Priority Claims and Related Patent Applications

[0001] This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/267,700, filed on December 15, 2015, the entire content of which is incorporated herein by reference in its entirety.

Technical Fields of the Invention

[0002] The invention generally relates to therapeutics and treatment methods for certain diseases and conditions. More particularly, the invention provides novel chemical compounds, including /V-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6 -oxaspiro[4.5]decan-9- yl]ethanaminewith one or more deuterium-substitutions at strategic positions, that exhibit functionally selective μ-opioid receptor agonist activities and are useful for treating various pain or related diseases and conditions, and pharmaceutical compositions and methods of preparation and use thereof.

Background of the Invention

[0003] Pain is one of the most common reasons for physician visits as it is a major symptom in many medical conditions. If not treated properly, pain can impact a person's quality of life and general functioning. Pain treatment and management is an important aspect of surgical operations, intensive care, accident and emergency medicine, as well as in general medicine. Inadequate treatment of pain, however, is widespread even in advanced medical settings.

[0004] Acute pain can usually be treated with medications such as analgesics and anesthetics. Opioid medications, for example, can provide short, intermediate or long acting analgesia. Adverse effects associated with opioids, however, can be severe when used for prolonged periods, including drug tolerance, chemical dependency, diversion and addiction. [0005] There is an urgent and growing need for innovative pain treatment and management therapeutics and treatment methods that provide improved clinical effectiveness with reduced side effects.

Summary of the Invention

[0006] The invention provides novel compounds that are biochemically potent and physiologically active and possess improved pharmacokinetic and toxicological properties over N- [(3 -methoxythiophen-2-yl)m ethyl] -2- [(9R)-9-pyridin-2-yl-6-oxaspiro[4.5 ] decan-9- yl]ethanamine.

[0007] In one aspect, the invention generally relates to a compound having the structural formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D, or a pharmaceutically acceptable salt or ester thereof.

[0001] In certain embodiments, each of Ri, R ₂ and R ₃ is D, having the structural formula of:

[0002] In certain embodiments, one of Ri, R ₂ and R ₃ is D, and each of the remaining ones is H.

[0003] In certain embodiments, two of Ri, R ₂ and R ₃ are D, and the remaining one is H.

[0004] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound having the structural formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain), or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0008] In yet another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition disclosed herein. The unit dosage is suitable for administration to a subject suffering pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain) and related diseases and conditions.

[0009] In yet another aspect, the invention generally relates to a method for treating, reducing, or preventing a disease or disorder. The method includes: administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D„ or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain), or related a related disease or disorder thereof.

[0010] In certain preferred embodiments, the method of treatment includes administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D, or a pharmaceutically acceptable form thereof, in combination with one or more other pain-reducing or pain-preventing agents.

Brief Description of the Drawings

[0011] FIG. 1 shows certain exemplary pharmacokinetic results from monkey IV studies. Definitions

[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0013] As used herein, "administration" of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, as discussed herein.

[0014] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. In some embodiments, the amount is that effective to alleviate pain, e.g., one or more of acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain. The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0015] As used herein, the terms "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%) as measured by any standard technique.

[0016] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and/or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0017] As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein.

Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0018] As used herein, the term "pharmaceutically acceptable enol ethers" include, but are not limited to, derivatives of formula -C=C(OR) where R can be selected from alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula -C=C(OC(0)R) where R can be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.

[0019] As used herein, a "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to,

pharmaceutically acceptable salts, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[0020] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0021] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (Ci- ₄ alkyl) ⁴ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0022] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0023] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis {e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0024] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in

Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0025] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0026] As used herein, the term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0027] As used herein, the "low dosage" refers to at least 5% less (e.g., at least 10%, 20%, 50%), 80%), 90%), or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition. For example, a low dosage of an agent that reduces glucose levels and that is formulated for administration by inhalation will differ from a low dosage of the same agent formulated for oral administration.

[0028] As used herein, the "high dosage" is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%), 200%), or even 300%>) more than the highest standard recommended dosage of a particular compound for treatment of any human disease or condition.

[0029] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95%o ("substantially pure"), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0030] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

Detailed Description of the Invention

[0031] The invention provides novel chemical entities that may be used to treat, prevent, reduce, or manage pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain). These compounds are biochemically potent and physiologically active with improved pharmacokinetic, therapeutic and toxicological properties over N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6- oxaspiro[4.5]decan-9- yljethanamine, a.k.a. Oliceridine, shown below.

