WO2020006563A1

WO2020006563A1 - Fluorinated compounds as ph-sensitive analgesics

Info

Publication number: WO2020006563A1
Application number: PCT/US2019/040157
Authority: WO
Inventors: Christopher DOCKENDORFF; Ricardo ROSAS, Jr.
Original assignee: Marquette University
Priority date: 2018-06-29
Filing date: 2019-07-01
Publication date: 2020-01-02

Abstract

The present invention provides novel fluorinated analogs of fentanyl and methods of use. Specifically, the analogs of fentanyl can be used for the treatment of pain, including inflammation associated pain or chronic pain.

Description

FLUORINATED COMPOUNDS AS PH-SENSITIVE ANALGESICS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US Provisional Application No. 62/692,335 filed on June 29, 2018, the contents of which are incorporated by reference in its entirety.

STATEMENT REGARD 1NG FEDERALLY SPONSORED RESEARCH

[0002] N/A

BACKGROUND OF THE INVENTION

[0003] The field of the invention is related to safer novel pH-sensitive analogs of fentanyl that can activate targeted opioid receptors with reduced side effects.

[0004] There are many opioid receptor ligands that are used as analgesic drugs, of which morphine is the oldest and most widely used. These drugs typically act at the mu opioid receptor (MOR). Opioid analgesics, including fentanyl and its analogs, have been used for treatment of moderate to severe pain for many years but use comes with a number of side effects.

[0005] Fentanyl is a synthetic opioid (See U.S. Patent No. 3,141,823). lt and its analogs, including, sufentanil, alfentanil, and remifentanil, are used for the treatment of both acute and chronic pain, or as analgesic anaesthetics during surgery. They are extremely powerful analgesics, but also highly addictive, as physical dependence can develop over a few days. Further, prolonged use results in the development of tolerance, which results in the need to increase the effective dose. Fentanyl, like most MOR agonists, has a myriad of significant and dangerous side effects, including respiratory depression, high abuse potential, constipation, and decreased motor control. Fentanyl and its analogs are responsible for the recent large increase in overdose deaths from street narcotics. For many decades, medicinal chemists have strived to identify new compounds with similar analgesic ability to morphine, but with less danger of overdose and abuse potential.

[0006] Fentanyl acts preferentially on MORs. Other derivatives have also been contemplated that may reduce side effects, for example, the fluorinated fentanyl analog disclosed in US Patent 9,133,120, and Science, 355: 966-969 (2017), termed NFEPP. During the course of this work, an additional fluorinated fentanyl analog was disclosed in a publication (Scientific Reports, 8: 8965 (2018)) termed FF3, though the preparation of this compound was not disclosed.

[0007] There is a need for novel fentanyl derivatives that provide lower levels of side effects commonly associated with fentanyl and other conventional opioid compounds, but provide equivalent or better pain management.

SUMMARY OF THE INVENTION

[0008] The present invention provides novel fluorinated compounds that are fentanyl analogs with a fluorine attached to carbon 2 of the side chain relative to the piperidine, i.e.“beta-fluorine”, and they may have additional fluorine(s) on the arene ring of the phenethyl side chain. These compounds are less basic than the parent unfluorinated compounds and may be selective for inflamed and damaged tissues at lower pH, promoting analgesic effects in these tissues with decreased CNS-related side effects. Specifically, these compounds are easier to prepare than the prior compound NFEPP, they are not generated as diastereomeric mixtures requiring complex separation conditions, and they may have superior properties, such as superior selectivity for peripheral receptors at inflamed sites over those in the brain that contribute to dangerous effects such as respiratory depression and the euphoric effects leading to addiction.

[0009] ln one aspect, the present invention provides a compound of formula 11, salts or enantiomer thereof,

wherein

R¹ is a C1-C12 alkyl group, preferably ethyl (Et),

R² is selected from the group consisting of:

(i) (ii) and (in)

Ar¹ is selected from the group consisting of:

Ar¹

Ar² is wherein each X and Y are independently selected from H, F and Cl, and wherein if R² is (i), then Ar¹ and Ar² are not both phenyl.

[0010] ln another aspect, the present invention provides a compound of formula 1, salts or enantiomer thereof,

wherein

R¹ is a C₁-C₁₂ alkyl group,

Ar¹ is selected from the group consisting of:

Ar¹ :

Ar

2 is wherein each X and Y are independently selected from H, F and Cl, and wherein Ar¹ and Ar² are not both phenyl ln a preferred example, R¹ is an ethyl. [0011] ln another aspect, the disclosure provides a compound comprising:

wherein Ar is a halogenated phenyl and Ph is phenyl, wherien the halogenated phenyl has one or more halogens selected from F, Br or Cl.

[0012] ln yet another aspect, the present invention provides a compound

formula (111), salts or enantiomer thereof:

(111)

wherein ArUs selected from the group consisting of:

Ar¹

Ar² is , and each X and Y are independently selected from H, F and Cl.

[0013] ln another aspect, the present invention provides a compound of formula (IV), salts or enantiomer thereof: [0014]

wherein ArUs selected from the group consisting of: Ar¹ _s

Ar² is , and each X and Y are independently selected from H, F and Cl.

[0015] ln another aspect, the compound is selected from the group consisting of

, salts or an enantiomer thereof.

[0016] ln a further aspect, the invention provides a composition comprising a fluorinated compound described herein and a pharmaceutically acceptable carrier.

[0017] ln yet another aspect, the present invention provides a method of treating chronic or acute pain, the method comprising administering an effective amount of the fluorinated compound described herein or the composition comprising the fluorinated compound, wherein the administration is characterized by the reduction of one or more side effects observed with use of fentanyl.

[0018] The foregoing and other aspects and advantages of the invention will appear from the following description ln the description, reference is made to the accompanying drawings which form a part hereof, and in which there are shown, by way of illustration, preferred embodiments of the invention. Such embodiments do not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention.

BR1EF DESCRIPTION OF THE DRAW1NGS

[0019] F1G. 1 is a representative schematic of the making of b-fluorinated fentanyl analogs of the present invention.

