covalently bound to a hydrogen or a carbon based group. Some non-limiting examples include methylmercapto, ethylmercapto, n- propylmercapto, isopropylmercapto or n-butylmercapto, ethylthio, n-propylthio or isopropylthio group.
- the thio group also can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulf ⁇ nyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected,
- esters refers to a carbonyl flanked by an alkoxy group and a carbon based group. Esters may be formed from the reaction of a hydroxy group on the compound of the invention with a carboxyl group of another group. Alternatively, an ester may be formed by reaction of a carboxyl group on the compound of the invention with a hydroxy group of another molecule.
- esters of amino acids include groups where a carboxyl group of the amino acid forms an ester bond with a hydroxyl group of the molecule. Also included are groups where a hydroxyl group on the amino acid forms a ester bond with a carboxyl group on the molecule.
- the ester group also can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulf ⁇ nyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or
- Modifications of the active compound can affect the bioavailability and rate of metabolism of the active species, thus providing control over the delivery of the active species. Further, the modifications can affect the activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its activity according to the methods described herein, or other method known to those skilled in the art.
- pharmaceutically acceptable salts or “complexes” refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects.
- Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ - ketoglutarate and ⁇ -glycerophosphate.
- Suitable inorganic salts may also be formed, including, hydrochloride, sulfate, nitrate, bicarbonate and carbonate salts.
- the pharmaceutically acceptable salts may be made with sufficiently basic compounds such as an amine with a suitable acid affording a physiologically acceptable anion.
- Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
- Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N 5 N- dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylened
- quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the Formula -NR + A " , wherein R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
- R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate
- prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
- Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
- Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
- any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the compound.
- a number of prodrug ligands are known.
- alkylation, acylation or other lipophilic modification of the compound will increase the stability of the compound.
- substituent groups that can replace one or more hydrogens on the compound are alkyl, aryl, steroids, carbohydrates, including sugars, 1 ,2-diacylglycerol and alcohols. Any of these can be used in combination with the disclosed compounds to achieve a desired effect.
- the present invention provides methods and compositions for the treatment or prevention of neurodegeneration following an injury to the central nervous system or due to certain neurodegenerative disorders comprising administering an effective amount of steroid analog, or a pharmaceutically acceptable salt, ester or prodrug thereof to a host in need thereof.
- Multiple physiological events lead to neurodegeneration. These events include, for example, increase in the immune and inflammatory response, demyelinization, and lipid peroxidation.
- the present invention provides compositions and methods for reducing or eliminating neuronal cell death, edema, ischemia, and enhancing tissue viability following injury to the central nervous system or certain disorders.
- the analogues, salts, esters or prodrugs of the steroid or secosteroid analogs may be optionally administered with a pharmaceutically acceptable carrier or diluent.
- treatment or prevention is intended any enhanced survival, proliferation, and/or neurite outgrowth of the neurons that either prevents or retards neurodegeneration, the progressive loss of neurons.
- neuroprotective effect includes both improved morphological (i.e., enhanced tissue viability) and/or behavioral recovery.
- CNS injuries that are encompassed within the scope of treatment of the present invention include both traumatic injuries, in particular TBI, and physiological insults such as an ischemic or hemorrhagic stroke. In both instances, a progressive loss of neurons after the initial insult occurs and can be alleviated by use of the inventive compounds.
- a method of preventing or reducing inflammatory reactions in a patient includes administering a steroid analog to a host in need thereof.
- methods of neuroprotection comprising administering a compound of the invention, its physiologically acceptable salt or prodrug, optionally in a pharmaceutically acceptable carrier, to a patient at risk of suffering from a stroke.
- methods of treating or preventing neuronal damage comprising administering a compound of the invention or its physiologically acceptable salt or prodrug, optionally in a pharmaceutically acceptable carrier, to a patient who has suffered from an ischemic stroke.
- the method can reduce or prevent neurodegeneration such as that caused by excitotoxic or inflammatory reactions, or can enhance neuronal proliferation, growth or differentiation in the period after the injury.
- methods of treating or preventing cognitive or behavioral deficits after a stroke comprising administering a compound of the invention or its physiologically acceptable salt or prodrug, optionally in a pharmaceutically acceptable carrier, to a patient who has suffered a stroke.
- the stroke is an ischemic stroke, but it can alternatively be a hemorrhagic stroke.
- the present invention provides a method to achieve a neuroprotective effect following a traumatic CNS injury in a mammal, in particular in a human, comprising administering a therapeutically effective amount of steroid analogue of the invention.
- a traumatic injury to the CNS is characterized by a physical impact to the central nervous system. The physical forces resulting in a traumatic brain injury cause their effects by inducing three types of injury: skull fracture, parenchymal injury, and vascular injury. A blow to the surface of the brain typically leads to rapid tissue displacement, disruption of vascular channels, and subsequent hemorrhage, tissue injury and edema.
- Morphological evidence of injury in the neuronal cell body includes pyknosis of nucleus, eosinophilia of the cytoplasm, and disintegration of the cell. Furthermore, axonal swelling can develop in the vicinity of damage neurons and also at great distances away from the site of impact.
- the compound is administered within twelve hours after onset of a stroke.
- the steroid analogue of the invention is administered within twelve hours after an injury, such as a TBI.
- the compounds are administered within 11 hours of a TBI, stroke or other injury to the brain, or within 10 hours, or within 9 hours, or within 8 hours, or within 7 hours, or within 6 hours, or within 5 hours, or within 4 hours, or within 3 hours, such as within two or one hour.
- the compounds are administered within one day (i.e. 24 hours) of the injury.
- the compounds are provided to individuals at risk of a stroke, such as those who are suffering from atherosclerosis or have a family history of heart disease. These compounds can be provided to individuals as a preventative therapy to descrease neural trauma.
- a method for decreasing ischemia following a brain injury comprising administering an effective amount of a steroid analogue of the invention.
- the methods of the invention provide a means to reduce or eliminate the inflammatory immune reactions that follow a CNS injury.
- the steroid analogues of the present invention can substantially reduce brain swelling and reduce the amount of neurotoxic substances (e.g., free radicals and excitotoxins) that are released from the site of injury.
