Organic compound

Abstract

The present invention relates to certain prodrugs and analogs of (3α,5α)-3-hydroxy-21-(1H-imidazol-1-yl)-3-methoxymethyl)-pregnan-20-one in free or pharmaceutically acceptable salt and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use as sedatives, hypnotics, anxiolytics and / or anesthetics, and for the treatment of depression, anxiety, insomnia, epilepsy and other central nervous system disorders, and in combination with other drugs.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 62 / 780,703, filed December 17, 2018, the contents of which are incorporated herein by reference in their entirety. FIELD OF THEINVENTION The present invention relates to certain prodrugs and analogs of (3α,5α)-3-hydroxy-21-(1H-imidazol-1-yl)-3-methoxymethyl)-pregnan-20-one in free or pharma- ceutically acceptable salt and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use as sedatives, hypnotics, anxiolytics and / or anesthetics, and methods of treating depression, anxiety, insomnia, epilepsy and other central nervous system disorders, and in combination with other drugs. [Background technology]

[0002] Brain excitability, defined as the level of arousal of an animal on a continuum from coma to seizures, is regulated by various neurotransmitters that generally serve to regulate the conductance of ions across neuronal membranes.

[0003] Up to 40% of neurons in the brain utilize gamma-aminobutyric acid (GABA) as a neurotransmitter, so the neurotransmitter GABA has a profound effect on excitability throughout the brain. GABA interacts with the GABA receptor complex (GRC) to mediate its effects on neurons throughout the nervous system, including the brain. GABA regulates the excitability of individual neurons by regulating the transmissibility of chloride ions across the neuronal membrane. GABA interacts with recognition sites on the GRC to facilitate the flow of chloride ions down the electrochemical gradient of the GRC into the cell. An intracellular increase in the level of this anion causes hyperpolarization of the membrane potential, making the neuron less susceptible to excitatory inputs; that is, reducing the excitability of the neuron. In other words, the higher the chloride ion concentration in neurons, the lower the level of brain excitability and arousal.

[0004] GRC plays an important role in mediating anxiety, seizure activity, depression and sedation. As a result, GABA and drugs that act like GABA and enhance the effects of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) produce therapeutically useful effects by interacting with specific regulatory sites in GRC. Accumulating evidence now indicates that in addition to the binding sites for benzodiazepines and barbiturates, GRC contains separate sites for neuroactive steroids.

[0005] Neuroactive steroids occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α,21-dihydroxy-5-reduced pregnan-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. As described in U.S. Patent Application Publication No. 2017 / 0240589 (incorporated herein by reference in its entirety), several recent clinical observations suggest an important role for progesterone and deoxycorticosterone and their metabolites in the homeostatic control of brain excitability. This is manifested, for example, in increased seizure activity or symptoms associated with catamenial epilepsy, PMS and PND, and in the correlation of reduced levels of progesterone with symptoms associated with PMS, PND and catamenial epilepsy. However, progesterone is not consistently effective in treating the aforementioned syndromes. Natural neuroactive metabolites of progesterone include pregnanolone and allopregnanolone, and these metabolites may mediate at least some of the effects of progesterone and deoxycorticosterone.

[0006] Naturally occurring neuroactive steroids are generally unsuitable as pharmacological agents because of their short half-lives and poor oral bioavailability, likely due to rapid metabolism. One such steroid is allopregnanolone. [ka] It is an endogenous neuroactive steroid that exhibits promising pharmacological activity, but suffers from poor oral bioavailability and a short half-life. Nevertheless, allopregnanolone is being explored for the intravenous treatment of epilepsy, depression and other CNS disorders.

[0007] There is a need for new and improved neuroactive steroids that act as modulators of brain excitability, such as sedatives, hypnotics and anxiolytics, as well as drugs for the prevention or treatment of CNS-related diseases.

[0008] Synthetic and semi-synthetic neuroactive steroids are known in the art and have been investigated as potential CNS drugs.

[0009] The addition of 3β substitutions has been shown to result in neuroactive steroids with potent oral activity but undesirably long half-lives. For example, sedative / hypnotics preferably have an excretion half-life of less than 5 hours in humans to avoid next-day residual effects and accumulation with continued nighttime administration. It has previously been discovered that 3β-methoxymethyl substituted steroids maintain the desirable oral activity of other 3β-substituted neuroactive steroids but have a sustained action that makes them useful as sedative / hypnotics and anesthetics. Such compounds are disclosed, for example, in U.S. Patent Nos. 5,939,545 and 6,277,838.

[0010] 3α-Hydroxy-3β-methoxymethyl-21-(1H-imidazol-1-yl)-5α-pregnan-20-one is a synthetic neuroactive steroid. Its primary molecular target is the synthesis of γ-aminobutyric acid type A (GABA A ) receptor and acts as a positive allosteric modulator of GRC channel function. ALike other classes of modulators, neuroactive steroids have many potential indications, such as for the treatment of sleep disorders, anxiety, depression, and epilepsy. The compounds are disclosed, for example, in U.S. Patent Application Publication Nos. 2004 / 0034002 and 2009 / 0131383, the contents of which are incorporated herein by reference in their entireties.

[0011] Clinical trials suggest that 3α-hydroxy-3β-methoxymethyl-21-(1H-imidazol-1-yl)-5α-pregnan-20-one has the following pharmacokinetic properties in humans after oral administration: (1) rapid absorption with a Tmax of about 1 to about 3 hours; (2) variable Cmax levels between subjects; (3) Cmax values ​​that are more than proportional to dose; and (4) a T1 / 2 value of about 12 hours averaged across five different dose groups. See Table I below. Pharmacokinetic parameters, such as AUC, Cmax, and Tmax, refer to mean values. Values ​​shown in parentheses correspond to standard deviations. [Table 1]

[0012] However, it would be beneficial to develop derivatives of 3α-hydroxy-3β-methoxymethyl-21-(1H-imidazol-1-yl)-5α-pregnan-20-one that have improved pharmacokinetic properties, such as improved distribution, higher resistance to metabolic degradation, and / or improved bioavailability. Summary of the Invention

[0013] The compound of formula A, having the chemical name 2-(1H-imidazol-1-yl)-1-((3S,5S,8R,9S,10S,13S,14S,17S)-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, and the common name 3α-hydroxy-3β-methoxymethyl-21-(1H-imidazol-1-yl)-5α-pregnan-20-one, is a potent GABA inhibitor.A It is a positive allosteric modulator of the receptors. The compound can also interact with acetylcholine receptors and 5-HT3 serotonin receptors. [ka] Formula A Although the compounds of formula A are useful as sedatives / hypnotics or anesthetics and for treating or preventing central nervous system disorders, there is a need in the art for analogs, such as isotopic analogs, and prodrugs of the compounds of formula A that can provide improved therapeutic concentrations or improved pharmacokinetic distribution or dynamics of these compounds when administered to a patient. This is met by the present disclosure by providing compounds of formula I et seq., which are deuterated analogs and / or prodrugs of the compounds of formula A. Due to their useful metabolic and pharmacokinetic profiles, the compounds of the present disclosure may be particularly suitable for formulation as long-acting or sustained release compositions that provide improved therapeutic concentrations of compound A and its analogs over time when administered to a patient.

[0014] In a first aspect, the disclosure provides a compound of formula I: [ka] Formula I [In the formula, X is H, -(C=O)-R a , -CH2-(C=O)-OR a and -CH2-(C=O)-N(R a )(R b ) selected; R 1 is selected from CH3, CDH2, CD2H, and CD3; R 2 From R 9 each is independently selected from H and D; R a and R b However, independently, H, C 1-20Alkyl (e.g., methyl), and C 1-4 alkyl-aryl (e.g. benzyl); However, R 1 is CH3 and R 2 From R 9 are all H, X is -(C=O)-R a , -CH2-(C=O)-OR a and -CH2-(C=O)-N(R a )(R b ) selected from The present invention provides a compound (Compound 1) represented by the formula:

[0015] In a second aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula I et seq. in admixture with a pharma- ceutically acceptable diluent or carrier.

[0016] In a third aspect, the present disclosure provides a GABA A Receptor modulators (e.g. GABA A The present invention provides a method for the treatment or prevention of a central nervous system disorder suitable for amelioration with a positive allosteric modulator of the central nervous system receptor, the method comprising administering a compound of formula I or a pharmaceutical composition thereof to a patient in need thereof.