[0020] F1G. 2 is an alternative protocol for the making of b-fluorinated fentanyl derivatives of the present invention.

[0021] F1G. 3 is a graph depicting the activity of a fluorinated fentanyl derivative of the present invention (B-fluorofentanyl, labeled in our schemes as S13) in activating the mu opioid receptor using a cellular cAMP assay at pH 6.5 and 7.4.

DETA1LED DESCRIPTION OF THE INVENTION

[0022] pH dependent compounds

[0023] The present invention provides novel fluorinated fentanyl analogs. These compounds may be selective for inflamed and damaged tissues with lower pH, promoting analgesic effects with decreased CNS-related side effects ln particular, this may lead to less respiratory depression and abuse potential. The compounds of the present invention are also easier to manufacture than prior reported fluorinated fentanyl analogs, and may have fewer CNS-related side effects. The fluorinated compounds of the present invention have pH-dependent activity at the mu opioid receptor. pH dependence is determined by methods known in the art, for example, performing the cell assay at different pH to determine activity.

ln one embodiment, the present invention provides a compound of formula 1, 11, 111 or IV, or a salt or enantiomer thereof as described above and demonstrated in Examples in S1-S12. ln a preferred embodiment, the compound is of formula 1, and comprises at least one F. ln one example, Ar¹ is phenyl , and at least one of X and Y is F. ln another example, both X and Y are F, preferably where R² is (i).

[0024] ln one example, the invention is a fluorinated compound of the following or a salt or an enantiomer thereof:

Ar = halogenated phenyl,

e.g. 2-fluorophenyl

wherein the halogenated phenyl contains one or more halogens selected from F, Cl, or Br. ln one example, the halogenated phenyl comprises one or more F.

[0025] ln another embodiment, a fluorinated pH-dependent compound is selected from one of the following:

[0026] Suitable compounds of the present invention can be found as S1-S12 in the Examples below.

[0027] ln another embodiment, the fluorinated compounds of the present disclosure optimally provide analgesic effects in tissues that exhibit lower pH, for example, but not limited to, inflamed or injured tissue lt has been shown that pH values as low as 4-5 have been measured in painful inflammation (Reeh, P. W. & Steen, K. H., Prog Brain Res 113, 143-51 (1996), Woo, Y. C., et al., Anesthesiology 101, 468-75 (2004)). Thus, in one embodiment, the fluorinated compounds of the present invention are able to target areas of damage, inflammation and/or pain by preferentially targeting mu receptors in low pH locations within a subject.

[0028] ln one embodiment of the present invention the fluorinated compounds as described herein are characterized by being able to target an opioid receptor selected from the mu-receptor, delta-receptor and kappa-receptor. The opioid receptors mu (m), delta (d) and kappa (K) are partially redundant in function and are intended as target opioid receptors. Suitable target receptors include the mu (m), delta (d) and kappa (K) sub-types, for example, but not limited, to, mi, m2, m₃, di, d2, ki, K2 and K₃ receptors.

[0029] ln one embodiment, the present invention provides fluorinated compounds as described herein wherein the compounds activate the target opioid receptor in inflammation-associated conditions, for example, low pH. Suitable low physiological pH values in inflamed tissue include, but are not limited to, for example, pH from 4-6.5, for example, 4, 4.5, 5, 5.5, 6 or 6.5, or any pH values or ranges in-between 4-6.5.

[0030] The present disclosure also contemplates compositions comprising or consisting essentially of the fluorinated compound and a pharmaceutically acceptable carrier ln some embodiments, the compositions can be used for treatment of acute or chronic pain.

[0031] ln some emboidments, the compounds of the present invention are provided in a salt form. Suitable salts of the compounds would be understood by one skilled in the art, for example, ammonium salts.

[0032] A "pharmaceutically acceptable carrier" means any conventional pharmaceutically acceptable carrier, vehicle, or excipient that is used in the art for production and administration of compositions to a subject. Pharmaceutically acceptable carriers are typically non-toxic, inert, solid or liquid carriers which are physiologically balanced. Typically phosphate buffer saline or other saline solutions are physiologically acceptable carriers ln some embodiments, additional components may be add to preserve the structure and function of the analogs of the present invention, but are physiologically acceptable for administration to a subject. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Lipid carriers may be used to formulate certain formulations for specific routes of administration. As used herein,“carrier” includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, polymers, colloids, and the like. The use of such carriers for pharmaceutical active substances is well known in the art.

[0033] A pharmaceutical composition of the present invention can include pharmaceutically acceptable salts of the components therein.

[0034] The composition according to the present invention may be formulated for oral administration, parenteral administration, including, but not limited to, injection, continuous infusion, intravenous administration, intramuscular, and subcutaneous, transdermal administration, buccal administration, intranasal administration, sublingual administration, rectal administration, among others. The route of administration will determine the pharmaceutically acceptable carrier to be used.

[0035] The active compound is preferably administered with a pharmaceutically acceptable carrier selected on the basis of the selected route of administration and standard pharmaceutical practice. The active agent may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, Pa. Suitable dosage forms may comprise, for example, tablets, capsules, solutions, parenteral solutions, troches, suppositories, or suspensions.

[0036] For oral administration, the compounds may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules or other suitable oral dosage forms. For example, the active agent may be combined with at least one excipient such as fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents absorbents or lubricating agents. Suitable oral formulations include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, nanocarriers, liposomes, gels, lollipops, mucosal adhesives, or syrups or elixirs. Oral formulations may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions. Tablets contain the compound in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. The tablets may be uncoated or they may be coated by known techniques to provide extended release, e.g. delay disintegration and absorption in the gastrointestinal tract providing sustained release over a longer period.