- the present invention provides for a method of treating a brain injury by administering to a subject steroid analogue of the invention, a pharmaceutically acceptable salt or a prodrug or ester thereof.
- concentration of the steroid analogue or salt, ester or prodrug thereof, in accordance with the present invention is effective in the treatment or prevention of neuronal damage that follows either a traumatic, ischemic or hemorrhagic injury to the CNS and hence, elicits a neuroprotective effect.
- the therapeutically effective amount will depend on many factors including, for example, the specific activity of the steroid analogue administered, the type of injury, the severity and pattern of the injury, the resulting neuronal damage, the responsiveness of the patient, the weight of the patient along with other intraperson variability, the method of administration, and the formulation used.
- a traumatic injury to the CNS results in multiple physiological events that impact the extent and rate of neurodegeneration, and thus the final clinical outcome of the injury.
- the treatment of a traumatic injury to the CNS encompasses any reduction and/or prevention in one or more of the various physiological events that follow the initial impact.
- cerebral edema frequently develops following a traumatic injury to the CNS and is a leading cause of death and disability.
- Cortical contusions for example, produce massive increases in brain tissue water content which, in turn, can cause increased intracranial pressure leading to reduced cerebral blood flow and additional neuronal loss.
- the methods of the invention find use in reducing and/or eliminating cerebral edema and/or reducing the duration of the edemic event following a traumatic injury to the CNS.
- Assays to determine a reduction in edema are known in the art and include, but are not limited to, a decrease in tissue water content following the administration of the progestin or the progestin metabolite (Betz et al. (1990) Stroke 21 : 1199- 204, which is herein incorporated by reference).
- an overall improvement in behavioral recovery can also be used as a measure for a decrease in edema.
- a decrease in edema in the effected tissue by at least about 15% to 30%, about 30% to 45%, about 45% to 60%, about 60% to 80%, or about 80% to 95% or greater will be therapeutically beneficial, as will any reduction in the duration of the edemic event.
- Infiltrating leukocytes are thought to contribute to secondary ischemic damage by producing toxic substances that kill brain cells and disrupt the blood-brain barrier (see del Zoppo, et al. (2000) Advances in the vascular pathophysiology of ischemic stroke. Thromb Res. 98:73-81) Infiltration occurs when leukocytes bind endothelial intercellular adhesion molecule- 1 (ICAM-I) and ICAM-I is upregulated after ischemia.
- IAM-I endothelial intercellular adhesion molecule- 1
- TBI also elicits inflammatory, and in particular a immune responses. See, for example, Soares et al. (1995) J. Neurosci. 15:8223-33; Holmin et al. (1995) Acta Neurochir. 132:110-9; Arvin et al. (1996) Neurosci. Biobehav. Rev. 20:445-52.
- a cortical impact severe inflammatory reactions and gliosis at the impact site and at brain areas distal to the primary site of injury occurs.
- the inflammatory response is characterized by the expression of adhesion molecules on the vascular surfaces, resulting in the adherence of immune cells and subsequent extravasation into the brain parenchyma.
- cytokines By releasing cytokines, the invading macrophages and neutrophils stimulate reactive astrocytosis. Release of different chemokines by other cell types induces these immune cells to become phagocytic, with the simultaneous release of free radicals and pro-inflammatory compounds, e.g., cytokines, prostaglandins, and excitotoxins (Arvin et al. (1996) Neurosci. Biobehav. Ref. 20:445-52; Raivich et al. (1996) KeIo J. Med. 45:239-47; Mattson et al. (1997) Brain Res. Rev. 23:47-61; all of which are herein incorporated by reference).
- cytokines e.g., cytokines, prostaglandins, and excitotoxins
- Assays for assessing the efficacy of the compounds described herein include assays to determine a decrease in an ischemic event include, for example, a decrease in infarct area, improved body weight, and improved neurological outcome.
- Assays to measure a reduction in lipid peroxidation in both brain homogenate and in mitochondria are known in the art and include, for example, the thiobarbituric acid method (Roof et al. (1997) MoI. Chem. Neuropathol. 31 : 1-11; Subramanian et al. (1993) Neurosci. Lett. 155:151-4; Goodman et al. (1996) J. Neurochem. 66:1836-44; Vedder et al. (1999) J. Neurochem.
- the neuroprotection resulting from the methods of the present invention will result in at least about a 10% to 20%, 20% to 30%, 30% to 40%, 40% to 60%, 60% to 80% or greater increase in neuronal survival and/or behavioral recovery as compared to the control groups.
- GAP -43 Growth Associated Protein 43
- Other histological markers can include a decrease in astrogliosis and microgliosis.
- a delay in cellular death can be assayed using TUNEL labeling in injured tissue.
- anatomical measures that can be used to determine an increase in neuroprotection include counting specific neuronal cell types to determine if the progestin or the progestin metabolite is preferentially preserving a particular cell type (e.g., cholinergic cells) or neurons in general.
- behavioral assays can be used to determine the rate and extent of behavior recovery in response to the treatment. Improved patient motor skills, spatial learning performance, cognitive function, sensory perception, speech and/or a decrease in the propensity to seizure may also be used to measure the neuroprotective effect.
- Such functional/behavioral tests used to assess sensorimortor and reflex function are described in, for example, Bederson et al. (1986) Stroke 17:472-476, DeRyck et al. (1992) Brain Res. 573:44-60, Markgraf et al. (1992) Brain Res. 575:238-246, Alexis et al. (1995) Stroke 26:2336-2346; all of which are herein incorporated by reference.
- Enhancement of neuronal survival may also be measured using the Scandinavian Stroke Scale (SSS) or the Barthl Index. Behavioral recovery can be further assessed using the recommendations of the Subcommittee of the NIH/NINDS Head Injury Centers in Humans (Hannay et al. (1996) J. Head Trauma Rehabil. 11 :41-50), herein incorporated by reference. Behavioral recovery can be further assessed using the methods described in, for example, Beaumont et al. (1999) Neural Res. 21 :742-754; Becker et al. (1980) Brain Res. 200:07-320; Buresov et al. (1983) Techniques and Basic Experiments for the Study of Brain and Behavior; Kline et al.