Oliceridine

[0032] The compounds disclosed herein are deuterium-substituted versions of the above compound, where hydrogen is substituted with deuterium at strategic locations of the molecule. Such strategic deuterium substitution leads to positive impact on the pharmacokinetic, therapeutic and toxicological profiles of select compounds. The compounds disclosed herein are G protein biased ligands. The substitution locations are selected with the specific objective to impact pharmacokinetic, therapeutic, and toxicological properties of the molecule. The resulting compounds have 1 to 3 deuterium substitutions and exhibit more desirable profiles in terms of safety, efficacy and tolerability in the treatment of pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain).

[0033] Oliceridine (a.k.a. TRV130) is an intravenous G protein biased ligand that targets the μ-opioid receptor (MOR). The compound is a functionally selective μ-opioid receptor agonist and is being developed to treat moderate to severe acute pain where intravenous therapy is preferred (e.g., acute postoperative pain, acute pain management). Oliceridine is potently analgesic with potency and efficacy similar to that of morphine but displays far less β-arrestin 2 recruitment and receptor internalization thus less adverse effects (respiratory depression and GI dysfunction) than morphine, which is the primary psychoactive alkaloid in opium. (Chen, et al. 2013 J. Med. Chem. 56 (20): 8019-31; DeWire, et al. 2013 J. Pharmacol. Exp. Ther. 344 (3): 708-17; Soergel, et al. 2013 J. Clin. Pharmacol. 54 (3): 351-7.)

[0034] In one aspect, the invention generally relates to a compound having the structural formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D, or a pharmaceutically acceptable form thereof.

[0035] In certain embodiments, each of Ri, R ₂ and R ₃ is D, having the structural formula of:

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D , or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain), or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0037] In yet another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition disclosed herein. The unit dosage is suitable for administration to a subject suffering pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain) and related diseases and conditions.

[0038] In yet another aspect, the invention generally relates to a method for treating, reducing, or preventing a disease or disorder. The method includes: administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce pain (e.g., acute pain, acute severe pain, chronic pain, postoperative pain, moderate to severe postoperative pain), or related a related disease or disorder thereof.

[0039] In certain embodiments, the pain is moderate pain. In certain embodiments, the pain is severe pain. In certain embodiments, the pain is acute pain. In certain embodiments, the pain is chronic pain. In certain embodiments, the pain is acute severe pain. In certain embodiments, the pain is postoperative pain. In certain embodiments, the pain is moderate to severe postoperative pain. [0040] In certain embodiments, the diseases and conditions that may benefit from treatment using the compounds, pharmaceutical composition, unit dosage form and treatment method disclosed herein include any diseases and disorders that may be addressed by functionally selective μ-opioid receptor agonists.

[0041] In certain preferred embodiments, the method of treatment includes administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of Ri, R ₂ and R ₃ is independently selected from H and D, and at least one of Ri, R ₂ and R ₃ is D, or a pharmaceutically acceptable form thereof, in combination with one or more other pain-reducing or pain-preventing agents.

[0042] In certain preferred embodiments, the one or more other pain-reducing or pain- preventing agents are selected from opioids.

[0043] In certain preferred embodiments, the one or more other pain-reducing or pain- preventing agents are selected from oxycodone, methadone, oxymorphone, morphine, buprenorphine, meperidine, ketorolac, tapentadol, ziconotide, fentanyl, hydromorphone, tapentadol, hydrocodone, ibuprofen, and clonidine, for example.

[0044] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound. [0045] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium

compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0046] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[0047] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[0048] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and tra^s-isomers, R- and ^-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.

Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0049] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures. If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

Examples

Oliceridine

[0050] Oliceridine (TRV130) was synthesized according to the following synthetic route and was purchased from MadKoo (Chapel Hill, NC).

B 8

OSkersdine

[0051] (R)-N-((3-D3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl )-6- oxaspiro[4.5]decan-9-yl)ethanamine was a white solid. (0.2 g, 30 % yield) HPLC purity was 97.5%. LC-MS: [M+H]=387. 1H MR (CDC1 ₃ ): 8.55(B, IH), 7.61 (t, IH), 7.30-7.26(m, IH), 7.12-7.04(m, 2H), 6.76(d, IH), 3.78-3.71 (m, 7H), 2.55-2.34 (m, 3H), 2.15-2.09 (m, IH), 2.00- 1.89 (m, 2H), 1.78-1.26 (m, 9H), 1.13-1.10 (b, IH), 1.26-1.10(m, 3H). 0.72-0.64 (m, IH).