[0037] For parenteral administration, the active compound may be mixed with a suitable carrier or diluent such as water, an oil (e.g., a vegetable oil), ethanol, saline solution (e, g., phosphate buffer saline or saline), aqueous dextrose (glucose) and related sugar solutions, glycerol, or a glycol such as propylene glycol or polyethylene glycol. Stabilizing agents, antioxidant agents and preservatives may also be added. Suitable antioxidant agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol. The composition for parenteral administration may take the form of an aqueous or nonaqueous solution, dispersion, suspension or emulsion.

[0038] For example, for buccal administration, the fluorinated compounds may be formulated into dissolvable tablets or lozenges.

[0039] Suitable transdermal administration techniques are known in the art, including, but not limited to, for example, patches (by simple diffusion across a gradient) and transdermal patch technology using a small amount of iontophoretic electric current to drive compound across the skin barrier ("on-demand" administration). Suitable compositions for use in transdermal patches are known in the art. For example, transdermal patches containing a pressure sensitive adhesive (e.g. silicone pressure sensitive adhesive) that adheres to a patient's skin with slight pressure and releases from the surface with negligible transfer of the adhesive to the surface are known in the art. For example, a polymer matrix or monolithic device in which the fluorinated fentanyl compound is contained in a polymer matrix film through which the compound diffuses to the skin, for example, as detailed in U.S. Pat. Nos. 4,839,174, 4,908,213 and 4,943,435, transdermal patches containing silicone pressure sensitive adhesive compositions are described in U.S. Pat. No. 5,232,702 (Pfister et al.), WO 00/33812 (Miranda et al.), WO 96/40085 (Mantelle et al.), and U.S. Pat. Nos. 5,603,947 and 5,232,702, transdermal patches containing fentanyl in a silicone pressure sensitive adhesive are described, for example, in U.S. Pat. Nos. 4,588,580 (Gale et al.), 5,186,939 (Cleary et al.), 4,588,580, and 5,186,939 (a laminated composite), U.S. Appl. No. US20090238861, U.S. Patent No. 7556823, all of which may be modified for use in the present invention ln addition, a reservoir-type transdermal patch described in the 2002 Physician's Desk Reference. Duragesic® which is a rectangular transparent patch comprising a protective liner and four functional layers may be used in the practice of the present invention (the layers are: 1) a backing layer of polyester film; 2) a drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetate copolymer membrane that controls the rate of fentanyl delivery to the skin surface; and 4) a fentanyl containing silicone adhesive).

[0040] The pharmaceutical composition is preferably in unit dosage form ln such form the preparation is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0041] Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0042] The fluorinated compounds described herein may be associated with the inhibition, reduction or elimination of one or more side effects associated with fentanyl treatment. The one or more side effects include, but are not limited to, for example, respiratory depression, high abuse potential, tolerance, constipation, nausea, vomiting, and decreased motor control.

[0043] ln one embodiment of the present invention the fluorinated compounds exhibits inflammation-specific peripheral analgesic function in inflamed or injured tissues without causing central nervous system or intestinal side effects. The fluorinated compounds have pH-dependent efficacy that produce a reduced pKa in order to enable inflammation-related pH-specific activity.

[0044] The fluorinated compounds described herein may be used for the treatment of acute or chronic pain. Sources of chronic pain include, but are not limited to, for example, arthritis, chronic back pain, headache, skin inflammation, neuropathic pain, cancer pain, disorders of the immune system, multiple sclerosis, burn injury, among others. Sources of acute pain may include, but are not limited to, slipped disc, back pain, traumatic pain, post-operative pain, inflamed joints, surgery, dental surgery, burn injury, or eye lesions.

[0045] The fluorinated compounds described herein may also be used as a short acting analgesic during surgery. They can be used when rapid but short duration pain control is needed, for example, during a nerve block, head pinning, etc. ln a preferred embodiment, the drug is administered parenterally (e.g. injection) for fast onset and precise control of dosage ln some embodiments, the fluorinated compounds provide sedation in addition to pain control for short periods of time. Suitably, the compounds may be used in any surgery in which sedation and/or fast acting anesthetic is needed. Suitable surgeries include, but are not limited to, for example, carniotomies, spinal surgery, cardiac surgery, gastric bypass surgery, orthopedic surgery, dental surgery, and the like.

[0046] Alternatively defined, the invention relates to the use of a composition comprising the compounds of formula 1, 11, 111 or IV, or salts thereof, for the preparation of a medicament for the treatment of pain in a mammal.

[0047] Methods of treatment

[0048] Methods of the present disclosure include methods of using the fluorinated compounds and pharmaceutical compositions described herein for the treatment of a subject in need thereof ln some embodiments, methods of treating acute or chronic pain in a subject are contemplated. Suitably, the methods provided reduce one or more side effects seen with use of fentanyl.

[0049] For purposes of the present invention,“treating” or“treatment” describes the management and care of a subject for the purpose of reducing chronic or acute pain that may be associated with inflammation, injury, a disease, condition, or disorder. Treating includes the administration of fluorinated fentanyl compounds of the present invention to prevent the onset of pain, alleviating pain, or eliminating pain associated with inflammation, injury, disease, condition or disorder. Treating also encompasses therapeutic and palliative treatment. The aim of treatment includes the alleviation or prevention of pain symptoms. The term "treatment" can be characterized by at least one of the following: (a) the reducing, slowing or inhibiting pain from inflammation, injury, disease, condition or disorder; (b) preventing pain associated with inflammation, injury, disease, condition or disorder ln some embodiments, the optimum effective amount can be readily determined by one skilled in the art using routine experimentation ln some embodiments, the compounds are used for treatment of pain, including but not limited to, inflammatory pain or inflammation-associated pain, which refers to any type of pain that is associated or experienced by a subject when inflammation is involved. For example, suitable pain that may be treated by the compounds described herein include, but are not limited to, pain associated with arthritis, skin inflammation, back pain, headache, neurogenic migraine, inflammatory lesions of the central and peripheral nervous system (neuropathic pain), cancer pain, disorders of the immune system, multiple sclerosis, traumatic pain, posteoperative pain, inflamed joints, dental surgery, visceral pain, bone pain , burn injury, eye lesions, chronic pain, among others.