[0017] In a fourth aspect, the disclosure provides a method of inducing sedation or anesthesia in a patient in need thereof, comprising administering a compound of formula I or a pharmaceutical composition thereof to a patient in need thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] In a first aspect, the disclosure provides a compound of formula I: [ka] Formula I [In the formula, X is H, -(C=O)-R a, -CH2-(C=O)-OR a and -CH2-(C=O)-N(R a )(R b ) selected; R 1 is selected from CH3, CDH2, CD2H, and CD3; R 2 From R 9 each is independently selected from H and D; R a and R b However, independently, H, C 1-20 Alkyl (e.g., methyl), and C 1-4 alkyl-aryl (e.g. benzyl); However, R 1 is CH3 and R 2 From R 9 are all H, X is -(C=O)-R a , -CH2-(C=O)-OR a and -CH2-(C=O)-N(R a )(R b ) selected from The present invention provides a compound (Compound 1) represented by the formula:

[0019] The present disclosure relates to 1.1 Compound I, wherein X is H; 1.2 X is -(C=O)-R a , -CH2-(C=O)-OR a , and -CH2-(C=O)-N(R a )(R b Compound I, selected from 1.3 X is -(C=O)-R a Compound I; 1.4 X is -CH2-(C=O)-OR a Compound I; 1.5 X is CH2-(C=O)-N(R a )(R b ), Compound I; 1.6 R a is H; 1.7 Ra C 1-20 Alkyl (e.g. methyl) or C 1-4 any of compounds I or 1.1-1.5, which is alkyl-aryl (e.g., benzyl); 1.8 R a C 1-20 any of compounds I or 1.1-1.5, which is alkyl (e.g., methyl); 1.9 R a C 1-4 any of compounds I or 1.1-1.5, which is alkyl-aryl (e.g., benzyl); 1.10 R a is methyl; 1.11 R a is benzyl; 1.12 X is CH2-(C=O)-N(R a )(R b ) and R b is H; 1.13 R 1 is CH3; any of compounds I or 1.1-1.12; 1.14 R 1 is CDH2, CD2H, or CD3; 1.15 R 1 is CD3, or any of compounds I or 1.1 to 1.12; 1.16 R 2 From R 9 Any of compounds 1.1 to 1.15, wherein all of are H; 1.17 R 2 From R 9 Any of compounds 1.1 to 1.15, wherein any one of is D; 1.18 R 2 From R 9 Any of compounds 1.1 to 1.15, wherein any two of are D; 1.19 R 2 From R 9 Any of compounds 1.1 to 1.15, in which any three of are D; 1.20 R 2 From R 9 Any of compounds 1.1 to 1.15, wherein any four of are D; 1.21 R 2 and R 3 Any of compounds 1.1 to 1.20, wherein is D; 1.22 R 5 From R 6 Any of compounds 1.1 to 1.21, wherein is D; 1.23 R 7 From R 9 any of compounds 1.1 to 1.22, in which any one, two or three are D; 1.24 A compound is [ka] [ka] Compound I or any of 1.1 to 1.23 selected from the group consisting of: 1.25 Compound I or any of 1.1-1.24, in free form (free base form); 1.26 Compound I or any of 1.1-1.24, in salt form, e.g., a pharma- ceutically acceptable salt form (e.g., the hydrochloride salt); 1.27 Compound I or any of 1.1-1.24, in solid form; 1.28 Compound I or any of 1.1-1.27, in substantially pure diastereomeric form (i.e., substantially free of other diastereomers); 1.29 Compound I or any of 1.1-1.28 having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; 1.30 Compound I or any of 1.1-1.28, which incorporates greater than 50% deuterium (i.e., greater than 50 atomic % D) at one or more specified positions in the structure, e.g., greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98% or greater than 99%; 1.31 Compound I or any of 1.1-1.30, in isolated or purified form. Further exemplary embodiments of compounds of formula I, in free or salt form, for example isolated or purified free or salt form, are provided, including:

[0020] In a second aspect, the disclosure provides a pharmaceutical composition (Pharmaceutical Composition 2) comprising a compound of formula I, e.g., any of compounds 1 or 1.1-1.31, e.g., in admixture with a pharma- ceutical acceptable diluent or carrier. 2.1 Pharmaceutical composition 2, wherein the compound of formula I et seq. is in solid form; 2.2 Pharmaceutical composition 2 or 2.1, wherein the composition is an immediate release composition; 2.3 Pharmaceutical composition 2 or 2.1, wherein the composition is a delayed release composition; 2.4 Pharmaceutical composition 2 or 2.1, wherein the composition is a sustained release composition; 2.5 Any of Pharmaceutical Compositions 2 or 2.1-2.4, wherein the composition is an oral dosage form (e.g., a tablet or capsule); 2.6 Pharmaceutical composition 2.5, wherein the composition is a sublingual, buccal and / or orally dissolving tablet; 2.7 Any of Pharmaceutical Compositions 2 or 2.1-2.4, wherein the composition is an injectable composition (e.g., formulated for intravenous, subcutaneous, or intramuscular injection); 2.8 Pharmaceutical composition 2.7, wherein the composition is a sustained release injectable composition (e.g., a depot formulation, e.g., formulated as a long-acting injectable for intramuscular or subcutaneous injection); 2.9 Any of Pharmaceutical Compositions 2 or 2.1-2.4, wherein the composition is a transmucosal composition, e.g., a buccal, sublingual, intranasal or pulmonary aerosol composition; 2.10 Any of Pharmaceutical Compositions 2 or 2.1-2.4, wherein the composition is an ophthalmic composition, e.g., a topical or intraocular injectable composition; 2.11 Pharmaceutical composition 2 or any of 2.1 to 2.10, wherein the compound of formula I or later is in a polymer matrix. A further exemplary embodiment of Pharmaceutical Composition 2 is provided, comprising:

[0021] Pharmaceutical Composition 2 onwards includes all compositions in which the compounds of the present invention are contained in an amount effective to achieve its intended purpose. While individual needs vary, determining the optimal range of effective amounts of each component is within the skill of the art. Typically, the compounds may be orally administered to a mammal, such as a human, at a dose of 0.0025-50 mg / kg per day of body weight of the mammal undergoing treatment for insomnia, or the equivalent of a pharma- ceutical acceptable salt thereof. For intramuscular injection, the dose is generally about half of the oral dose.

[0022] A unit oral dose may contain from about 0.01 to about 50 mg, preferably from about 0.1 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets, each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or a salt thereof.

[0023] The pharmaceutical composition of the present invention can be administered by any means that achieves its intended purpose.For example, administration can be parenteral, sublingual, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, transdermal or buccal.Alternatively or simultaneously, administration can be oral.The dose administered depends on the age, health and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment and the nature of the desired effect.

[0024] Therapeutic plasma levels for Compound 1 and thereafter can range from about 5 ng / mL to about 500 ng / mL. Other effective therapeutic ranges include about 50 ng / mL to about 500 ng / mL, about 50 ng / mL to about 400 ng / mL, about 50 ng / mL to about 325 ng / mL, about 50 ng / mL to about 250 ng / mL, about 50 ng / mL to about 100 ng / mL, and about 100 ng / mL to about 250 ng / mL.

[0025] In some embodiments, the pharmaceutical compositions of the present disclosure are injectable compositions for sustained or delayed release, such as depot formulations.

[0026] In some embodiments, the pharmaceutical composition comprises a compound of formula 1 or later in a polymer matrix. In one embodiment, the compound of the present disclosure is dispersed or dissolved in the polymer matrix. In a further embodiment, the polymer matrix comprises a polymer selected from standard polymers used in depot formulations, such as polyesters of hydroxy fatty acids and their derivatives, or polymers of alkyl alpha-cyanoacrylates, polyalkylene oxalates, polyorthoesters, polycarbonates, polyortho-carbonates, polyamino acids, hyaluronic acid esters and mixtures thereof. In a further embodiment, the polymer is selected from the group consisting of polylactic acid, poly d,l-lactic acid, polyglycolic acid, PLGA50:50, PLGA65:35, PLGA75:25, PLGA85:15 and PLGA90:10 polymers. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers thereof, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers such as albumin, casein, and waxes, such as glycerol mono- and distearate. In a preferred embodiment, the polymer matrix comprises poly(d,l-lactic acid-glycolic acid copolymers).

[0027] (Pharmaceutical) compositions 3 and 3.1-3.4 are particularly useful for sustained or delayed release, where the compound of the present disclosure is released upon degradation of the polymer matrix. These compositions can be formulated (e.g., as a depot composition) for controlled and / or sustained release of the compound of the present disclosure for up to 180 days, such as from about 14 to about 30 to about 180 days. For example, the polymer matrix can degrade and release the compound of the present disclosure for about 30, about 60, or about 90 days. In another example, the polymer matrix can degrade and release the compound of the present disclosure for about 120 or about 180 days.

[0028] In yet another embodiment, the pharmaceutical compositions of the present disclosure, such as the depot compositions of the present disclosure, are formulated for administration by injection.