- Assays that can be used to determine if the steroid analogue of the invention is imparting an anti-inflammatory and a nonspecific suppressive effect on the immune system following a traumatic CNS injury include, for example, a reduction in cytokine induced microglial proliferation in vitro (Hoffman et al. (1994) J. Neurotrauma 11 :417-31; Garcia- Estrada et al. (1993) Brain Res. 628:271-8; both of which are herein incorporated by reference); a reduction in the generation of cytotoxic free radicals by activated macrophages (Chao et al. (1994) Am. J. Reprod. Immunol. 32:43-52; Robert et al.
- a reduction in the inflammatory immune reactions following a traumatic brain injury can be assayed by measuring the cytokines level following the injury in the sham controls versus the progestin treated subjects.
- Cytokines are mediators of inflammation and are released in high concentrations after brain injury.
- the level of pro-inflammatory cytokines e.g., interleukin 1-beta, tumor necrosis factor, and interleukin 6
- the level of anti-inflammatory cytokines e.g., interleukin 10 and transforming growth factor-beta
- PCR polymerase chain reactions
- ELISA can be used to determine protein levels.
- histological analysis for different inflammatory cell types e.g., reactive astrocytes, macrophages and microglia
- histological analysis for different inflammatory cell types e.g., reactive astrocytes, macrophages and microglia
- a reduction in the inflammatory response e.g., reactive astrocytes, macrophages
- the compounds of the invention can also have potential for use in other disorders including multiple sclerosis, catamenial epilepsy, diabetic neuropathy, inflammatory disorders (e.g., rheumatoid arthritis, inflammatory bowel disease), hemorrhagic shock, Niemann-Pick disorder, cerebral palsy, and congenital heart disorders.
- inflammatory disorders e.g., rheumatoid arthritis, inflammatory bowel disease
- hemorrhagic shock e.g., rheumatoid arthritis, inflammatory bowel disease
- Niemann-Pick disorder e.g., rheumatoid arthritis, inflammatory bowel disease
- cerebral palsy e.g., cerebral palsy
- congenital heart disorders e.g., congenital heart disorders.
- a method of treatment or prevention of neural degeneration related to Amyotrophic Lateral Sclerosis comprising administering a steroid analog described herein, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a patient suffering from or at risk of suffering from ALS.
- ALS more commonly known as Lou Gehrig's Disease, strikes both males and females, typically between the ages of 40 and 70. This is a motor neuron disorder in which both the upper and lower motor neurons are affected. Patients' muscles atrophy as the motor neurons cease sending signals to initiate movement. This affects not only muscles required for locomotion but also the muscles used in swallowing. Up until the age of 60, males are disproportionally affected at a ratio of 1.5 to 1.
- a method of treatment or prevention of neural degeneration related to Parkinson's Disease comprising administering a steroid analog described herein, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a patient suffering from or at risk of suffering from PD.
- PD is a neurodegenerative disease of unknown etiology that results in the progressive loss of nerve cell function in the brain. Life expectancy is 15 - 25 years post-diagnosis; however, there is no cure. It is estimated that one million people in the U.S. are living with Parkinson's; a number that is greater than the combined total of multiple sclerosis, muscular dystrophy and amyotrophic lateral sclerosis patients. The incidence of PD increases with age.
- a method of treatment or prevention of neural degeneration related to spinal cord trauma comprising administering a steroid analog described herein, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a patient in need thereof.
- a method of treatment or prevention of neural degeneration related to hypoxia comprising administering a steroid analog described herein, or a pharmaceutically acceptable salt, ester or prodrug thereof, to a patient in need thereof.
- the steroid analogues of the invention may be administered in combination or alternation with at least one additional neuroprotective agent to enhance neuroprotection following a traumatic CNS injury.
- the inventive steroid analogues of the invention may be administered in combination or alternation with other steroid analogues or with progesterone.
- neuroprotective agents of interest include, for example, compounds that reduce glutamate excitotoxicity and enhance neuronal regeneration. Such agents may be selected from, but not limited to, the group comprising growth factors.
- growth factor refers to an extracellular polypeptide-signaling molecule that stimulates a cell to grow or proliferate. Preferred growth factors are those to which a broad range of cell types respond.
- neurotrophic growth factors include, but are no limited to, fibroblast growth factor family members such as basic fibroblast growth factor (bFGF) (Abraham et al. (1986) Science 233:545-48), acidic fibroblast growth factor (aFGF) (Jaye et al.
- Additional neuroprotective agents include, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF) (Seiler, M. (1984) Brain Research 300:33-39; Hagg T. et al. (1988) Exp Neural 101 :303-312; Kramer L. F. (1987) Science 235:214-216; and Hagg T. et al. (1990) J. Neurosci 10(9):3087-3092), brain derived neurotrophic factor (BDNF) (Kiprianova, I. et al. (1999) J. Neurosci. Res.
- CNTF ciliary neurotrophic factor
- NTF nerve growth factor
- BDNF brain derived neurotrophic factor
- Neurotrophin 3 Neurotrophin 3
- Neurotrophin 4 Neurotrophin 4
- TGF- ⁇ l transforming growth factor- ⁇ l
- BMP-2 bone morphogenic protein
- GDNF glial-cell line derived neurotrophic factor
- ADNF activity-dependant neurotrophic factor
- neuroprotective therapeutic agents include, for example, Clomethiazole (Zendra) (Marshal, J. W. et al. (1999) Exp. Neural. 156:121-9); kynurenic acid (KYNA) (Salvati, P. et al. (1999) Prog Neruopsychopharmacol Biol Psychiatry 23:741- 52), Semax (Miasoedova, N. F. et al. (1999) Zh Nevrol Psikhiatr Imss Korsakova 99:15-19), FK506 (tacrolimus) (Gold, B. G. et al. (1999) J. Pharmacol. Exp. Ther.
- MK-801 Barth, A. et al. (1996) Neuro Report 7:1461-4
- glutamate antagonist such as, NPS1506, GV1505260, MK801 (Baumgartner, W. A. et al. (1999) Ann Thorac Surg 67:1871-3), GV150526 (Dyker, A. G. et al. (1999) Stroke 30:986-92); AMPA antagonist such as NBQX (Baumgartner, W. A. (1999) et al. Ann Thorac Surg 67:1871-3, PD152247 (PNQX) (Schielke, G. P. et al.