[0001] The term "effective amount" or“therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and/or clinical results. A therapeutically effective amount of the fluorinated fentanyl compound or compositions described herein may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the disclosed compounds to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the disclosed compounds are outweighed by the therapeutically beneficial effects.

[0050] An“effective treatment” refers to treatment producing a beneficial effect, e.g., amelioration of pain associated with inflammation or injury. A beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method. A beneficial effect can also take the form of reducing, inhibiting or preventing pain associated with inflammation, chronic disease or injury.

[0051] By "ameliorate", "amelioration", "improvement" or the like we mean a detectable improvement or a detectable change consistent with improvement occurring in a subject or in at least a minority of subjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range between any two of these values. Such improvements or changes may be observed in treated subjects as compared to subjects not treated with the compounds of the present invention, where the untreated subjects have, or are subject to developing, the same or similar acute or chronic pain. Amelioration may be determined subjectively or objectively, e.g., self-assessment by a subject(s), by a clinician's assessment, or by conducting an appropriate assay or measurement, including, e.g., a quality of life assessment, a reduced severity of acute or chronic pain, or a suitable assay(s) for the level or activity(ies) of a biomolecule(s) associated with pain within a subject. Amelioration may be transient, prolonged or permanent, or it may be variable at relevant times during or after the compound of the present invention is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within about 1 hour of the administration or use of the compounds of the present invention to about 3, 6, 9 months or more after a subject(s) has received the compounds of the present invention.

[0052] By "modulation" of, e.g., acute or chronic pain and the like means that the pain is detectably decreased. Such decrease may be observed in treated subjects as compared to subjects not treated with the compounds of the present invention, where the untreated subjects have, or are subject to developing, the same or similar acute or chronic pain. Such decreases may be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or about within any range between any two of these values. Modulation may be determined subjectively or objectively, e.g., by the subject's self- assessment, by a clinician's assessment or by conducting an appropriate assay or measurement, including, e.g., quality of life assessments or suitable assays for the level or activity of molecules or receptors within a subject. Modulation may be transient, prolonged or permanent or it may be variable at relevant times during or after the compounds of the present invention is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within about 1 hour of the administration or use of the compounds of the present invention to about 3, 6, 9 months or more after a subject(s) has received the compounds of the present invention. [0053] By "administering" we mean any means for introducing the compounds of the present invention into the body, preferably into the systemic circulation. Examples or routes of administration are described above.

[0054] Suitable effective dosages may range from about 0.0001 mg/kg to 1500 mg/kg, more preferably 1 to 1000 mg/kg, more preferably from about 1 to 150 mg/kg of body weight, alternatively about 50 to 100 mg/kg of body weight, alternatively about 0.01 mg/kg to about 500 mg/kg of body weight per day. lt will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0055] By "subject" or "patient" we mean mammals and non-mammals. "Mammals" means any member of the class Mammalia including, but not limited to, humans, non human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like ln a preferred embodiment, the subject is a human. The term "subject" does not denote a particular age or sex.

[0056] Methods of Making

[0057] The present invention provides simple methods of manufacturing fluorinated fentanyl compounds.

[0058] The fluorinated compounds described here can be made convergently via alkylation of readily available piperidine building blocks with fluorinated alkyl halide electrophiles. Alternatively, they can be made by alkylating the piperidine with an alpha- haloacetophenone, reducing the resulting ketone to an alcohol, and converting the resulting alcohol to a fluoride using known fluorinating agents, such as DAST, according to reported protocols, such as that disclosed in WO 2016/069426. These compounds can optionally be made in enantioenriched form by asymmetrically reducing the ketone intermediates, and/or performing chiral resolutions using chiral acids. [0059] A suitable method of making is shown in the below Examples.

[0060] The present invention has been described in terms of one or more preferred embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention.

[0061] The invention will be more fully understood upon consideration of the following non-limiting examples.

EXAMPLES

[0062] Example 1: Fluorinated fentanyl analogs

[0063] One fluorine atom is incorporated into the phenethyl side chain of fentanyl in order to make safer analgesics as depicted as S1-S13 depicted below. Doing so will decrease the pKa value of the tertiary amine, making it less able to be protonated at physiological pH (~7.4), which is generally required for activation of the mu opioid receptor. However, these compounds may be protonated at the lower pH that can be present in damaged and inflamed tissues.

[0064] Abbreviations used in this example: CDCb-chloroform-deuterated; DCM- dichloromethane (solvent); EtOAc-ethyl acetate (solvent); HPLC-high performance liquid chromatography; K2CO3 -potassium carbonate; LCMS-liquid chromatography-mass spectrometry; Na2S04-sodium sulfate; Na2C0₃-sodium carbonate; NMR-nuclear magnetic resonance; MeOH- methanol (solvent); TLC- thin-layer chromatography.

[0065] Synthetic procedures

[0066] A) General lnformation

[0067] All reagents and solvents, including anhydrous solvents, were purchased from commercial vendors and used as received. Deionized water was purified by charcoal filtration to a minimum resistance of 15 MW and used for reaction workups and in reactions with water. NMR spectra were recorded on Varian 300 MHz or 400 MHz spectrometers as indicated. Proton and carbon chemical shifts are reported in parts per million (ppm; d) relative to tetramethylsilane (1H d 0), or CDC13 (13C d 77.16), (CD3)2CO (1H d 2.05, 13C d 29.84), d6-DMSO (1H d 2.50, 13C d 39.5), or CD30D (1H d 3.31, 13C d 49.00). NMR data are reported as follows: chemical shifts, multiplicity (obs = obscured, app = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = complex overlapping signals); coupling constant(s) in Hz; integration. Unless otherwise indicated, NMR data were collected at 25 °C. Filtration was performed by vacuum using VWR Grade 413 filter paper, unless otherwise noted. Flash chromatography was performed using Biotage SNAP cartridges filled with 40-60 pm silica gel on Biotage lsolera automated chromatography systems with photodiode array UV detectors. Analytical thin layer chromatography (TLC) was performed on Agela Technologies 0.25 mm glass plates with 0.25 mm silica gel. Visualization was accomplished with UV light (254 nm) and KMn04 stain, unless otherwise noted. Chemical names were generated and select chemical properties were calculated using either ChemAxon Marvin suite or ChemDraw Professional 15.1. NMR data were processed using either MestreNova or ACD/NMR Processor Academic Edition using the JOC report format. High-resolution mass spectra (HRMS) were obtained either at the University of Wisconsin-Milwaukee Mass Spectrometry Laboratory with a Shimadzu LCMS-1T-TOF with ES1 and APC1 ionization or from the University of Cincinnati with an Agilent 6540 Accurate-Mass with Q-TOF LC/MS.