[0029] In a third aspect, the present disclosure provides a GABA A Receptor modulators (e.g. GABA A In yet another embodiment, the disclosure provides a method for the treatment or prevention of a central nervous system disorder amenable to amelioration with a positive allosteric modulator of a central nervous system receptor, the method comprising administering to a patient in need thereof a compound of formula I, e.g., any of compounds 1 or 1.1-1.31, or a pharmaceutical composition thereof, e.g., any of compositions 2 or 2.1-2.11 (Method 3). In further embodiments, the disclosure provides: 3.1 Method 3 comprising administering any of Compounds 1 or 1.1-1.31 in free or pharma- ceutically acceptable salt form; 3.2 Method 3 comprising administering any of pharmaceutical compositions 2 or 2.1 to 2.11; 3.3 Central nervous system disorders caused by GABA A any of Method 3 or Methods 3.1-3.2, suitable for treatment with a positive allosteric modulator of the receptor; 3.4 The central nervous system disorder is sleep disorder (e.g., insomnia), circadian rhythm disorder, phase shift disorder (e.g., jet lag), anxiety (including generalized anxiety, social anxiety, and panic disorder), post-traumatic stress disorder, depression (e.g., treatment-refractory depression, major depressive disorder, bipolar depression, postpartum depression, seasonal affective disorder, dysthymia, treatment-resistant depression, suicidal thoughts or behavior, and premenstrual dysphoric disorder), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder), schizophrenia, schizoaffective disorder, attention disorder, harm (e.g. attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD)), seizure disorders (e.g. seizure disorders, epilepsy or status epilepticus, e.g. early status epilepticus, established status epilepticus, refractory status epilepticus, super refractory status epilepticus, and non-convulsive status epilepticus, e.g. generalized status epilepticus and complex partial status epilepticus), aggression disorders (e.g. acute or chronic aggression), agitation disorders (e.g. acute or chronic agitation), memory and / or cognition disorders disorders (e.g. neurodegenerative disorders, Alzheimer's disease, aging, Lewy body dementia, vascular dementia), movement disorders (e.g. Parkinson's disease, Huntington's disease, tremors), autism and autism spectrum disorders (e.g. Asperger's syndrome), pain disorders (e.g. neuropathic pain, acute pain, chronic pain), personality disorders (e.g. antisocial personality disorder, depressive personality disorder), vascular disorders (e.g. stroke, ischemia, vascular malformations), eating disorders (e.g. overeating Method 3.3, wherein the disorder is selected from the group consisting of: anxiety disorder, anorexia, binge eating disorder, cachexia), traumatic brain injury, substance abuse disorder, substance use disorder, substance withdrawal syndrome, Rett syndrome, fragile X syndrome, Angelman syndrome, and tinnitus, and neurodegenerative diseases (e.g., Alzheimer's, amyotrophic lateral sclerosis, coma, dementia, Parkinson's disease, Huntington's disease, dyskinesia, dystonia); and any disorder requiring sedation or sensory deprivation for effective treatment; 3.5 Method 3.4, wherein the central nervous system disorder is selected from the group consisting of sleep disorders (e.g., insomnia), anxiety (including generalized anxiety, social anxiety and panic disorder), post-traumatic stress disorder, depression (e.g., treatment-resistant depression, major depressive disorder, bipolar depression, postpartum depression), and convulsive disorders (e.g., seizure disorders, epilepsy or status epilepticus); 3.6 Method 3.5, wherein the central nervous system disorder is selected from the group consisting of sleep disorders (e.g., insomnia), anxiety (including generalized anxiety, social anxiety and panic disorder), depression (e.g., treatment-resistant depression, major depressive disorder, bipolar depression, postpartum depression), and convulsive disorders (e.g., seizure disorders, epilepsy or status epilepticus); 3.7 Any of Methods 3 or 3.1-3.6, wherein the compound or composition is administered orally; 3.8 Method 3.7, wherein the composition administered is a solid oral dosage form (e.g., a tablet or capsule); 3.9 Method 3.7, wherein the solid oral dosage form is a sublingual or buccal orally dissolving tablet; 3.10 Any of Methods 3 or 3.1-3.6, wherein the compound or composition is administered, e.g., in the form of an aerosol, by intranasal or pulmonary inhalation; 3.11 Any of Methods 3 or 3.1-3.6, wherein the compound or composition is administered ophthalmically, e.g., as a topical eye drop; 3.12 Any of Methods 3.7-3.11, wherein the compound or composition is administered three times per day, twice per day, or once per day; 3.13 Any of Methods 3 or 3.1-3.6, wherein the compound or composition is administered by injection, e.g., intravenous, subcutaneous, intraocular, intraperitoneal or intramuscular injection; 3.14 Method 3.13, wherein the compound or composition is administered as a long-acting injectable composition, e.g., a depot formulation; 3.15 Methods 3.13 or 3.14, wherein the injection is administered once a day or once every two days or once every 3-7 days or once a week or once every 1-4 weeks or once a month.

[0030] GABA in the present disclosure A Other diseases and disorders suitable for treatment with the modulators are disclosed and described in U.S. Patent Application Publication No. 2017 / 0240589, the contents of which are incorporated herein by reference in their entirety.

[0031] The compounds of the invention described herein are generally designed to modulate GABA function and therefore act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or enhancement of GABA receptor function, particularly the inhibition of GABA receptor function. A It refers to the positive allosteric modulation (enhancement) of receptor function. Thus, the compounds and pharmaceutical compositions provided herein have utility as therapeutics for preventing and / or treating CNS conditions in mammals, including humans and non-human mammals. Thus, as stated above, the present invention is within its scope and extends to the described treatment methods, as well as compounds for such methods, and the use of such compounds for the manufacture of medicaments useful for such methods.

[0032] In another embodiment, the disclosure provides any of Methods 3.1-3.15 comprising administration of a pharmaceutical composition 2 or any of 2.1-2.11, which is formulated for delayed and / or sustained release of a compound of the invention over about 14 days, over about 30 to about 180 days, preferably over about 30, about 60 or about 90 days. Controlled and / or sustained release is particularly useful to avoid premature cessation of treatment, especially drug treatment, where non-compliance or non-adherence to dosing regimens commonly occurs.

[0033] In yet another embodiment, the present invention provides Methods 3 or 3.1-3.15 above, comprising administration of a pharmaceutical composition, wherein a depot composition of the disclosure is administered for controlled and / or sustained release of a compound of the present invention over a period of time.

[0034] In a fourth aspect, the disclosure provides a method of inducing sedation or anesthesia in a patient in need thereof (Method 4), comprising administering to a patient in need thereof a compound of formula I, e.g., Compound 1 or any of 1.1-1.31, or a pharmaceutical composition thereof, e.g., Compositions 2 or any of 2.1-2.11. In further embodiments, the fourth aspect provides: 4.1 Method 4, wherein the dose administered is effective to produce sedation and / or anesthesia in the patient within 2 hours of administration, e.g., within 1 hour of administration; 4.2 Method 4, wherein the dose administered is effective to produce sedation and / or anesthesia in the patient within 45 minutes of administration, e.g., within 30 minutes, within 20 minutes, or within 10 minutes of administration; 4.3 Method 4, wherein the administered dose is effective to produce sedation and / or anesthesia in the patient within 5 minutes of administration, e.g., within minutes, within 2 minutes, or within 1 minute of administration; 4.4 Any of Methods 4 or 4.1-4.3, wherein the sedation and / or anesthesia provided by a single dose has a duration of 1 hour to 24 hours, e.g., 1 hour to 12 hours, 1 hour to 6 hours, 1 hour to 4 hours, or 1 hour to 2 hours; 4.5 Any of Methods 4 or 4.1-4.4, wherein the compound or composition is administered orally; 4.6 Method 4.5, wherein the composition administered is a solid oral dosage form (e.g., a tablet or capsule); 4.7 Method 4.6, wherein the solid oral dosage form is a sublingual or buccal orally dissolving tablet; 4.8 Any of Methods 4 or 4.1-4.4, wherein the compound or composition is administered, e.g., in the form of an aerosol, by intranasal or pulmonary inhalation; 4.9 Any of Methods 4 or 4.1-4.4, wherein the compound or composition is administered by injection, for example, intravenous, subcutaneous, intraperitoneal or intramuscular injection.

[0035] The compounds of the present disclosure, pharmaceutical compositions of the present disclosure, or depot compositions of the present disclosure may be combined with a second therapeutic agent, particularly at lower dosages than when the individual drugs are used as monotherapy, to enhance the therapeutic activity of the combined drugs without causing undesirable side effects that normally occur in conventional monotherapy. Thus, the compounds of the present disclosure may be administered simultaneously, sequentially, or contemporaneously with one or more antidepressants, antipsychotics, sedative / hypnotics (e.g., benzodiazepines, antiepileptics, substance abuse medications (e.g., methadone, naloxone), and / or drugs used to treat Parkinson's disease or mood disorders. In another example, side effects may be reduced or minimized by administering the compounds of the present disclosure in free or salt form in combination with one or more second therapeutic agents, where the dosage of (i) the second therapeutic agent or (ii) both the compounds of the present disclosure and the second therapeutic agent is lower than when the drugs / compounds are administered as monotherapy.

[0036] Thus, in some embodiments, the disclosure provides methods that further include administering to the patient one or more therapeutic agents, wherein the one or more therapeutic agents are compounds that modulate GABA activity (e.g., enhance activity and facilitate GABA transmission), GABA-B agonists, 5-HT receptor modulators (e.g., 5-HT 1A Agonist, 5-HT 2A Antagonist, 5-HT 2Ainverse agonists, serotonin reuptake inhibitors, melatonin receptor agonists, ion channel modulators (e.g., blockers), serotonin-2 antagonists / reuptake inhibitors (compounds that have both 5-HT2 antagonism and serotonin reuptake inhibition, i.e., SARIs), orexin receptor antagonists, H3 agonists or antagonists, noradrenergic agonists or antagonists, galanin agonists, CRH antagonists, human growth hormone, growth hormone agonists In some embodiments, the method further comprises administering to the patient a therapeutically effective amount of a steroid, an opiate, an estrogen, an estrogen agonist, another neuroactive steroid, a progesterone or progesterone metabolite, a neurokinin-1 drug, an antidepressant, an opiate agonist and / or an opiate partial agonist (e.g., a μ-, κ-, or δ-opiate receptor agonist or partial agonist), a nociceptin agonist, and an antipsychotic, e.g., an atypical antipsychotic. In some embodiments, such drugs include an inhibitor of drug metabolism, such as a reductase inhibitor, an oxidoreductase inhibitor, or a cytochrome oxidase (CYP enzyme) inhibitor, which serves to reduce the rate of metabolism of the compound of the present disclosure that is administered. For example, such drugs may include inhibitors of ketone reductases and steroid hydrogenases (e.g., 20α-hydroxysteroid hydrogenase or 20β-hydroxysteroid hydrogenase). In addition to inhibitors of such reductases, oxidoreductases and hydrogenases, such inhibitors of drug metabolism may also include competitive substrates of these enzymes.