- the steroid analogues of the present invention are administered in combination or alternation with other pharmaceutically active agents, (i.e., other neuroprotective agents) even less of the steroid analogue may be therapeutically effective.
- the steroid analogue may be administered once or several times a day.
- the duration of the treatment may be once per day for a period of from two to three weeks and may continue for a period of months or even years.
- the daily dose can be administered either by a single dose in the form of an individual dosage unit or several smaller dosage units or by multiple administration of subdivided dosages at certain intervals.
- a dosage unit can be administered from 0 hours to 1 hr, 1 hr to 24 hr or 24 hours to at least 100 hours post injury.
- the dosage unit can be administered from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or longer post injury.
- Subsequent dosage units can be administered any time following the initial administration such that a therapeutic effect is achieved.
- additional dosage units can be administered to protect the subject from the secondary wave of edema that may occur over the first several days post-injury.
- effective dosages of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially.
- the dosages will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It Dosage values will also vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
- compositions may be administered once or several times a day.
- the duration of the treatment may be once per day for a period of from two to three weeks and may continue for a period of months or even years.
- the daily dose can be administered either by a single dose in the form of an individual dosage unit or several smaller dosage units or by multiple administration of subdivided dosages at certain intervals.
- a dosage unit can be administered from 0 hours to 1 hr, 1 hr to 24 hr or 24 hours to at least 100 hours post injury.
- the dosage unit can be administered from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or longer post injury.
- Subsequent dosage units can be administered any time following the initial administration such that a therapeutic effect is achieved.
- additional dosage units can be administered to protect the subject from the secondary wave of edema that may occur over the first several days post-injury.
- the efficacy of a drug can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, agent.
- the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy.
- combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the condition.
- the active compound is administered in combination or alternation with one or more other non-steroidal anti-inflammatory drug(s) (NSAIDS).
- NSAIDS non-steroidal anti-inflammatory drug(s)
- NSAIDS non-steroidal anti-inflammatory drug(s)
- COX-2 cylcooxygenase-2
- Some nonlimiting examples of COX-2 inhibitors are Celebrex (celecoxib) and Vioxx (rofacoxib).
- NSAIDS are aspirin (acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate, salicylsalicylate), Trisilate (choline magnesium trisalicylate), sodium salicylate, Cuprimine (penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxen sodium), Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen), Daypro (oxaprozin), meclofenamate (meclofanamic acid, Meclomen), mefenamic acid, Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac, Butazolidin (phenylsalicylic
- the described compounds can be formulated as pharmaceutical compositions and administered for the treatment or prevention of CNS injury from trauma or disease, and in particular for injury resulting from traumatic brain injury or stroke.
- the compositions can be administered in any of a variety of forms adapted to the chosen route of administration, including systemically, such as orally, or parenterally, by intravenous, intramuscular, topical, transdermal or subcutaneous routes.
- the compound can be included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount of compound to treat traumatic CNS injury in vivo without causing serious toxic effects in the patient treated.
- the steroid analogues used in the methods of the invention may further comprise an inorganic or organic, solid or liquid, pharmaceutically acceptable carrier.
- the carrier may also contain preservatives, wetting agents, emulsifiers, solubilizing agents, stabilizing agents, buffers, solvents and salts.
- Compositions may be sterilized and exist as solids, particulants or powders, solutions, suspensions or emulsions.
- the steroid analogues can be formulated according to known methods to prepare pharmaceutically useful compositions, such as by admixture with a pharmaceutically acceptable carrier vehicle. Suitable vehicles and their formulation are described, for example, in Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005 (). In order to form a pharmaceutically acceptable composition suitable for effective administration, such compositions will contain an effective amount of the steroid analogue, either alone, or with a suitable amount of carrier vehicle.
- the pharmaceutically acceptable carrier of the present invention will vary depending on the method of drug administration.
- the pharmaceutical carrier employed may be, for example, either a solid, liquid, or time release.
- Representative solid carriers are lactose, terra alba, sucrose, talc, geletin, agar, pectin, acacia, magnesium stearate, stearic acid, microcrystalin cellulose, polymer hydrogels, and the like.
- Typical liquid carriers include syrup, peanut oil, olive oil, cyclodextrin, and the like emulsions.
- Those skilled in the art are familiar with appropriate carriers for each of the commonly utilized methods of administration.
- the total amount of steroid analogue administered as a therapeutic effective dose will depend on both the pharmaceutical composition being administered (i.e., the carrier being used) and the mode of administration.
- a steroid analogue, pharmaceutically acceptable salt, ester or prodrug thereof is administered via parenteral administration in a dose of about 0.1 ng to about 100 g per kg of body weight, about 10 ng to about 5O g per kg of body weight, from about 100 ng to about 1 g per kg of body weight, from about 1 ⁇ g to about 100 mg per kg of body weight, from about 1 ⁇ .g to about 50 mg per kg of body weight, from about 1 mg to about 500 mg per kg of body weight; and from about 1 mg to about 50 mg per kg of body weight.
- the amount of steroid analogue administered to achieve a therapeutic effective dose is about 0.1 ng, 1 ng, 10 ng, 100 ng, 1 ⁇ g, 10 ⁇ .g, 100 ⁇ g, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of body weight or greater.
- the compounds described herein are compounded with a suitable pharmaceutically acceptable carrier in a unit dosage form.
- a unit dosage form such as a preselected amount of liquid composition, can, for example, contain the compound in amounts ranging from about 5 to about 1000 mg, or from about 250 to about 750 mg. Expressed in proportions, the active compound is generally present in from about 10 to about 750 mg/ml of carrier.
- Liquid formulations of steroid analogs can comprise about 1-100 mg/ml of vehicle. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
- the active ingredients can exhibit activity, particularly in treatment or prevention of secondary reactions from brain injuries such as TBI or stroke when administered in amounts ranging from about 0.1 mg to about 100 mg per kilogram of body weight per day.