[0068] B) LC-MS characterization methods

[0069] Tandem liquid chromatography/mass spectrometry (LC-MS) was performed on a Shimadzu LCMS-2020 with autosampler, photodiode array detector, and single- quadrupole MS with ES1 and APC1 dual ionization using a Peak Scientific nitrogen generator.

Method A

Column: Phenomenex Gemini C18 (100 x 4.6 mm, 3 pm particle size, 110 A pore size)

Column temperature: 40 °C

Sample lnjection: 1-5 pL of sample in MeCN or MeOH

Chromatographic monitoring: UV absorbance at 210 or 254 nm Mobile Phase: Solvent A: H20 w/ 0.1% formic acid; Solvent B: MeOH w/ 0.1% formic acid

Flow Rate: 1.0 mL/min

Gradient: 0 to 0.1 min: 25% MeOH (lsocratic)

0.1 min to 5 min: 25% to 95% MeOH (Gradient)

5 min to 7 min: 95% MeOH (lsocratic) Synthetic schemes are depicted in F1G. 1 and F1G. 2.

d) Experimental procedures for fluorinated fentanyl analogs

/V-{l-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-/V-phenylpropanamide (SI)

To a 20 mL scintillation vial with a stir bar was added A-phenyl-A-(4-piperidyl)propanamide (50.0 mg, 0.215 mmol), 2-bromo-l-(4-fluorophenyl)ethanone (60.0 mg, 0.276 mmol), and K2CO3 (37.9 mg, 0.274 mmol). The vial was sealed, flushed with nitrogen, and dissolved in ethanol (10 mL). The reaction was chilled to -5 °C and allowed to warm up to room temperature over 4 h, after which time a sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half-saturated aq. Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was concentrated under reduced pressure, and the crude material was dissolved in a minimal amount of DCM and loaded onto a 25 g silica column, and purified by flash chromatography (25 g S1O2; 0-5% MeOH/DCM) to give SI as an off-white solid (75 mg, 95%). TLC: mobile phase: MeOH:DCM (10:90), Rf = 0.68; LC/MS t_R = 3.94 min (Characterization Method A); m/z = 368.90 (M + H); ¾ NMR (400

MHz, CDCh) d = 7.99 - 7.90 (m, 2 H), 7.43 - 7.31 (m, 3 H), 7.12 - 7.01 (m, 4 H), 4.68 (tt, J = 3.9, 12.2 Hz, 1 H), 3.70 (s, 2 H), 3.02 - 2.90 (m, 2 H), 2.24 (dt, J= 2.0, 11.8 Hz, 2 H), 1.90 (q, J = 7.5 Hz, 2 H), 1.80 - 1.70 (m, 2 H), 1.50 (dq, J = 3.8, 12.3 Hz, 2 H), 0.99 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCh) d =194.8, 173.5, 167.0, 164.4, 138.8, 132.4, 132.3, 130.7, 130.6, 130.4, 129.3, 128.3, 115.7, 115.5, 64.3, 53.7, 51.8, 30.4, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCh) d = -104.86.

/V-{l-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-/V-phenylpropanamide (S2) To an oven dried 20 mL scintillation vial with a stir bar was added SI (67.5 mg, 0.183 mmol)), which was subsequently diluted in anhydrous MeOH (10 mL). The vial was cooled in ice bath to 0 °C, to which NaBTL (20.0 mg, 0.529 mmol) was added. The vial was sealed and stirred while attached to a bubbler and allowed to gradually warm up to room temperature over 2 h. A sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half saturated Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was diluted with EtOAc (30 mL), washed with half-saturated aq. Na2CCb (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 25 g silica column, and purified with flash chromatography (25 g S1O2; 0-6% MeOH/DCM) to give S2 as a yellow oil (66 mg, 50%). TLC: mobile phase: MeOfLDCM (10:90), Rf = 0.65; LC/MS tR = 3.68 min (Characterization Method A); m/z = 370.95 (M + H); ¾ NMR (400 MHz, CD2CI3) d =7.46 - 7.36 (m, 3 H), 7.30 - 7.23 (m, 2 H), 7.11 - 7.04 (m, 2 H), 7.02 - 6.93 (m, 2 H), 4.66 (tt, J = 3.9, 12.2 Hz, 1 H), 4.58 (dd, J = 3.4, 10.6 Hz, 1 H), 3.16 - 3.07 (m, 1 H), 2.82 - 2.72 (m, 1 H), 2.50 - 2.38 (m, 2 H), 2.35 - 2.26 (m, 1 H), 2.15 (dt, J = 2.3, 11.8 Hz, 1 H), 1.91 (q, J = 7.4 Hz, 2 H), 1.86 - 1.70 (m, 2 H), 1.48 - 1.29 (m, 2 H), 1.00 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCh) d =173.5, 163.3, 160.9, 138.8, 137.7, 130.3, 129.4, 128.4, 127.4, 127.3, 115.2, 115.0, 68.3, 65.9, 54.9, 52.0, 51.0, 30.9, 30.5, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCh) d = -115.38.