[0037] In some embodiments, the combination of the compound of the present disclosure and one or more second therapeutic agents can be administered to patients as the pharmaceutical composition or depot composition.Combination compositions can include the mixture of combined drugs, as well as two or more separate compositions of drugs, where each composition can be co-administered to patients, for example, together.

[0038] In a fifth aspect, the disclosure discloses the use of a compound of Formula I, compound 1 or any of 1-1.31, or a pharmaceutical composition thereof, e.g., composition 2 or any of 2.1-2.11, in the manufacture of a medicament for the treatment or prevention of one or more of the disorders described above, e.g., method 3 or any of methods 3.1-3.15, or for the induction of sedation or anesthesia, e.g., method 4 or any of 4.1-4.9, or any of the other methods of embodiments described herein.

[0039] In a sixth aspect, the disclosure provides for the use of a compound of formula I, e.g., compound 1 or any of 1-1.31, or a pharmaceutical composition thereof, e.g., composition 2 or any of 2.1-2.11, in the treatment or prevention of one or more of the disorders described above, e.g., method 3 or any of methods 3.1-3.15, or in the induction of sedation or anesthesia, e.g., method 4 or any of 4.1-4.9, or any of the other methods of the embodiments described herein.

[0040] Without being bound by theory, the present invention relates to compound A: [ka] Formula A The present invention provides compounds which specifically limit, slow, alter and / or prevent the metabolism that has been found to occur in animals and / or humans treated with compounds such as ribozymes.

[0041] deuterium( 2 The chemical and physical properties of the H atom, such as its electronic charge, electronic volume, polarity, and electronic valence, are similar to those of a normal hydrogen atom ( 1Because deuterium is very similar to protium (H), drug compounds with hydrogen substitutions of deuterium are generally expected to have similar biological activity as non-deuterated analogs, but may have improved pharmacokinetic properties. It is particularly important that deuterium atoms have roughly twice the atomic mass of protium atoms, but similar spatial volume and charge distribution, where these latter factors are important for binding to biomolecules. The improved pharmacokinetic properties arise from the much stronger bond strength of CD bonds compared to HD bonds, and therefore the higher energy barrier to D / H abstraction during enzymatic (metabolic) reactions (kinetic isotope effect). The extent to which such substitutions result in improved pharmacokinetic properties without too severe a loss of pharmacological activity is variable. Thus, in some situations the resulting deuterated compounds show only a moderate increase in pharmacokinetic stability, while in other situations the resulting deuterated compounds may have a significant improvement in metabolic stability. Furthermore, the effects of simultaneous deuterium substitutions may be difficult to predict with certainty. They may or may not result in additive (synergistic) improvements in metabolic stability.

[0042] Although many deuterated pharmaceutical compounds have been proposed and investigated to date, only one deuterated pharmaceutical compound has been approved by the U.S. Food and Drug Administration: deutetrabenazine (Teva Pharmaceuticals, April 2017), a deuterated form of the Huntington's disease drug tetrabenazine, which has a therapeutically useful longer half-life than its non-deuterated counterpart.

[0043] In some embodiments, the present disclosure provides compounds containing deuterium atoms at certain selected positions in the structure of the compound of formula A. These specific deuterations are expected to have an effect on the metabolic degradation and clearance of the compounds due to their association with enzymatic pathways that the inventors have determined are likely to affect these compounds. Thus, these novel compounds are expected to exhibit substantially the same pharmacological activity as the compound of formula A, while also unexpectedly improving metabolic stability and pharmacokinetic properties.

[0044] In other embodiments, the present disclosure provides compounds that are analogs of compounds of formula A with biologically labile functional groups arranged within the compound such that natural metabolic activity removes the labile functional groups and results in compounds of formula A in vivo. Thus, administration of some compounds of the present disclosure to a patient in need thereof results in both immediate and delayed release of compounds of formula A into the tissues of the human. Such compounds of the present disclosure have significant pharmacological activity in themselves, but act as reservoirs of pharmacologically active compounds of formula A. Thus, compounds of the present disclosure are particularly suitable for formulation as long-acting injectables (LAI) or "depot" pharmaceutical compositions. Without wishing to be bound by theory, an injected "depot" containing a compound of the present disclosure slowly releases the compound into body tissues, where it is slowly metabolized to produce compounds of formula A. Such depot formulations can be further tailored by the selection of suitable ingredients to control the rate of dissolution and release of the compounds of the present disclosure.

[0045] As used herein, unless otherwise specified, "alkyl" refers to a saturated or unsaturated hydrocarbon moiety, e.g., from 1 to 21 carbon atoms in length; any such alkyl may be straight or branched chain (e.g., n-butyl or tert-butyl), and is preferably straight chain, unless otherwise specified. For example, "C 1-21 "Alkyl" means an alkyl having 1 to 21 carbon atoms. In one embodiment, the alkyl is selected from the group consisting of one or more hydroxyl or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group. In another embodiment, the alkyl is preferably linear, optionally saturated or unsaturated, and contains 1 to 21 carbon atoms, e.g., in some embodiments where R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, 16 to 21 carbon atoms, e.g., together with the -C(O)- to which it is attached, e.g., when cleaved from the compound of formula I, forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.

[0046] The term "D" or "deuterium" refers to the hydrogen atom 2 H isotope. The natural abundance of the two stable isotopes of hydrogen is about 99.98% protium ( 1 H) and 0.02% deuterium ( 2 H). Thus, on average, any hydrogen atom in a molecule synthesized using common reagents has about 0.02% deuterium at every hydrogen atom position. Thus, as described herein, one skilled in the art will understand that when referring to a chemical structure having a CD bond or a "D" atom, this means that the position of the molecule is enriched to have more than the natural 0.02% abundance of deuterium. Thus, the label "D" in a molecule refers to, for example, at least 0.1% deuterium, or at least 1% deuterium, or at least 10% deuterium. Preferably, any compound according to the present disclosure incorporates more than 50% deuterium (i.e., more than 50 atomic % D) at each designated "D" atom position of the compound structure, for example, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99%.

[0047] The term "pharmaceutical acceptable diluents or carriers" is intended to mean diluents and carriers that are useful in pharmaceutical formulations and that do not contain substances that are allergenic, pyrogenic or pathogenic, and substances known to potentially cause or promote disease. Thus, pharmaceutical acceptable diluents or carriers exclude bodily fluids, such as blood, urine, cerebrospinal fluid, saliva, and the like, and components thereof, such as blood cells and circulating proteins. Suitable pharma- ceutically acceptable diluents and carriers can be found in any of a number of well-known texts on pharmaceutical formulations, such as Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0048] The terms "purified," "in purified form," and "in isolated and purified form" with respect to a compound refer to the physical state of the compound after it has been isolated from a synthetic process (e.g., a reaction mixture) or a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," and "in isolated and purified form" with respect to a compound refer to the physical state of the compound after it has been obtained from a purification process or a process described herein or known to one of skill in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques, etc.) of sufficient purity to be characterized by standard analytical techniques described herein or known to one of skill in the art.

[0049] Unless otherwise specified, the compounds of the present disclosure, such as compounds I or 1.1-1.31, can exist in the free or salt form, such as an acid addition salt. An acid addition salt of a compound of the present invention that is sufficiently basic is, for example, an acid addition salt with an inorganic or organic acid, such as hydrochloric acid.

[0050] The compounds of the present disclosure are intended for use as pharmaceuticals, and therefore pharma- ceutically acceptable salts are preferred. Salts not suitable for pharmaceutical use may be useful, for example, in isolating or purifying the free compounds of the present invention, and therefore are included within the scope of the compounds of the present disclosure.

[0051] The compounds of the present disclosure may contain one or more chiral carbon atoms. Thus, the compounds exist in individual isomers, such as enantiomeric or diastereomeric forms, or as mixtures of individual forms, such as racemic / diastereomeric mixtures. Any isomers in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration may exist. It should be understood that the present invention encompasses both individual optically active isomers and mixtures thereof (e.g., racemic / diastereomeric mixtures). Thus, the compounds of the present invention may be racemic mixtures, or may be, for example, predominantly pure or substantially pure isomeric forms, such as, for example, greater than 70% enantiomeric / diastereomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, and most preferably greater than % ee. Purification of the isomers and separation of the isomeric mixtures may be achieved by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed, etc.).

[0052] Geometric isomers, by the nature of substituents on double bonds or rings, may be cis (Z) or trans (E) forms and both isomers are encompassed within the scope of the present invention.

[0053] The compounds of the present disclosure are also intended to include stable or unstable isotopes. Stable isotopes are non-radioactive isotopes that contain one additional neutron compared to the same abundant nuclide (i.e., element). The activity of compounds containing such isotopes is retained, and such compounds are also expected to have utility for measuring the pharmacokinetics of non-isotopic analogs. For example, hydrogen atoms at certain positions of the compounds of the present disclosure can be replaced with deuterium (a non-radioactive stable isotope). Examples of known stable isotopes include deuterium, 13 C. 15 N, 18 Alternatively, unstable isotopes, which are radioactive isotopes that contain additional neutrons compared to the homogeneous abundant nuclide (i.e., element), e.g., 123 I, 131 I, 125 I, 11 C.18 F may be replaced by the corresponding abundant species of I, C, and F. Another example of a useful isotope of the compounds of the invention is: 11 C isotope. These radioisotopes are useful for radioimaging and / or pharmacokinetic studies of the compounds of the invention.