- a preferred dosage regimen for optimum results would be from about 0.5 mg to about 50 mg per kilogram of body weight per day, and such dosage units are employed that a total of from about 0.25 gram to about 3.0 grams of the active compound for a subject of about 70 kg of body weight are administered in a 24-hour period.
- This dosage regimen may be adjusted to provide the optimum therapeutic response and can be administered one to three times a day in dosages of about 600 mg per administration. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- the neuroprotective steroid is administered once or several times a day.
- the duration of the treatment may be once per day for a period of about 1 , 2, 3, 4, 5, 6, 7 days or more.
- the daily dose can be administered either by a single dose in the form of an individual dosage unit or several smaller dosage units or by multiple administration of subdivided dosages at certain intervals.
- a dosage unit can be administered from about 0 hours to about 1 hr, about 1 hr to about 24 hr, about 1 to about 72 hours, about 1 to about 120 hours, or about 24 hours to at least about 120 hours post injury.
- the dosage unit can be administered from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 40, 48, 72, 96, 120 hours or longer post injury.
- the duration of the constant dosing regimen is about 12, 24, 36, 60, 72, 84, or 120 hours or about 1 to 24 hours, about 12 to 36 hours, about 24 to 48 hours, about 36 to 60 hours, about 48 to 72 hours, about 60 to 96 hours, about 72 to 108 hours, about 96 to 120 hours, or about 108 to 136 hours.
- Subsequent dosage units can be administered any time following the initial administration such that a therapeutic effect is achieved.
- additional dosage units can be administered to protect the subject from the secondary wave of edema that may occur over the first several days post-injury.
- the subject undergoing the therapy with is administered a constant neuroprotective steroid dosing regimen.
- constant dosing regimen is intended the subject undergoing therapy is administered a constant total hourly infusion dose over the course of treatment.
- Administration of the steroid analogues of the invention may be performed by many methods known in the art.
- the present invention comprises all forms of dose administration including, but not limited to, systemic injection, parenteral administration, intravenous, intraperitoneal, intramuscular, transdermal, buccal, subcutaneous and intracerebroventricular administration.
- the steroid analogue may be administered directly into the brain or cerebrospinal fluid by any intracerebroventricular technique including, for example, lateral cerebro ventricular injection, lumbar puncture or a surgically inserted shunt into the cerebro ventricle of a patient.
- Methods of administering may be by dose or by control release vehicles.
- preferred carriers are physiological saline or phosphate buffered saline (PBS).
- Controlled release preparations may be achieved by the use of polymers to complex or absorb the steroid analogue.
- the controlled delivery may be exercised by selecting appropriate macromolecules (for example, polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene -vinylacetate, methylcellulose, carboxymethylcellulose, or protamine sulfate).
- the rate of drug release may also be controlled by altering the concentration of such macromolecules.
- Another possible method for controlling the duration of action comprises incorporating the therapeutic agents into particles of a polymeric substance such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers.
- a polymeric substance such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers.
- the compounds should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 ⁇ M, preferably about 1.0 to 10 ⁇ M. This may be achieved, for example, by the intravenous injection of an appropriate concentration of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.
- the concentration of the compounds in the drug composition will depend on absorption, inactivation and excretion rates of the extract as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the compounds may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
- Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal silicon dioxide
- the compounds can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
- a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
- the compounds can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories, or other anti-autoimmune compounds.
- Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the active compound, which can be isotonic with the blood of the recipient.
- Nasal spray formulations comprise purified aqueous solutions of the active agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.
- Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids.
- Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye.
- Topical formulations comprise the active compound dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical formulations.
- media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical formulations.
- the addition of other accessory ingredients as noted above may be desirable.
- the present invention provides liposomal formulations of the steroid analogues, salts, esters and prodrugs thereof.
- the technology for forming liposomal suspensions is well known in the art.
- the steroid analogue or salt thereof is an aqueous- soluble salt, using conventional liposome technology, the same may be incorporated into lipid vesicles. In such an instance, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic center or core of the liposomes.
- the lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol-free.
- the salt When the compound or salt of interest is water-insoluble, again employing conventional liposome formation technology, the salt may be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome. In either instance, the liposomes that are produced may be reduced in size, as through the use of standard sonication and homogenization techniques.
- the liposomal formulations containing the progesterone analogue or salts thereof, may be lyophilized to produce a lyophilizate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
- compositions are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of the desired steroid analogue or a salt thereof or a plurality of solid particles of the compound or salt.
- the desired formulation may be placed in a small chamber and nebulized. Nebulization may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts.
- the compounds are prepared with carriers that will protect them against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- a controlled release formulation including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- the ester bond may be formed by reaction of the hydroxyl group of 2 with a protected amino acid acyl halide, where X is chloro, bromo, iodo or fluoro.
- the ester bond may be formed by reacting the hydroxyl group with an activated carboxylic acid, where X is an activated leaving group.
- X is an activated leaving group.
- Many reagents are known that will activate carboxyl groups to react with nucleophiles.
- a variety of peptide coupling reagents well known in the art are used to activate carboxyl groups in-situ to react with amino groups of amino acids to form peptide bonds.
- reagents can also activate carboxylic acids to form reactive intermediates that will react with hydroxy groups on the steroid compound.
- carboxyl activating groups include carbodiimide reagents, phosphonium reagents such as benzotriazolyloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP) and the like, uronium or carbonium reagents such as O-(benzotriazol-l-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol- 1 -yl-oxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like; l-ethoxycarbonyl-2-ethoxy-l,2-dihydroqunoline (EEDQ); l-methyl-2-chloropyridinium iodide (M
- the ester may be formed by trans-esterification of another ester group including active esters such as a /?-nitrophenyl ester, a pentafluorophenylester, an N- hydroxysuccinimidyl ester, a 1-hydroxybenzotriazolyl ester and the like.
- An acyl azide group may also be used to form the ester bond.
- the ester may also be formed by reaction of the hydroxy with a symmetric or mixed anhydride (X is RC(O)O-). Catalysts such as 4-dimethylaminopyridine (DMAP) and the like may be used to facilitate the ester formation.
- DMAP 4-dimethylaminopyridine
- Scheme 2 illustrates the general synthetic process for the formation of steroid analogues that comprise amino acid residues at the 20-position of the ring.