/V-{l-[2-fluoro-2-(4-fluorophenyl)ethyl]piperidin-4-yl}-/V-phenylpropanamide (S3)

To an oven dried 20 mL scintillation vial with a stir bar was added S2 (39.0 mg, 0.105 mmol) The vial was sealed and flushed with nitrogen gas for 5 min and to this was syringed anhydrous DCM (10 mL). The solution was cooled to -78 °C in an acetone/dry ice bath and to this was syringed Triethylamine trihydrofluoride (40.0 pL, 0.245 mmol) and DAST (20.0 pL, 0.151 mmol), respectively. The reaction stirred at -78 °C for 4 h, and then allowed gradually warm up to room temperature overnight. A sample aliquot was taken from the reaction, diluted with EtOAc in a microtube, and washed with half-saturated Na2C03. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was quenched with half- saturated aq. Na2CCb (6 mL) and allowed to vigorously stir for 10 min. The reaction mixture was then transferred to a separatory funnel and diluted with EtOAc (30 mL), washed with half- saturated aq. Na2CCb (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 10 g silica column, and purified with flash chromatography (10 g S1O2; 0- 6% MeOH/DCM) to give S3 as an off-white solid (33 mg, 84%). TLC: mobile phase

MeOH:DCM (10:90), Rf = 0.67; LC/MS tR = 3.93 min (Characterization Method A); m/z =

373.30 (M + H); ¾ NMR (400 MHz, CD2CI3) d =7.44 - 7.34 (m, 3 H), 7.28 (s, 2 H), 7.12 - 6.99 (m, 4 H), 5.62 - 5.45 (m, 1 H), 4.69 (tt, J= 3.9, 12.2 Hz, 1 H), 3.09 - 2.96 (m, 2 H), 2.84 (ddd, J = 9.0, 14.3, 17.0 Hz, 1 H), 2.60 - 2.43 (m, 1 H), 2.35 - 2.22 (m, 2 H), 1.93 (q, J= 7.5 Hz, 2 H), 1.84 - 1.74 (m, 2 H), 1.55 - 1.38 (m, 2 H), 1.02 (t, J= 7.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCh) 5 =173.5, 163.8, 161.4, 138.8, 130.4, 129.3, 128.3, 127.4, 127.3, 127.2, 115.5, 115.3, 92.8, 91.1, 64.6, 64.4, 53.9, 53.4, 51.9, 30.5, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCh) d = -113.50, -175.40- -

175.30 (ddd, 1 Hz, 1 F).

/V-{l-[2-(3-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-/V-phenylpropanamide (S4)

To a 20 mL scintillation vial with a stir bar was added /V-phenyl-/V-(4-piperidyl)propanamide (50.0 mg, 0.215 mmol), 2-bromo-l-(3-fluorophenyl)ethanone (60.0 mg, 0.276 mmol), and K2C03 (37.9 mg, 0.274 mmol). The vial was sealed, flushed with nitrogen, and dissolved in ethanol (10 mL). The reaction was chilled to -5 °C and allowed to warm up to room temperature over 4 h, after which time a sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half-saturated aq. Na2CCh. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was concentrated under reduced pressure, and the crude material was dissolved in a minimal amount of DCM and loaded onto a 25 g silica column, and purified by flash chromatography (25 g S1O2; 0-5% MeOH/DCM) to give S4 as an off-white solid (75 mg, 94%). TLC: mobile phase: MeOH:DCM (10:90), Rf = 3.96 min (Characterization Method A); m/z = 368.95 (M + H); ¾ NMR (400 MHz, CD2CI3) d = 7.71 - 7.66 (m, 1 H), 7.63 - 7.57 (m, 1 H), 7.42 - 7.31 (m, 4 H), 7.24 - 7.18 (m, 1 H), 7.09 - 7.02 (m, 2 H), 4.68 (tt, J = 3.9, 12.2 Hz, 1 H), 3.72 (s, 2 H), 3.01 - 2.94 (m, 2 H), 2.25 (dt, J = 2.0, 11.8 Hz, 2 H), 1.90 (q, J = 7.5 Hz, 2 H), 1.81 - 1.71 (m, 2 H), 1.51 (dq, J = 3.8, 12.3 Hz, 2 H), 0.99 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCb) d =195.1, 173.5, 163.9, 161.5, 138.7, 138.0, 137.9, 130.4, 130.2, 130.2, 129.3, 128.3, 123.7, 123.6, 120.3, 120.1, 114.9, 114.7, 64.4, 53.7, 51.8, 30.4, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCb) d = -111.75.

/V-{l-[2-(3-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-/V-phenylpropanamide (S5)

To an oven dried 20 mL scintillation vial with a stir bar was added S4 (66.6 mg, 0.181 mmol), which was subsequently diluted in anhydrous MeOH (10 mL). The vial was cooled in ice bath to 0 °C, to which NaBH₄ (19.8 mg, 0.523 mmol) was added. The vial was sealed and stirred while attached to a bubbler and allowed to gradually warm up to room temperature over 2 h. A sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half saturated Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was diluted with EtOAc (30 mL), washed with half-saturated aq. Na2CCb (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 25 g silica column, and purified with flash chromatography (25 g S1O2; 0-6% MeOH/DCM) to give S5 as a yellow oil (45 mg, 68%). TLC: mobile phase: MeOH:DCM (10:90), Rf = 0.65; LC/MS tR = 3.65 min (Characterization Method A); m/z = 370.90 (M + H); ¾ NMR (400 MHz, CD2CI3) d = 7.46 - 7.36 (m, 3 H), 7.28 - 7.21 (m, 1 H), 7.10 - 7.01 (m, 4 H), 6.94 - 6.87 (m, 1 H), 4.67 (tt, J = 3.9, 12.2 Hz, 1 H), 4.60 (dd, J = 3.4, 10.6 Hz, 1 H), 3.15 - 3.06 (m, 1 H), 2.81 - 2.72 (m, 1 H), 2.49 - 2.39 (m, 2 H), 2.31 (dd, 7 = 10.7, 12.5 Hz, 1 H), 2.17 (dt, J = 2.3, 11.8 Hz, 1 H), 1.91 (q, J = 7.4 Hz, 2 H), 1.85 - 1.70 (m, 2 H), 1.48 - 1.27 (m, 2 H), 1.00 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCb) d =173.5, 164.1, 161.7, 145.0, 144.9,

138.8, 130.3, 129.8, 129.7, 129.4, 128.4, 121.3, 121.2, 114.3, 114.1, 112.8, 112.5, 68.3, 65.7,

54.8, 52.0, 51.0, 30.8, 30.4, 9.6. ¹⁹F NMR (376 MHz, CDCb) d = -113.22.