D3-OHceridine

D3-01iceridine (D3-TRV130) was synthesized according to the following synthetic

2 4

D3-01l€erIdin¾ Preparation of 6-oxaspiro[4.5]decan-9-ol (C)

[0053] To a solution of but-3-en-l-ol (100 g, 1.38 mol), cyclopentanone (232 g, 2.77 mol) was added in dichloromethane (DCM, 1200 mL). The well-stirred suspension was cooled to 0 °C and a solution of trifluoroacetic acid (TFA, 1000 mL) was added over 60 min. The solution was stirred at room temperature for 12 hours. The reactant solution was concentrated. The residue was dissolved in MeOH (2,000 mL), Na ₂ CC"3 (300 g) was added in it and was stirred at room temperature for 2 hours, filtered and concentrated. The crude product was extracted with CH ₂ C1 ₂ (2 x 500 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to give compound 6-oxaspiro[4.5]decan-9-o/ (20 g, crude).

Preparation of 6-oxaspiro [4.5] decan-9-one (2)

[0054] To a solution of 6-oxaspiro[4.5]decan-9-o/ (20 g, crude), PCC (20 g) and silica gel (20 g) was added in THF (200 mL). The solution was stirred at room temperature for 12 hours. The reactant solution was concentrated. The crude product was purified via flash

chromatography (Si0 ₂ ; 20: 1 hexanes:EtOAc) to give 6-oxaspiro[4.5]decan-9-one as a colorless clear liquid. (10 g, 4.7 % yield, 2 steps, 1H NMR confirmed)

Preparation of methyl 2-cyano-2-(6-oxaspiro[4.5]decan-9-ylidene)acetate (3)

[0055] To a solution of 6-oxaspiro[4.5]decan-9-one (10 g, 64.8 mmol), methyl 2- cyanoacetate (9.6 g, 97.2 mmol), AcOH (0.8 g, 14 mmol) and H ₄ OAc (1.2 g, 16.2 mmol) was added in toluene (100 mL). The solution was stirred at refluxed until no more water collected in the Dean-stark for 4 hours. The reaction mixture was slowly quenched with water (100 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified via flash

chromatography (Si0 ₂ ; 20: 1 hexanes:EtOAc) to give methyl 2-cyano-2-(6-oxaspiro[4.5]decan-9- ylidene)acetate as a colorless clear liquid. (8 g, 55 % yield, 1H NMR confirmed)

Preparation of methyl 2-cyano-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetat e (4)

[0056] To a solution of 2-bromopyridine (5.3 g, 34.1 mmol) was added in anhydrous tetrahydrofuran (THF, 50 mL). The well stirred suspension was cooled to 0 °C and a solution of chloro(l-methylethyl)magnesium (17 mL, 34.1 mmol) was added over 0.5 hour. The solution was stirred at room temperature for 4 hours. Cul (2 g, 3.41 mmol) was added in it and stirred at room temperature for 0.5 hour. Methyl 2-cyano-2-(6-oxaspiro[4.5]decan-9-ylidene)acetate (8 g, 34.1 mmol) in anhydrous THF (50 mL) was added in it. The resultant mixture was stirred at room temperature for 16 hours and it was poured into 100 g ice and 2N HC1 (50 mL). The aqueous layer was then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified via flash chromatography (Si0 ₂ ; 5: 1 hexanes:EtOAc) to give methyl 2-cyano-2-(9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl)acetate as a colorless clear liquid. (4 g, 38 % yield, 1H NMR confirmed)

Preparation of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile (5)

[0057] To a solution of methyl 2-cyano-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl)acetate (4 g, 12.7 mmol) and KOH (1.4 g, 25.4 mmol) was added in ethylene glycol (50 mL). The solution was stirred at 120 °C for 4 hours. The reaction mixture was slowly quenched with water (100 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified via flash chromatography (Si0 ₂ ; 4: 1 hexanes:EtOAc) to give 2-(9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl)acetonitrile as a white solid. (3 g, 90 % yield, 1H NMR confirmed).