- progesterone is reduced to the diol using a strong reducing reagent, such as lithium aluminum hydride.
- the allylic hydroxyl group is then selectively oxidized to produce the enone 4, with the C-20 hydroxyl group intact.
- Any suitable oxidizing agent that will selectively oxidize an allylic alcohol may be used.
- One non-limiting example is manganese dioxide (MnO 2 ).
- MnO 2 manganese dioxide
- the resulting alcohol 3 is then esterif ⁇ ed to produce the desired steroid analogue 5 comprising an amino acid residue at the 20-position.
- the esterification reaction may be accomplished with a variety of reagents, including a protected amino acid halide or with a protected amino acid using a coupling reagent known in the art to activate carboxylate groups.
- the C20 carbonyl is first protected with a suitable protecting group such as the cyclic ketal 6 to prevent reaction with the nucleophilic hydroxylamine.
- the remaining enone is reacted with hydroxylamine to produce a mixture of E/Z 7a and 7b.
- the E-oxime 7a is then esterified with a suitably protected amino acid halide or using a protected amino acid with a coupling reagent as described above for Scheme 1 to produce the E-isomer of protected analogue 8a.
- R amino acid side chain
- P amino protecting group
- X leaving group
- the C-3 carbonyl is reacted with hydrazine to produce the hydrazone 10.
- the hydrazone is then reacted with a suitable reactive amino acid derivative as described above for Scheme 1 to yield the hydrazide 11.
- the hydrazide may be converted to a pharmaceutically acceptable salt by treatment with a pharmaceutically acceptable acid, such as HCl.
- Scheme 5 shows the preparation of allopregnanolone (ALLO) analogues substituted at C-3 with an amino acid residue.
- ALLO allopregnanolone
- Pregnenolone is first reduced with hydrogen catalyzed by palladium on carbon to produce compound 12 in the 3-beta, 5-alpha configuration.
- Compound 12 is then esterified as described for Scheme 1 above with a reactive protected amino acid reagent followed by deprotection to produce compound 13 substituted at the C-3 position with an amino acid residue.
- the HCl salt is formed by treatment with HCl as before.
- R amino acid side chain
- P protecting group
- X leaving group 3-alpha,5-alpha 15
- Scheme 6 shows a general process for the preparation of C-3 substituted pregnanolone analogues in different stereoisomeric configurations.
- reduction of the enone with hydrogen under palladium on carbon forms compound 16.
- Esterif ⁇ cation of alcohols 17a and 17b followed by removal of the protecting group and salt formation provides pregnanolone analogues 18a and 18b.
- Steroid analogues with a double bond between the C5 and C6 positions may be prepared according to the general process shown in Scheme 7 below.
- Scheme 7 pregnenolone separable E and Z isomers 21a 21a
- Esterif ⁇ cation of pregnenolone with a suitably protected amino acid as described for scheme 1 above provides compound 19, with an amino acid residue at the 3-position. Protection of the hydroxyl of pregnenolone followed by reaction with hydroxylamine provides the E- and Z-isomers 20a and 20 b. If desired, the isomers may be separated at this stage. Reaction of 20a and 20b with a suitably protected amino acid, followed by deprotection and treatment with HCl provides compounds 21a and 21b.
- the invention provides enantiomeric progesterone and neuroprotective steroid compounds.
- the enantiomer of progesterone (ent-PROG) has shown similar efficacy to progesterone and allopregnanolone across several measures relevant to neuroprotection, including the reduction of cerebral edema, reduction of pro-inflammatory cytokine expression, and reduction in proapoptotic p53 protein expression.
- Ent-PROG treatment was also shown to result in significantly increased glutathione reductase activity, a measure of its potential to minimize oxidative stress following TBI, relative to both progesterone and allopregnanolone.
- a well established whole animal model of TBI was employed in order to investigate the potential efficacy of the PROG analogue compounds relative to PROG in reducing cerebral edema following injury.
- Anesthetized male rats were first subjected to cortical contusion and were then given two 8 mg/kg doses of the test compound, the first at 1 h post- surgery and the second at 6 h.
- the animals were then sacrificed and tissue samples were taken from both injured and non-injured sections of the brain. Wet and dry weights were collected for each sample and cerebral edema (% water content) was determined as the difference in wet and dry weights divided by the wet weight.
- a “% mean difference” value could then be calculated based on the relative edema difference between injured and non- injured tissue samples for a given animal.
- the "sham” animals did not receive an injury but served as a control group for possible anesthesia and stress factors.
- the "vehicle” group were subjected to cortical injury but received only the drug carrier (22.5% 2-hydroxypropyl- ⁇ - cyclodextrine in water). All experimental treatments given by injection were made in stock solutions using 2-Hydroxypropyl-b-cyclodextrin (HBC; 45% w/v solution in H 2 O) as the solvent. These experimental solutions were then diluted 1 :1 with sterile water for a final concentration of HBC of 22.5%.
- HBC 2-Hydroxypropyl-b-cyclodextrin
- Figure 1 shows the % difference edema results for brain tissue 24 hours post brain injury.
- the mean % difference calculated for sham, vehicle, progesterone, Compound 31 , Compound 57 and Compound 79 subjects were 0.6%, 1.2%, 2.0%, 2.2%, 3.3% and 1.9%, respectively.
- Example 2 Preparation of Compounds General Experimental
- dichloromethane (DCM), diethyl ether (ether), water (DI), hexane (hex), ethyl acetate (ea), dimethylformamide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), round bottomed flask (RBF), hours (h), minutes (min), millimole (mmol), equivalents (eq).
- Reaction progress was monitored via thin-layer chromatography (TLC) on pre-coated glass-backed plates (silica gel 60 A F254, 0.25 mm thickness) purchased from EM Science. Flash chromatography was carried out with silica gel 60 A (230 - 400 mesh) from Sorbent Technologies.
- PROG and ALLO are used for progesterone and allopregnanolone, respectively.
- Scheme 13 below depicts the synthesis of various C3 amino acid derivatives of the invention, along with representative reaction conditions and reagents.