/V-{l-[2-fluoro-2-(3-fluorophenyl)ethyl]piperidin-4-yl}-/V-phenylpropanamide (S6)

To an oven dried 20 mL scintillation vial with a stir bar was added S5 (39.7 mg, 0.107 mmol).

The vial was sealed and flushed with nitrogen gas for 5 min and to this was syringed anhydrous DCM (10 mL). The solution was cooled to -78 °C in an acetone/dry ice bath and to this was syringed Triethylamine trihydrofluoride (40.0 gL, 0.245 mmol) and DAST (20.0 gL, 0.151 mmol), respectively. The reaction stirred at -78 °C for 4 h, and then allowed gradually warm up to room temperature overnight. A sample aliquot was taken from the reaction, diluted with EtOAc in a microtube, and washed with half-saturated Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was quenched with half- saturated aq. Na2CCb (6 mL) and allowed to vigorously stir for 10 min. The reaction mixture was then transferred to a separatory funnel and diluted with EtOAc (30 mL), washed with half- saturated aq. NaHC03 (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 10 g silica column, and purified with flash chromatography (10 g S1O2; 0- 6% MeOH/DCM) to give S6 as a clear yellow oil (35 mg, 86%). TLC: mobile phase

MeOLfDCM (10:90), Rf = 0.67; LC/MS tR = 3.98 min (Characterization Method A); m/z = 373.25 (M + H); ¾ NMR (400 MHz, CD2CI3) d = 7.45 - 7.27 (m, 4 H), 7.12 - 6.94 (m, 5 H), 5.64 - 5.46 (m, 1 H), 4.69 (tt, J= 3.9, 12.2 Hz, 1 H), 3.09 - 2.95 (m, 2 H), 2.83 (ddd, J= 9.0,

14.4, 17.5 Hz, 1 H), 2.63 - 2.44 (m, 1 H), 2.38 - 2.23 (m, 2 H), 1.93 (q, J= 7.5 Hz, 2 H), 1.85 - 1.73 (m, 2 H), 1.46 (ttt, J= 4.1, 8.2, 12.3 Hz, 2 H), 1.02 (t, J= 7.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCh) 5 = 173.5, 161.5, 138.8, 130.4, 130.0, 129.3, 128.3, 120.9, 115.3, 115.1, 112.6, 112.5, 112.4, 112.3, 94.5, 92.6, 90.9, 64.6, 64.3, 53.9, 53.4, 51.9, 30.5, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCh) d = -112.48, -178.15- -178.42 (ddd, J= 1 Hz).

/V-{l-[2-(2-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-/V-phenylpropanamide (S7)

To a 20 mL scintillation vial with a stir bar was added A-phenyl-A-(4-piperidyl)propanamide (28.1 mg, 0.121 mmol), 2-bromo-l-(2-fluorophenyl)ethanone (33.7 mg, 0.155 mmol), and K2C03 (21.3 mg, 0.154 mmol). The vial was sealed, flushed with nitrogen, and dissolved in ethanol (10 mL). The reaction was chilled to -5 °C and allowed to warm up to room temperature over 4 h, after which time a sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half-saturated aq. Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was concentrated under reduced pressure, and the crude material was dissolved in a minimal amount of DCM and loaded onto a 25 g silica column, and purified by flash chromatography (25 g S1O2; 0-5% MeOH/DCM) to give S7 as a clear yellow oil (37 mg, 81%). TLC: mobile phase: MeOH:DCM (10:90), Rf = 0.68; LC/MS tR = 3.76 min (Characterization Method A); m/z = 368.90 (M + H); 'H NMR (400 MHz,

CD2CI3) d =7.82 (dt, J = 1.8, 7.5 Hz, 1 H), 7.53 - 7.44 (m, 1 H), 7.41 - 7.31 (m, 3 H), 7.22 - 7.14 (m, 1 H), 7.12 - 7.01 (m, 3 H), 4.68 (tt, J= 4.0, 12.2 Hz, 1 H), 3.73 (d, J= 3.3 Hz, 2 H), 2.99 (d, J= 11.4 Hz, 2 H), 2.27 (dt, 7= 2.0, 11.8 Hz, 2 H), 1.91 (q, J= 7.4 Hz, 2 H), 1.81 - 1.70 (m, 2 H), 1.52 (dq, J= 3.9, 12.3 Hz, 2 H), 0.99 (t, J= 7.5 Hz, 3 H).¹³C NMR (101 MHz, CDCh) d = 195.0, 173.5, 163.0, 160.5, 138.8, 134.6, 134.5, 130.6, 130.6, 130.4, 129.2, 128.2, 124.5, 124.5, 116.6, 116.4, 68.1, 68.0, 54.0, 51.9, 30.1, 28.6, 9.6. ¹⁹F NMR (376 MHz, CDCh) d = -107.73.