[0054] Thus, in addition to the deuteration specifically provided by the scope of the compounds of formula I, the present disclosure also provides compounds in which one or more carbon, nitrogen or oxygen atoms are substituted with a stable or unstable isotope, e.g., 11 C. 13 C. 15 N, 18 O. 18 F), and one or more hydrogen atoms have been replaced by tritium ( 3 H). These compounds are useful, for example, for purposes of structure determination (e.g., by nuclear magnetic resonance or mass spectrometry) and radioimaging studies to elucidate metabolic and excretion pathways and measure clearance of potential drug candidates.

[0055] Polymers useful for the polymeric matrix in the compositions of the invention (e.g., depot compositions of the invention) may include polyesters of hydroxy fatty acids and their derivatives, or other chemicals such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers, or polyglycolic acid-polyethylene glycol copolymers), alkyl α-cyanoacrylates (e.g., poly(butyl 2-cyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyortho-carbonates, polyamino acids (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid, or poly-y-methyl-L-glutamic acid), hyaluronic acid esters, and the like, one or more of which may be used.

[0056] In a preferred embodiment, the polymer matrix of the present invention is biocompatible and biodegradable. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not induce significant inflammation in body tissues. The matrix material should be biodegradable, where the polymeric material should be broken down by internal processes into products that can be easily excreted by the body and should not accumulate in the body. The products of biodegradation should also be biocompatible with the body in that the polymeric matrix is ​​biocompatible with the body.

[0057] The terms "disease," "disorder," and "condition" are used interchangeably and are not intended to be interpreted separately.

[0058] A "therapeutically effective amount" is an amount of a compound of the invention (e.g., as contained in a pharmaceutical depot) that, when administered to a subject suffering from a disease or disorder, is effective to cause relief, remission or regression of the disease or disorder over the time period contemplated for treatment.

[0059] Dosages used in the practice of the present invention will, of course, vary depending, for example, on the particular disease or condition to be treated, the particular compound of the invention being used, and the desired therapy. Unless otherwise specified, amounts of the compounds of the invention for administration (administered as free base or salt form) refer to or are based on the amount of the compound of the invention in free base form (i.e., amount calculations are based on the amount of free base).

[0060] The compound of the present invention can be administered by any suitable route, including oral, subcutaneous, parenteral (intravenous, intramuscular, intranasal or subcutaneous) or transdermal, but is preferably administered orally.In certain embodiments, the compound of the present invention is, for example, in a depot preparation, and is preferably administered parenterally, for example by injection.

[0061] Pharmaceutically acceptable salts of the compounds of the present disclosure can be synthesized from the parent compound containing a basic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid in water or an organic solvent or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0062] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared using conventional diluents or additives (such as, but not limited to, sesame oil) and techniques known in the galenic art. Thus, oral dosage forms can include tablets, capsules, solutions, suspensions, and the like.

[0063] Methods for the synthesis of compounds of Formula A, including intermediates, are disclosed in U.S. Patent Application Publication Nos. 2004 / 0034002 and 2009 / 0131383, the contents of which are incorporated herein by reference in their entireties.

[0064] Other essential core compounds of the present disclosure may be prepared by analogous procedures disclosed in the above publications and known to those skilled in the art. Specific deuterated compounds of the present disclosure may generally be prepared by analogous means by substituting commercially available deuterated reagents for non-deuterated reagents, if such reagents are available.

[0065] The diastereomers of the compounds of the present invention can be isolated or purified by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving bed technology, and the like.

[0066] The diastereomers of the produced compounds can be separated by HPLC using a Chiralpak® AY-H (5μ, 30×250 mm) at room temperature and eluted with 10% ethanol / 90% hexane / 0.1% dimethylethylamine. Peaks can be detected at 230 nm to produce diastereomers with 98-99.9% ee.

[0067] 3α-Hydroxy-3β-methoxymethyl-5α-pregnan-20-one is a GABA derivative that has been reported in Hogenkamp, ​​et al., "Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones: Allosteric Modulators of the GABA receptor." A21-Substituted steroids can be prepared from the corresponding 21-bromo steroids, which are synthesized from the 20-keto steroids using Br2 in MeOH with catalytic HBr. Other sources of useful synthetic methods include Botella et al., J. Med Chem., 48: 3500-3511 (2015); Botella et al., J. Med Chem., 60: 7810-7819 (2017); Wong et al., Steroids 71: 77-82 (2006); Botella et al., WO 2016 / 061527; Hogenkamp, ​​Derek L., WO 2000 / 66614; Goliber et al., US 2006 / 0074059; Chang et al., WO 2005 / 105822; Woodward, Richard M., WO 2006 / 131392, the contents of each of which are incorporated herein by reference in their entirety. Generally speaking, the compounds of the present disclosure can be prepared according to methods known in the art starting from the widely known compound 3α-hydroxy-5α-pregnan-2-one and its diastereomers.

[0068] For example, this compound can be prepared according to the following scheme of Wong et al.: [ka] EXAMPLES

[0069] Example 1: Synthesis of 3α-hydroxy-21-(1′-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one (compound of formula A) [ka] Step 1: 21-Bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one To a solution of 3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one (30.0 g, 82.9 mmol) in 900 mL of methanol is added 3 drops of 48% aqueous HBr while stirring at room temperature. Bromine (13.9 g, 87.1 mmol) is then added dropwise as a solution in 200 mL of methanol over 2 h while the reaction is protected from light. After TLC (1% acetone / methylene chloride) indicates the absence of starting material and the formation of a less polar product, the reaction is concentrated to approximately 300 mL. CHCl (400 mL) is then added and the reaction is poured into a separatory funnel containing 200 mL of water. The phases are separated and the aqueous phase is extracted with CHCl (3×100 mL). The organic phases are combined, washed with 200 mL of saturated aqueous NaHCO, dried over NaSO, and concentrated under reduced pressure to give the bromide as a pale yellow foam. No further purification is necessary.

[0070] Step 2: 3α-hydroxy-21-(1'-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one To a suspension of the bromide prepared above (36.7 g, 82.9 mmol) in 800 mL of CH3CN is added imidazole (28.2 g, 415 mmol) and the reaction is heated to reflux under argon. The reaction is complete after 1 h at reflux (TLC, 95:4.5:0.5 CH2Cl2:MeOH:triethylamine (TEA)). The reaction is cooled to room temperature and then concentrated in vacuo. The resulting oil is dissolved in 600 mL of CHCl2, washed with dilute NaHCO3 solution (4 x 200 mL), dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 95:4.5:0.5 CH2Cl2:MeOH:TEA gives the title compound 18 g as a white solid, mp 185-187 °C (vacuum capillary). 1H NMR (300 MHz, CDCl3) δ7.40 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 4.72 (d, 1H, J=17.7 Hz), 4.64 (d, 1H, J=18 Hz), 3.39 (s, 3H), 3.18 (s, 2H), 2.57 (t, 1H, J=8.7 Hz), 0.76 (s, 3H), 0.66 (s, 3H).

[0071] Example 2: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl-d3)ethan-1-one [ka] To a solution of imidazole-d4 (0.193 g, 2.72 mmol, 3.0 equiv) in THF (2 mL) at 0° C. is added lithium hydride (0.0237 g, 2.8 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. 21-Bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one (0.40 g, 0.906 mmol, 1.0 equiv) in THF (2.5 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with methanol in an ice bath. The organic layer is separated and concentrated under reduced pressure. The residue is further purified by column chromatography to give the pure title compound (0.184 g, 0.426 mmol) as a white powder in 50% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 4.86 - 4.60 (m, 2H), 3.41 (s, 3H), 3.20 (s, 2H), 2.60 (t, J = 8.9 Hz, 1H), 2.31 - 2.12 (m, 1H), 2.06 - 1.90 (m, 1H), 1.84 - 1.66 (m, 4H), 1.66 - 1.13 (m, 12H), 1.63-1.51 (m, 3H) 1.00 (m, 1H), 0.87 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0072] Example 3: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl)ethan-1-one [ka] Step 1: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane]-17-yl)ethan-1-one

[0073] A slurry solution of trimethylsulfoxonium iodide (2.09 g, 9.5 mmol) and potassium tert-butoxide (1.134 g, 10.01 mmol) in DMSO (30.0 mL) is heated at 60° C. for 1 h under Ar. 5α-pregnane-3,20-dione (2.0 g, 6.3 mmol) is added to the reaction mixture and stirred at room temperature overnight. After completion of the reaction, the reaction mixture is quenched and precipitated with water (30 mL) in an ice bath. The resulting precipitate is collected by filtration and washed with water (50 mL×2). The residue is further purified by recrystallization from MeOH / acetone (4 / 1) followed by drying the solid under vacuum overnight to give the pure final product (1.83 g, 5.54 mmol) as a white powder in 87% yield. 1H NMR (500 MHz, chloroform-d) δ 2.64 (d, J = 1.4 Hz, 2H), 2.56 (t, J = 8.9 Hz, 1H), 2.25 - 2.15 (m, 1H), 2.14 (s, 3H), 2.11 - 1.99 (m, 2H), 1.89 (t, J = 14.0, 13.1 Hz, 1H), 1.79 - 1.60 (m, 6H), 1.60 - 1.51 (m, 1H), 1.50 - 1.05 (m, 9H), 1.06 - 0.94 (m, 2H), 0.90 (s, 3H), 0.63 (s, 3H).