- 3- ⁇ -L-Valine-progesterone (3a) A 25 mL RBF was charged with 0.340 g (0.533 mmol) compound 3a. The flask was evacuated and inert gas flushed and 5 mL each of acetonitrile and dimethylformamide were added. A 0.527 mL (5.33 mmol, 10.0 eq) volume of piperidine was added and the clear colorless solution was stirred at room temperature for 30 min. The solvent was removed with addition of toluene for complete removal of DMF. A white solid formed that was redissolved in a minimum amount of toluene and loaded neat onto a 12 g silica column and eluted with 0-75% ea in hexanes.
- the solution was stirred at 0 0 C for an additional 1 h.
- the reaction was diluted with 50 mL ether and washed with saturated sodium bicarbonate solution (3 X 25 mL).
- the aqueous layers were combined and extracted with ether.
- the organic layers were combined, dried, filtered, and concentrated to give a pale orange oil.
- the oil was loaded onto a 40 g silica column in a minimum amount of DCM and eluted with 0-25% ea in hex over 35 min. Main peak fractions were combined and concentrated to give a clear oil that crystallized on standing. Crude wet mass was 0.820 g.
- the reaction was stirred at room temperature for 36 h.
- the solution was quenched and washed with saturated amnmonium chloride solution (2 X 20 mL).
- the aqueous layers were combined and extracted with DCM.
- the organic layers were combined, washed with brine, dried, filtered, and concentrated.
- the clear oil was loaded in a minimum amount of DCM. onto a 12 g silica column and eluted with a 0- 15% ea in hex gradient over 45 minutes.
- the desired product was obtained as 0.193 g (96%) white foam.
- Scheme 15 describes the synthesis of C20 valine derivative Pl-57 with representative reagents and conditions. This procedure may be used to prepare C20 derivatives of other amino acid using the same or alternate reagents.
- the silica cake was was eluted with 0-75% ethyl acetate in hexanes over 45 minutes on a 12 g silica column. Main product containing fractions were combined and concentrated to give a white solid. The solid was recrystallized from hexanes/ethyl acetate to give 0.097 g (40%) white powdery solid.
- Scheme 15 depicts the synthesis of P 1-79, a C20 tryptophan oxime derivative. Similar reagents and conditions may be used to prepare C20 oxime derivatives.
- the recovered oil was re-dissolved in DCM and prepared as a silica cake with 0.750 g silica.
- the cake was eluted on a 12 g silica column with a 0-35% EA in hex gradient over 45 minutes.
- the main product was recovered as 0.245 g (99%) waxy off-white solid.
- the oil was loaded neat with minimum DCM rinse onto a 12 g silica column and eluted with 0-80% ea in hexane over 40 min. Main product containing fractions were combined and concentrated by rotary evaporation at 10 0 C. After being brought to complete dryness and re-dissolved in 10 mL ethyl acetate, the sample was concentrated and dried under high vacuum while being chilled in an ice bath. Anhydrous ether (7-8 mL) was added and the clear colorless solution was allowed to cool to 0 0 C. HCl ether solution (0.195 mL, 2.0 M. 1.0 eq) was added dropwise to the rapidly stirring solution. A white precipitate was observed.
- the crude mixture (assumed to be 5.00 mmol), was dissolved in anhydrous DCM and added with JV-Fmoc-L-valine (1.87 g, 5.50 mmol, 1.10 eq) and DMAP (0.0611 g, 0.500 mmol, 0.100 eq) to a 250 mL RBF under argon. After complete dissolution of the reaction components, DCC (5.50 mL 1 M soln. in DCM, 5.50 mmol, 1.10 eq) was added. After stirring overnight, the mixture was filtered through Celite.
- the filtrate was concentrated and prepared as a silica cake that was eluted on a 120 g silica column with 0-45% EA in hex over 45 min. Main peak containing fractions were combined and concentrated to give 1.91 g (55%) off- white solid that was a ⁇ 2:1 mixture of the two main products.
- the sample was loaded in a minimum amount of DCM onto a 12 g silica column and eluted with 0-5 % MeOH in DCM over 35 mm (initial 5 mm 100% DCM). Main peak containing fractions were combined and concentrated to give 0.079 g (92%) clear oil.
- An oven dried 25 mL RBF was charged with oxime 11 (0.187 g, 0.500 mmol), JV-Fmoc-L-tryptophan (0.242 g, 0.22 mmol, 1.05 eq), and DMAP (0.0061 g, 0.021 mmol, 0.10 eq).
- the flask was sealed, evacuated, and inert gas flushed and 15 mL anhydrous dichloromethane was added, followed after complete dissolution by addition of 0.550 mL (0.23 mmol, 1.10 eq) 1 M DCC in dichloromethane.
- the solution was stirred for 16 h at room temperature.
- the mixture was filtered through Celite, the filtrates concentrated, and the crude oil loaded as a silica cake onto 1.17 g silica.
- the cake was eluted on a 40 g silica column in 0-35% ea in hex over 90 minutes.
- the main product peak was isolated as 0.383 g (98%) white foam.
- the crude off-white solid was redissolved in a minimum amount of DCM, loaded neat onto a 12 g silica column, and eluted with a 0-95% ea in hex gradient over 60 min.
- the main product was obtained as 0.120 g (61%) off-white solid.
- the solid was recrystallized from hexane/ethyl acetate ( ⁇ 3:1 total 175 mL) to give 3.19 g white solid.
- a second recrystallization provided an additional 0.43 g for a total of 3.62 g (90%) white crystalline solid.
- the mixture was filtered through Celite and rinsed with DCM.
- the sample was prepared as a silica cake and eluted on a 40 g silica column with 0- 25% ea in hex over 45 min. Main product containing fractions were combined and isolated as 0.578 g (90%) white foam.
- the solid was prepared as a silica cake and eluted with 0-35% ea in hex on a 120 g silica column over 40 min. Main product containing fractions were combined and concentrated to give 1.46 g (92%) white solid.
- the mixture was filtered through Celite and rinsed with DCM. Silica ( ⁇ 3 g) was added and the mixture was concentrated. The silica cake was eluted on a 40 g silica column with 0-25% ea in hex over 45 min. The main product was isolated as 0.834 g (87%) white foam.