Preparation of (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitri le (6)

[0058] To a solution of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitrile (6.5 g, was purified by Chiral separation to give (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl)acetonitrile as a white solid. (3 g, 45 % yield, 1H NMR confirmed)

Preparation of (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine (7)

[0059] To a solution of (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetonitri le (2.9 g, 11.3 mmol) was added in THF (100 mL) at 0 °C and LiAlH (1.3 g, 33.9 mmol) was added in it. The solution was stirred at room temperature for 14 hours. The reaction mixture was slowly quenched with water (20 mL) and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified via flash chromatography (Si0 ₂ ; 2: 1 hexanes:EtOAc) to give (R)-2-(9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine as a white solid. (2.9 g, crude, ¹ H NMR confirmed)

Preparation of 3-hydroxythiophene-2-carbaldehyde (B) [0060] To a solution of 3-methoxythiophene-2-carbaldehyde (2 g, 14.1 mmol) was added in DCM (20 mL) at 0 °C and BBr3 (1.43 mL, 15.5 mmol) was added in it. The solution was stirred at room temperature for 14 hours. The reaction mixture was slowly quenched with water (20 mL) and the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified via flash

chromatography (Si0 ₂ ; 5: 1 hexanes:EtOAc) to give 3-hydroxythiophene-2-carbaldehyde as a white solid. (1.5 g, 80 % yield, 1H MR confirmed)

Preparation of 3-D3-methoxythiophene-2-carbaldehyde (8)

[0061] To a solution of 3-hydroxythiophene-2-carbaldehyde (1.5 g, 11.7 mmol), K ₂ C0 (3.2 g, 23.4 mmol) and Iodomethane-D3 (2 g, 14.1 mmol) was added in dimethylformamide (DMF, 15 mL). The solution was stirred at room temperature for 4 hours. The reaction mixture was poured onto water (100 mL) and the mixture was extracted with EA (2 x 100 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified via flash chromatography (Si0 ₂ ; 10: 1 hexanes:EtOAc) to give 3-D3-methoxythiophene- 2-carbaldehyde as a white solid. (1.3 g, 80 % yield, 1H MR confirmed)

Preparation of (R)-N-( ( 3-D3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6- oxaspirof 4.5] decan-9-yl)ethanamine

[0062] To a solution of 3-D3-methoxythiophene-2-carbaldehyde (300 mg, 2.4 mmol), (R)-2- (9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine (600 mg, 3.12 mmol) and Na ₂ S0 ₄ (1.4 g, 10 mmol) was added in DCM (5 mL) and the mixture was stirred at room temperature for 14 hours. NaBH ₄ (92 mg, 2.4 mmol) was added in it and the mixture was stirred at room

temperature for 0.5 hour. MeOH (5 mL) was added in it. The solution was stirred at room temperature for 4 hours. The reaction mixture was poured onto water (20 mL) and the mixture was extracted with EA (2 x 50 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified Pre-HPLC to give (R)-N-((3-D3- methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[ 4.5]decan-9-yl)ethanamine as a white solid. (0.2 g, 30 % yield) HPLC purity was 95.0%. LC-MS: [M+H]=390. 1H NMR (CDC1 ): 8.55(B, 1H), 7.63 (t, 1H), 7.30-7.27(m, 1H), 7.12-7.07(m, 2H), 6.76(d, 1H), 3.82-3.73 (m, 4H), 2.65-2.56 (m, 1H), 2.44-2.30 (m, 2H), 2.20-2.15 (m, 2H), 2.04-1.59 (m, 6H), 1.48-1.38 (b, 1H), 1.26-1.10(m, 3H). 0.88-0.67 (m, 2H). In vivo pharmacokinetic study on Cynomolgus Monkeys

[0063] In vivo study of Oliceridine and D3-01iceridine was conducted by an independent Contract Research Organization (CRO). The test articles were dissolved, respectively, in 5%DMSO+5%solutol HS 15+90% saline to yield a final concentration of 0.4 mg/mL for IV administration. The resulting formulations of four compounds were colorless and clear solution. A total of four cynomolgus monkeys (male) were used in the study. The study was conducted in a cross-over matter with four phases to minimize individual difference. Washout period lasted 5 days between two adjacent phases. The four animals assigned to the study had body weights within ± 20% of the mean body weight. The dose level was 2.0 mg/Kg and the drug was intravenously administrated (IV).

[0064] Blood samples (approximately 1.2 mL/sample) were collected from the

femintravenous vein at appropriate time points. The samples were placed in tubes containing sodium heparin and stored on ice until centrifuged. Blood samples were collected predose and postdose at postdose 2 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h and 4 h. The blood samples were centrifuged at approximately 3,500 rpm for 10 min at 2-8°C. Plasma samples were then collected and stored frozen at approximately -80°C until analysis. The bioanalytical work was performed on LC-MS/MS system.

Table 1. Improvement on Tl/2 by selectively modification of oliceridine

PK property Tl/2

SD 0.25 1.48

[0065] The results of in vivo PK study on monkey indicated that D3-01iceridine showed superior DMPK property over Oliceridine.

[0066] Applicant's disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0067] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant's composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0068] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed. Incorporation by Reference

[0070] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

[0071] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.