[0074] Step 2: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)ethan-1-one-2,2,2-d3

[0075] Sodium hydroxide (0.916 g, 22.9 mmol) is dissolved in methanol-d4 (40 mL) and heated to reflux under Ar for 30 min. The compound from step 1 (3.8 g, 11.4 mmol) is slowly added to the methanol solution at room temperature under Ar and the solution is heated at 40° C. overnight. The reaction mixture is quenched and precipitated with water (65 mL) in an ice bath. The resulting precipitate is filtered and washed with water (25 mL×2). The solid cake is further purified by recrystallization from ethyl acetate / hexane (1 / 1) and dried under vacuum to give the pure product (3.15 g, 8.52 mmol) as a white powder in 74% yield. 1 H NMR (500 MHz, chloroform-d) δ 3.20 (s, 2H), 2.26 - 2.13 (m, 1H), 2.04 - 1.95 (m, 1H), 1.80 - 1.51 (m, 8H), 1.52 - 1.12 (m, 12H), 0.98 (m 1H), 0.85 (m, 1H), 0.77 (s, 3H), 0.62 (s, 3H).

[0076] Step 3: 2-Bromo-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)ethan-1-one-2,2-d2

[0077] To a solution of compound of step 2 (3.11 g, 8.41 mmol) in MeOH (30 mL), add 3 drops of aqueous HBr (48%). Bromine (0.485 mL, 8.88 mmol) is dissolved in MeOH (20 mL) and added dropwise to the reaction mixture in the dark. After completion of the reaction, the reaction mixture is quenched with water (100 mL). Ethyl acetate (30 ml x 3) is added to extract the final product, the organic phases are combined and washed again with water (20 mL x 2). The solvent is evaporated and dried under vacuum overnight to give pure 7 (3.67 g, 8.20 mmol) as a white powder in 97% yield. 1 H NMR (500 MHz, chloroform-d) δ 3.20 (s, 2H), 2.19 (t, J = 10.8 Hz, 0H), 1.92 (ddd, J = 11.9, 4.1, 2.9 Hz, 1H), 1.79 - 1.51 (m, 7H), 1.51 - 1.15 (m, 12H), 1.06 - 0.93 (m, 1H), 0.89 - 0.80 (m, 1H), 0.77 (s, 3H), 0.65 (s, 3H).

[0078] Step 4: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl)ethan-1-one

[0079] To a solution of imidazole (0.274 g, 4.03 mmol, 3.0 equiv) in THF (2 mL) is added lithium hydride (0.035 g, 4.17 mmol, 3.1 equiv). The solution is heated to reflux under Ar for 30 min. The compound from step 3 (0.6 g, 1.34 mmol, 1.0 equiv) in THF (4 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with methanol in an ice bath. The solvent is evaporated and purified by column chromatography to give the title compound (0.12 g, 0.277 mmol) as a white powder in 21% isolated yield. 1 H NMR (500 MHz, chloroform-d) δ 7.39 (s, 1H), 7.13 (s, 1H), 6.88 (s, 1H), 4.93 - 4.56 (m, 2H), 3.20 (s, 1H), 2.60 (t, J = 8.8 Hz, 1H), 2.33 - 2.12 (m, 1H), 1.98 (dt, J = 11.8, 3.3 Hz, 1H), 1.83 - 1.66 (m, 4H), 1.63 - 1.54 (m, 4H), 1.51 - 1.13 (m, 12H), 1.07 - 0.94 (m, 1H), 0.91 - 0.82 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0080] Example 4: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl-d3)ethan-1-one [ka] To a solution of imidazole-d4 (0.291 g, 4.03 mmol, 3.0 equiv) in THF (2 mL) is added lithium hydride (0.035 g, 4.17 mmol, 3.1 equiv). The solution is heated to reflux under Ar for 30 min. The compound of Example 3, step 3 (0.6 g, 1.34 mmol, 1.0 equiv) in THF (4 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with methanol in an ice bath. The solvent is evaporated and purified by column chromatography to give the pure title compound (0.07 g, 0.016 mmol) as a white powder in 12% isolated yield. 1 H NMR (500 MHz, chloroform-d) δ 3.20 (s, 2H), 2.60 (t, J = 8.9 Hz, 1H), 2.31 - 2.15 (m, 1H), 2.08 - 1.90 (m, 1H), 1.82 - 1.66 (m, 4H), 1.64 - 1.14 (m, 15H), 1.08 - 0.93 (m, 1H), 0.92 - 0.83 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0081] Example 5: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)-2-(1H-imidazol-1-yl)ethan-1-one-2-d [ka] To a solution of imidazole (0.161 g, 2.37 mmol, 3.0 equiv) in THF (2 mL) is added lithium hydride (0.021 g, 2.45 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 3, step 3 (0.353 g, 0.79 mmol, 1.0 equiv) in THF (2.5 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with D2O (1.5 mL) in an ice bath. The solvent is evaporated and purified by column chromatography to give the pure title compound (0.097 g, 0.253 mmol) as a white powder in 29% isolated yield. 1 H NMR (500 MHz, chloroform-d) δ 7.56 (s, 1H), 7.14 (s, 1H), 7.04 - 6.84 (m, 1H), 5.05 - 4.43 (m, 1H), 3.20 (s, 2H), 2.33 - 2.14 (m, 1H), 1.97 (dt, J = 11.6, 3.4 Hz, 1H), 1.82 - 1.66 (m, 4H), 1.57 (m, 3H), 1.50 - 1.15 (m, 12H), 1.06 - 0.92 (m, 1H), 0.91 - 0.82 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0082] Example 6: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)-2-(1H-imidazol-1-yl-d3)ethan-1-one-2-d [ka] To a solution of imidazole-d4 (0.194 g, 2.69 mmol, 3.0 equiv) in THF (2 mL) is added lithium hydride (0.023 g, 2.78 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 3, step 3 (0.4 g, 0.89 mmol, 1.0 equiv) in THF (2.5 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with DO (1.5 mL) in an ice bath. The solvent is evaporated and purified by column chromatography to give pure 11 (0.17 g, 0.389 mmol) as a white powder in 44% isolated yield. 1 H NMR (500 MHz, chloroform-d) δ 4.92 - 4.38 (m, 1H), 3.20 (s, 2H), 2.36 - 2.06 (m, 1H), 1.97 (dt, J = 11.8, 3.4 Hz, 1H), 1.85 - 1.63 (m, 4H), 1.64 - 1.14 (m, 11H), 0.99 (m, 1H), 0.86 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0083] Example 7: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl)ethan-1-one [ka] Step 1: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane]-17-yl-3',3'-d2)ethan-1-one

[0084] A slurry solution of trimethylsulfoxonium-d9 iodide (2.17 g, 9.48 mmol) and potassium tert-butoxide (1.13 g, 10.1 mmol) in d6-DMSO (26.0 mL) is heated at 60° C. for 1 h under Ar. 5α-pregnane-3,20-dione (2.0 g, 6.3 mmol) is added to the reaction mixture and stirred at room temperature overnight. After completion of the reaction, the reaction mixture is quenched and precipitated with water (60 mL) in an ice bath. The resulting precipitate is collected by filtration and washed with water (50 mL×2). The residue is further purified by recrystallization from MeOH / acetone (4 / 1) and dried under vacuum to give the pure final product (2.08 g, 6.2 mmol) as a white powder in 99% yield and 91.5% isotopic purity. 1 H NMR (500 MHz, chloroform-d) δ 2.56 (t, J = 9.0 Hz, 1H), 2.28 - 2.09 (m, 3H), 2.08 - 1.98 (m, 2H), 1.89 (t, J = 13.5 Hz, 1H), 1.80 - 1.62 (m, 5H), 1.57 (m, 2H), 1.50 - 1.06 (m, 10H), 0.97 (m, 1H), 0.92 - 0.73 (m, 5H), 0.63 (s, 3H).

[0085] Step 2: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)ethan-1-one-2,2,2-d3

[0086] Sodium hydroxide (0.49 g, 12.2 mmol) is dissolved in methanol-d4 (20 mL) and heated to reflux under Ar for 30 min. The compound from step 1 (2.04 g, 6.12 mmol) is slowly added to the methanol solution at room temperature under Ar and the solution is heated at 40° C. overnight. The reaction mixture is quenched and precipitated with water (60 mL) in an ice bath. The resulting precipitate is filtered and washed with water (25 mL×2). The solid cake is further purified by recrystallization from ethyl acetate / hexane (1 / 1) and dried under vacuum to give the pure product (1.43 g, 3.85 mmol) as a white powder in 63% yield. 1 H NMR (500 MHz, chloroform-d) δ 2.23 - 2.12 (m, 1H), 2.01 (dt, J = 12.1, 3.4 Hz, 1H), 1.80 - 1.51 (m, 7H), 1.49 - 1.12 (m, 11H), 1.06 - 0.92 (m, 1H), 0.89 - 0.79 (m, 1H), 0.77 (s, 3H), 0.62 (s, 3H).