- Scheme 17 shows the synthesis of 5 ⁇ ALLO isomers 17a and 17b and C3 valine derivatives of the isomers.
- the isomers 17a and 17b were separated by conventional chromatography and carried forward as described above to prepare the valine derivatives Pl- 133 and Pl -135.
- Derivatives with other amino acids may be prepared from compounds 17a and 17b using similar reagents and conditions.
- the flask was stirred at room temperature for 24 h.
- the mixture was filtered through Celite and rinsed with DCM.
- the filtrate was concentrated with 2 g silica and the silica cake was eluted on a 40 g silica column with 0-25% ea in hex over 45 min.
- the main product was recovered as 0.541 g (81%) white foam.
- the mixture was concentrated with 1.5 g silica, and the silica cake was eluted on a 40 g silica column with 0-25% ea in hex over 45 min.
- the main product was isolated as 0.345 g (73%) white foam.
- Table 2 shows the effect of several compounds of the invention compared with PROG and ALLO in the reduction in cortical neuron cell death caused by glutamate toxicity.
- Several of the derivatives proved to be significantly more potent than PROG or ALLO when the compounds are compared at the 5 ⁇ M concentration.
- the Pl -185 and Pl-186 oxime prodrug compounds achieved the highest levels of cell survival among the compounds screeened.
- the C-20 reduced PROG derivative Pl-57 and the ent-PROG derivative P2-13 also showed significant reductions in cell death.
- the compounds were intravenously (IV) dosed at 10 mg/kg and serum samples were taken at several time points over the course of 12 h. Serum concentration levels were determined for the analogues, as well as for their respective parent compound.
- the derivatives Pl-31 and Pl-33 behaved very similarly in vivo ( Figure 7).
- the amino acid side chain in both compounds was cleaved almost immediately to give rapid conversion to their mutual parent, the C-3- ⁇ -hydroxy compound 3.
- the valine tethered compound was stable for a prolonged period of time and only gradually converted to its parent, ALLO (2, Figure4).
- ALLO 2, Figure4
- the oxime based compound Pl-186 did indeed generate PROG in vivo when dosed either IV or intraperitoneally (IP) at 10 mg/kg (Figure 5).
- the PROG levels observed via both modes of administration reached a maximum of approximately 100 ng/mL, which compares favorably to a previously reported maximum serum concentration of 28 ng/mL when PROG was administered IP at 4 mg/kg to male rats (Wright et al., J. Neurotrama, 2001, 18, 901-094).
- the amino acid tether of compound Pl-186 is readily cleaved to give primarily the parent oxime P2-02 ( Figure 8), which is stable in vivo for several hours.
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
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- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
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Abstract
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Claims
Priority Applications (6)
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AU2009219230A AU2009219230A1 (en) | 2008-02-26 | 2009-02-26 | Steroid analogues for neuroprotection |
EP09715569A EP2260052A4 (en) | 2008-02-26 | 2009-02-26 | Steroid analogues for neuroprotection |
CA2716095A CA2716095C (en) | 2008-02-26 | 2009-02-26 | Steroid analogues for neuroprotection |
US12/918,036 US9527881B2 (en) | 2008-02-26 | 2009-02-26 | Steroid analogues for neuroprotection |
US15/355,416 US20170065615A1 (en) | 2008-02-26 | 2016-11-18 | Steroid Analogues for Neuroprotection |
US15/945,678 US10716795B2 (en) | 2008-02-26 | 2018-04-04 | Steroid analogues for neuroprotection |
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US3156708P | 2008-02-26 | 2008-02-26 | |
US3162908P | 2008-02-26 | 2008-02-26 | |
US61/031,629 | 2008-02-26 | ||
US61/031,567 | 2008-02-26 | ||
US3231508P | 2008-02-28 | 2008-02-28 | |
US61/032,315 | 2008-02-28 | ||
US14881109P | 2009-01-30 | 2009-01-30 | |
US61/148,811 | 2009-01-30 |
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US12/918,036 A-371-Of-International US9527881B2 (en) | 2008-02-26 | 2009-02-26 | Steroid analogues for neuroprotection |
US15/355,416 Division US20170065615A1 (en) | 2008-02-26 | 2016-11-18 | Steroid Analogues for Neuroprotection |
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WO2009108804A2 true WO2009108804A2 (en) | 2009-09-03 |
WO2009108804A3 WO2009108804A3 (en) | 2009-12-10 |
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PCT/US2009/035336 WO2009108804A2 (en) | 2008-02-26 | 2009-02-26 | Steroid analogues for neuroprotection |
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US (3) | US9527881B2 (en) |
EP (1) | EP2260052A4 (en) |
AU (1) | AU2009219230A1 (en) |
CA (2) | CA2716095C (en) |
WO (1) | WO2009108804A2 (en) |
Cited By (21)
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- 2009-02-26 WO PCT/US2009/035336 patent/WO2009108804A2/en active Application Filing
- 2009-02-26 CA CA2716095A patent/CA2716095C/en active Active
- 2009-02-26 EP EP09715569A patent/EP2260052A4/en not_active Withdrawn
- 2009-02-26 CA CA2955684A patent/CA2955684A1/en not_active Abandoned
- 2009-02-26 AU AU2009219230A patent/AU2009219230A1/en not_active Abandoned
- 2009-02-26 US US12/918,036 patent/US9527881B2/en active Active
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2016
- 2016-11-18 US US15/355,416 patent/US20170065615A1/en not_active Abandoned
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2018
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Also Published As
Publication number | Publication date |
---|---|
EP2260052A4 (en) | 2013-01-16 |
US20110263553A1 (en) | 2011-10-27 |
US20180221390A1 (en) | 2018-08-09 |
US9527881B2 (en) | 2016-12-27 |
US20170065615A1 (en) | 2017-03-09 |
US10716795B2 (en) | 2020-07-21 |
AU2009219230A1 (en) | 2009-09-03 |
WO2009108804A3 (en) | 2009-12-10 |
CA2716095A1 (en) | 2009-09-03 |
CA2716095C (en) | 2017-02-07 |
EP2260052A2 (en) | 2010-12-15 |
CA2955684A1 (en) | 2009-09-03 |
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