[0087] Step 3: 2-Bromo-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)ethan-1-one-2,2-d2

[0088] To a solution of step 2 compound (1.43 g, 3.85 mmol) in MeOH (12 mL) is added 3 drops of aqueous HBr (48%). Bromine (0.209 mL, 4.04 mmol) is dissolved in MeOH (8 mL) and added dropwise to the reaction mixture in the dark. After completion of the reaction, the reaction mixture is quenched with water (60 mL). Ethyl acetate (40 ml x 2) is added to extract the final product, the organic phases are combined and washed again with water (30 mL x 2). The solvent is evaporated and dried under vacuum overnight to give the pure product (1.70 g, 3.78 mmol) as a white powder in 98% yield. 1H NMR (500 MHz, chloroform-d) δ 2.24 - 2.12 (m, 1H), 1.92 (dt, J = 11.8, 3.5 Hz, 1H), 1.79 - 1.64 (m, 4H), 1.62 - 1.50 (m, 3H), 1.50 - 1.15 (m, 11H), 1.04 - 0.92 (m, 1H), 0.90 - 0.80 (m, 1H), 0.77 (s, 3H), 0.65 (s, 3H).

[0089] Step 4: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl)ethan-1-one

[0090] To a solution of imidazole (0.182 g, 2.7 mmol, 3.0 equiv) in THF (1.5 mL) is added lithium hydride (0.023 g, 2.76 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. Step 3 compound (0.4 g, 0.89 mmol, 1.0 equiv) in THF (3.0 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with methanol (3.0 mL) in an ice bath. The solvent is evaporated and the residue is purified by flash column chromatography on silica gel to give the corresponding product, which is then purified again by semi-preparative HPLC to give the final product (0.063 g, 0.145 mmol) as a white powder in 16% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 7.49 (s, 1H), 7.13 (s, 1H), 6.88 (s, 1H), 4.97 - 4.45 (m, 2H), 2.60 (t, J = 9.0 Hz, 1H), 2.27 - 2.10 (m, 1H), 1.98 (d, J = 11.9, 3.4 Hz, 1H), 1.80 - 1.66 (m, 4H), 1.62 - 1.52 (m, 3H), 1.51 - 1.16 (m, 12H), 1.06 - 0.93 (m, 1H), 0.90 - 0.81 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0091] Example 8: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl-2-d)ethan-1-one [ka] To a solution of imidazole-d1 (0.184 g, 2.67 mmol, 3.0 equiv) in THF (2.0 mL) is added lithium hydride (0.023 g, 2.76 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 7, step 3 (0.4 g, 0.89 mmol, 1.0 equiv) in THF (3.0 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with methanol (3.0 mL) in an ice bath. The solvent is evaporated and the residue is purified by flash column chromatography on silica gel to give the corresponding product, which is then purified again by semi-preparative HPLC to give the final product (0.163 g, 0.375 mmol) as a white powder in 42% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 7.28 (s, 1H), 6.88 (s, 1H), 5.06 - 4.50 (m, 2H), 2.60 (t, J = 8.9 Hz, 1H), 2.34 - 2.12 (m, 1H), 1.98 (dt, J = 11.8, 3.4 Hz, 1H), 1.80 - 1.67 (m, 4H), 1.64 - 1.51 (m, 3H), 1.51 - 1.15 (m, 11H), 1.07 - 0.94 (m, 1H), 0.91 - 0.82 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0092] Example 9: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-imidazol-1-yl-d3)ethan-1-one [ka] To a solution of imidazole-d4 (0.144 g, 2.00 mmol, 3.0 equiv) in THF (2.0 mL) is added lithium hydride (0.0174 g, 2.07 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 7, step 3 (0.3 g, 0.667 mmol, 1.0 equiv) in THF (3.0 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with methanol (3.0 mL) in an ice bath. The solvent is evaporated and the residue is purified by flash column chromatography on silica gel to give the corresponding product, which is then purified again by semi-preparative HPLC to give the final product (0.147 g, 0.337 mmol) as a white powder in 51% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 4.87 - 4.36 (m, 2H), 2.60 (t, J = 8.9 Hz, 0H), 2.34 - 2.07 (m, 2H), 1.98 (dt, J = 11.7, 3.4 Hz, 0H), 1.80 - 1.65 (m, 2H), 1.64 - 1.52 (m, 1H), 1.51 - 1.15 (m, 11H), 1.06 - 0.94 (m, 1H), 0.90 - 0.82 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0093] Example 10: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)-2-(1H-imidazol-1-yl)ethan-1-one [ka] To a solution of imidazole (0.136 g, 2.00 mmol, 3.0 equiv) in THF (2.0 mL) is added lithium hydride (0.0174 g, 2.07 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 7, step 3 (0.3 g, 0.667 mmol, 1.0 equiv) in THF (2.5 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with DO (1.50 mL) in an ice bath. The solvent is evaporated and the residue is purified by flash column chromatography on silica gel to give the corresponding product, which is then purified again by semi-preparative HPLC to give the final product (0.140 g, 0.322 mmol) as a white powder in 48% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 7.60 (s, 1H), 7.15 (s, 1H), 6.89 (s, 1H), 5.20 - 4.42 (m, 2H), 2.41 - 2.11 (m, 1H), 2.05 - 1.87 (m, 1H), 1.80 - 1.65 (m, 4H), 1.63 - 1.52 (m, 3H), 1.50 - 1.15 (m, 13H), 1.06 - 0.93 (m, 1H), 0.91 - 0.83 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0094] Example 11: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)-2-(1H-imidazol-1-yl-2-d)ethan-1-one [ka] To a solution of imidazole-d1 (0.102 g, 1.48 mmol, 3.0 equiv) in THF (2.0 mL) is added lithium hydride (0.0128 g, 1.52 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 7, step 3 (0.221 g, 0.492 mmol, 1.0 equiv) in THF (3.0 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with D2O (1.50 mL) in an ice bath. The solvent is evaporated and the residue is purified by flash column chromatography on silica gel to give the corresponding product, which is then purified again by semi-preparative HPLC to give the final product (0.156 g, 0.358 mmol) as a white powder in 73% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 7.51 - 7.30 (m, 1H), 7.13 (d, J = 2.5 Hz, 1H), 5.76 - 5.03 (m, 2H), 2.26 - 2.14 (m, 1H), 2.10 (d, J = 12.2 Hz, 1H), 1.90 - 1.80 (m, 1H), 1.79 - 1.73 (m, 1H), 1.73 - 1.64 (m, 2H), 1.65 - 1.46 (m, 5H), 1.44 - 1.15 (m, 10H), 1.07 - 0.94 (m, 1H), 0.91 - 0.83 (m, 1H), 0.77 (s, 3H), 0.70 (s, 3H).

[0095] Example 12: 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-((methoxy-d3)methyl-d2)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl-17-d)-2-(1H-imidazol-1-yl-d3)ethan-1-one [ka] To a solution of imidazole-d4 (0.144 g, 2.00 mmol, 3.0 equiv) in THF (2.0 mL) is added lithium hydride (0.0174 g, 2.07 mmol, 3.1 equiv). The solution is stirred at 0° C. for 2 h under Ar. The compound of Example 7, step 3 (0.300 g, 0.667 mmol, 1.0 equiv) in THF (3.0 mL) is slowly added to the reaction mixture at 0° C. over 5 min under Ar. After stirring at 0° C. for 3 h, the reaction mixture is quenched with DO (1.50 mL) in an ice bath. The solvent is evaporated and the residue is purified by flash column chromatography on silica gel to give the corresponding product, which is then purified again by semi-preparative HPLC to give the final product (0.160 g, 0.366 mmol) as a white powder in 55% isolated yield. 1H NMR (500 MHz, chloroform-d) δ 5.04 - 4.56 (m, 2H), 2.30 - 2.13 (m, 1H), 1.98 (dt, J = 11.8, 3.4 Hz, 1H), 1.82 - 1.66 (m, 4H), 1.63 - 1.52 (m, 3H), 1.51 - 1.14 (m, 11H), 1.07 - 0.93 (m, 1H), 0.93 - 0.83 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H).

[0096] Example 13: Other analogues of 3α-hydroxy-21-(1'-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one Other deuterated analogs of compounds within the scope of the present disclosure can be prepared by suitable means known to those skilled in the art by substituting deuterated reagents for conventional reagents following the prior art reference procedures above. For example: [ka]

[0097] Example 14: Pharmacological activity of 3α-hydroxy-21-(1'-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one In vitro potency of 3α-hydroxy-21-(1'-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one [[ 35 S]-tert-butylbicyclophosphorothionate (TBPS) binding inhibitor], rotarod TD 50The dose at which half of the animals tested do not remain on the rotarod for one minute and the length of time before the animals tested are able to pass the rotarod test (duration of action) are determined. These methods for measuring the in vitro and in vivo activity of the compounds of the present invention are fully described in U.S. Patent No. 5,232,917, which is incorporated herein by reference in its entirety. The TBPS assay indicates the in vitro potency of the compound, while the rotarod assay estimates the sedative / hypnotic activity of the compound. The duration of action of the compound is dose-dependent and is extended at higher doses, so the duration of action is measured at the lowest dose at which all animals fail the rotarod test. IC 50 teeth,[ 35 S]-tert-butylbicyclophosphorothionate (TBPS) specific binding was inhibited by 50%. 50 is the dose at which half of the animals fail the rotarod test in rats. The duration of effect, measured at the lowest dose at which all animals fail the rotarod test, is the time required for all animals tested to again pass the rotarod test.

[0098] The results showed that the compound of formula A (Example 1), 3α-hydroxy-21-(1′-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one, had a TBPS IC 50 is 138nM, and the rotor rod TD 50 (po) is 28 mg / kg and the duration of action is 140 minutes.

[0099] Example 15: In vivo mouse pharmacokinetics of deuterated compounds In the first study, the compounds of Examples 2-6 are compared to the compound of formula A (Example 1) using standard procedures in mice. In each study, the two compounds are co-administered to one animal and the relative pharmacokinetics in plasma and brain are determined. Each test compound is dissolved in polyethylene glycol 400 vehicle and orally administered at a dose of 10 mg / kg. After a single oral dose of the test compounds together, plasma and brain levels are measured at 0.25, 0.5, 1, 2, 4 and 6 hours post-administration. The maximum concentration, time to maximum concentration and mean area under the curve (AUC) for both compounds are determined. The results for the various paired co-administration experiments are summarized in the table below. [Table 2] [Table 3] [Table 4]

[0100] These results unexpectedly show that each of the deuterated compounds of Examples 2, 4 and 6 provide significantly higher brain exposure of the drug compared to the non-deuterated compound of Example 1, and therefore also provide significantly higher brain / plasma AUC ratios. In contrast, the deuterated compound of Example 3 provides plasma and brain AUC values ​​B / P ratios similar to the compound of Example 1. These data suggest that deuteration on or near the imidazole ring favorably affects the partitioning of the compound between the brain and plasma, resulting in higher central nervous system exposure to the drug. This is particularly important since these compounds are neuroactive steroids intended to bind to central nervous system GABA receptors.

[0101] Example 16: In vitro human hepatocyte pharmacokinetics of deuterated compounds The compounds of Examples 1, 2, 5 and 6 are compared in a standard in vitro human hepatocyte stability assay performed in duplicate. Compounds are provided as 1 μM solutions in DMSO, and the concentration of test compound is determined at 0.5, 1.0 and 4.0 hours after addition of test compound. The results are shown in the table below as a percentage of the initial concentration. [Table 5]

[0102] These results suggest that increasing deuteration of the imidazole increases the metabolic stability of these compounds in hepatocytes (compare Example 1 with Example 2), while deuteration on the methoxy group or the carbon adjacent to the carbonyl group provides an unknown effect. The present application also includes the following aspects. [Aspect 1] A compound of formula I: [ka] Formula I [In the formula, X is H, -(C=O)-R a , -CH 2 -(C=O)-OR a and -CH 2 -(C=O)-N(R a )(R b ) selected; R 1 But, CH 3 , C.D.H. 2 , CD 2 H and CD 3 More selected; R 2 From R 9 each is independently selected from H and D; R a and R b However, independently, H, C 1-20 Alkyl (e.g., methyl), and C 1-4 alkyl-aryl (e.g., benzyl); However, R 1 CH 3 and R 2 From R 9 are all H, X is -(C=O)-R a , -CH 2 -(C=O)-OR a and -CH 2 -(C=O)-N(R a )(R b ) selected from A compound represented by the formula: [Aspect 2] The compound according to embodiment 1, wherein X is H. [Aspect 3] X is -(C=O)-R a , -CH 2 -(C=O)-OR a , and -CH 2 -(C=O)-N(R a )(R b 2. The compound according to embodiment 1, wherein the compound is selected from [Aspect 4] X is -(C=O)-R a 2. The compound according to embodiment 1, wherein [Aspect 5] X is -CH 2 -(C=O)-OR a 2. The compound according to embodiment 1, wherein [Aspect 6] X is CH 2 -(C=O)-N(R a )(R b 2. The compound of claim 1, wherein [Aspect 7] X is CH 2 -(C=O)-N(R a )(R b ) and R b is H. [Aspect 8] R 1 CH 3 The compound according to any one of aspects 1 to 7, [Aspect 9] R 1 CD 3 The compound according to any one of aspects 1 to 7, [Aspect 10] R 2 From R 9 The compound according to any one of embodiments 1 to 7, wherein any one, two, three or four of are D. [Aspect 11] R 2 and R 3 The compound according to any one of aspects 1 to 7, wherein [Aspect 12] R 5 From R 6 The compound according to any one of aspects 1 to 7, wherein [Aspect 13] R 7 From R 9 The compound according to any one of aspects 1 to 7, wherein any one, two or three of are D. [Aspect 14] The compound is

change

change

Claims

1. A compound of formula I, in free or pharma- ceutical acceptable salt form: 【Chemistry 1】 Formula I [In the formula, X is H; R 1 But, CH 3 and CDs 3 Selected from: R 2 each R 6 is independently selected from H and D; Each of R 7 to R 9 is D. A compound represented by the formula:

2. R 1 CH 3 2. The compound of claim 1,

3. R 1 CD 3 2. The compound of claim 1,

4. R 4 , R 5 and R 6 The compound according to any one of claims 1 to 3, wherein any one of the following is D.

5. R 4 The compound according to any one of claims 1 to 4, wherein is D.

6. R 2 and R 3 The compound according to any one of claims 1 to 5, wherein is D.

7. R 5 or R 6 The compound according to any one of claims 1 to 6, wherein is D.

8. R 5 and R 6 and both are D.

9. The compound is 【Chemistry 2】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

10. The compound is 【Chemistry 3】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

11. The compound is 【Chemistry 4】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

12. The compound is 【Chemistry 5】 The compound according to any one of claims 1 to 8, selected from the group consisting of:

13. A compound according to any one of claims 1 to 12 in the form of a pharma- ceutically acceptable salt.

14. 14. The compound of any one of claims 1 to 13, having greater than 90% incorporation of deuterium at one or more designated positions in the structure.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 in free or pharma- ceutically acceptable salt form, in admixture with a pharma- ceutically acceptable diluent or carrier.

16. 16. The pharmaceutical composition of claim 15, in an oral dosage form.

17. 16. The pharmaceutical composition of claim 15, formulated as a long-acting injectable for intramuscular or subcutaneous injection.

18. GABA A 18. A pharmaceutical composition according to any one of claims 15 to 17 for the treatment of a central nervous system disorder suitable for amelioration with a receptor modulator, wherein the disorder is selected from the group consisting of sleep disorders, circadian rhythm disorders, phase shift disorders, anxiety, post-traumatic stress disorder, depression, obsessive-compulsive disorder, schizophrenia, schizoaffective disorder, attention disorders, convulsive disorders, aggression disorders, agitation disorders, memory and / or cognition disorders, movement disorders, autism and autism spectrum disorders, pain disorders, personality disorders, vascular disorders, eating disorders, traumatic brain injury, substance abuse disorders, substance use disorders, substance withdrawal syndromes, neurodegenerative diseases and disorders requiring sedation or sensory deprivation for effective treatment.

19. 19. The pharmaceutical composition of claim 18, wherein the disorder is selected from the group consisting of sleep disorders, phase shift disorders, anxiety, depression, obsessive-compulsive disorder, schizophrenia, schizoaffective disorder, attention disorders, convulsive disorders, aggression disorders, agitation disorders, memory and / or cognition disorders, movement disorders, autism and autism spectrum disorders, pain disorders, personality disorders, vascular disorders, eating disorders, traumatic brain injury, substance abuse disorders, substance use disorders, substance withdrawal syndromes, Rett syndrome, Fragile X syndrome, Angelman syndrome, and tinnitus, neurodegenerative diseases, and disorders requiring sedation or sensory deprivation for effective treatment.

20. Disorders include insomnia, jet lag, generalized anxiety, social anxiety, panic disorder, treatment-refractory depression, major depressive disorder, bipolar depression, postpartum depression, seasonal affective disorder, dysthymia, treatment-resistant depression, suicidal ideation, suicidal behavior, premenstrual dysphoric disorder, obsessive-compulsive disorder, schizophrenia, schizoaffective disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), seizure disorder, epilepsy, status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, nonconvulsive status epilepticus, generalized status epilepticus 20. The pharmaceutical composition of claim 19, wherein the therapeutic effect of the therapeutic agent is selected from the group consisting of: chronic aggression, complex partial status epilepticus, acute or chronic aggression, acute or chronic agitation, Alzheimer's disease, aging, dementia with Lewy bodies, vascular dementia, Parkinson's disease, Huntington's disease, tremor, Asperger's syndrome, neuropathic pain, acute pain, chronic pain, antisocial personality disorder, depressive personality disorder, stroke, ischemia, vascular malformation, bulimia, anorexia, binge eating disorder, cachexia, amyotrophic lateral sclerosis, coma, dyskinesia, and dystonia.

21. 21. The pharmaceutical composition of claim 20, wherein the disorder is selected from the group consisting of insomnia, generalized anxiety, social phobia, panic disorder, treatment-refractory depression, major depressive disorder, bipolar depression, postpartum depression, treatment-resistant depression, seizure disorder, epilepsy, status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus, nonconvulsive status epilepticus, generalized status epilepticus, and complex partial status epilepticus.

22. A pharmaceutical composition according to any one of claims 15 to 17 for inducing sedation or anesthesia in a patient in need thereof.

Images