/V-{l-[2-(2-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-/V-phenylpropanamide (S8)

To an oven dried 20 mL scintillation vial with a stir bar was added S7 (32.6 mg, 88.4 pmol), which was subsequently diluted in anhydrous MeOH (10 mL). The vial was cooled in ice bath to 0 °C, to which NaBHi (9.20 mg, 243 pmol) was added. The vial was sealed and stirred while attached to a bubbler and allowed to gradually warm up to room temperature over 2 h. A sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half saturated Na2CCh. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was diluted with EtOAc (30 mL), washed with half-saturated aq. Na2CCh (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 25 g silica column, and purified with flash chromatography (25 g S1O2; 0-6% MeOH/DCM) to give S8 as a yellow oil (16 mg, 50%). TLC: mobile phase: MeOH:DCM (10:90), Rf = 0.65; LC/MS tR = 3.65 min (Characterization Method A); m/z = 370.90 (M + H); ¾ NMR (400 MHz, CD2CI3) d = 7.53 - 7.46 (m, 1 H), 7.46 - 7.36 (m, 3 H), 7.23 - 7.15 (m, 1 H), 7.15 - 7.04 (m, 2 H), 6.96 (ddd, J= 1.2, 8.2, 10.6 Hz, 1 H), 4.95 (dd, J= 2.9, 10.6 Hz, 1 H), 4.67 (tt, 7= 3.8, 12.1 Hz, 1 H), 3.14 (d, J= 12.3 Hz, 1 H), 2.77 (d, J= 11.7 Hz, O H), 2.61 - 2.51 (m, 1 H), 2.45 (dt, J = 2.4, 11.9 Hz, 1 H), 2.38 - 2.28 (m, 1 H), 2.25 - 2.14 (m, 1 H), 1.91 (q, J = 7.4 Hz, 2 H), 1.85 - 1.72 (m, 2 H), 1.50 - 1.30 (m, 2 H), 1.00 (t, j = 7.5 Hz, 3 H).¹³C NMR (101 MHz, CDCh) d = 173.5, 138.9, 130.3, 129.4, 128.7, 128.6, 128.4, 127.2, 127.2, 124.2, 115.1, 114.8, 64.1, 63.1, 54.9, 52.0, 51.1, 30.9, 30.5, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCh) d = - 120.33.

/V-{l-[2-fluoro-2-(2-fluorophenyl)ethyl]piperidin-4-yl}-/V-phenylpropanamide (S9)

To an oven dried 20 mL scintillation vial with a stir bar was added S8 (39.7 mg, 0.107 mmol). The vial was sealed and flushed with nitrogen gas for 5 min and to this was syringed anhydrous DCM (10 mL). The solution was cooled to -78 °C in an acetone/dry ice bath and to this was syringed Triethylamine trihydrofluoride (20.0 pL, 0.123 mmol) and DAST (10.0 pL, 0.0757 mmol), respectively. The reaction stirred at -78 °C for 4 h, and then allowed gradually warm up to room temperature overnight. A sample aliquot was taken from the reaction, diluted with EtOAc in a microtube, and washed with half-saturated Na2CCh. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was quenched with half- saturated aq. Na2CCh (6 mL) and allowed to vigorously stir for 10 min. The reaction mixture was then transferred to a separatory funnel and diluted with EtOAc (30 mL), washed with half- saturated aq. Na2C03 (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 10 g silica column, and purified with flash chromatography (10 g S1O2; 0- 6% MeOH/DCM) to give S9 as a clear yellow oil (13 mg, 82%). TLC: mobile phase

MeOH:DCM (10:90), Rf = 0.67; LC/MS tR = 4.10 min (Characterization Method A); m/z = 373.25 (M + H); ¾ NMR (300 MHz, CD2CI3) d =7.48 - 7.27 (m, 5 H), 7.21 - 6.95 (m, 4 H), 5.99 - 5.75 (m, 1 H), 4.70 (tt, J= 3.8, 12.2 Hz, 1 H), 3.13 - 3.00 (m, 1 H), 2.87 (ddd, 7= 9.1, 14.4, 18.2 Hz, 1 H), 2.71 - 2.49 (m, 1 H), 2.43 - 2.25 (m, 2 H), 1.93 (q, J= 7.4 Hz, 2 H), 1.80 (dd, 7= 2.1, 12.4 Hz, 2 H), 1.57 - 1.38 (m, 2 H), 1.25 (s, 1 H), 1.02 (t, 7= 7.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCh) d = 173.8, 139.0, 130.7, 130.2, 130.1, 129.5, 128.5, 127.3, 127.1, 124.5, 115.7, 115.4, 88.5, 86.1, 63.7, 63.4, 54.1, 53.4, 52.1, 30.7, 28.7, 9.8. ¹⁹F NMR (376 MHz, CDCh) d = -118.87, -184.19- -184.46 (ddd, J= 1 Hz).

/V-{l-[2-(2,4-difluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-/V-phenylpropanamide (Sll)

To a 20 mL scintillation vial with a stir bar was added /V-phenyl-/V-(4-piperidyl)propanamide (52.8 mg, 0.227 mmol), 2-bromo-l-(2,4-difluorophenyl)ethanone (65.7 mg, 0.280 mmol), and K2CO3 (45.3 mg, 0.328 mmol). The vial was sealed, flushed with nitrogen, and dissolved in ethanol (10 mL). The reaction was chilled to -5 °C and allowed to stir for 4 h, after which, a sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half-saturated aq. Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The vial was kept in the ice bath at 0°C, to which NaBH4 (29.0 mg, 0.767 mmol) was added. The vial was sealed and stirred while attached to a bubbler and allowed to gradually warm up to room temperature over 2 h. A sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half-saturated Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was diluted with EtOAc (30 mL), washed with half-saturated aq. Na2CCb (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 10 g silica column, and purified with flash chromatography (10 g S1O2; 0-6% MeOH/DCM) to give Sll as a yellow oil (39 mg, 45%). TLC: mobile phase: MeOH:DCM (10:90), Rr= 0.57; LC/MS t_R = 3.46 min (Characterization Method A); m/z = 389.35.25 (M + H); ¾ NMR (400 MHz, CD2CI3) d =7.52 - 7.37 (m, 4 H), 7.13 - 7.05 (m, 2 H), 6.89 - 6.80 (m, 1 H), 6.73 (ddd, J= 2.5, 8.7, 10.7 Hz, 1 H), 4.90 (dd, 7= 3.1, 10.5 Hz, 1 H), 4.68 (tt, J= 3.9, 12.2 Hz, 1 H), 3.17 - 3.08 (m, 1 H), 2.82 - 2.72 (m, 1 H), 2.59 - 2.41 (m, 2 H), 2.31 (dd, 7 = 10.5, 12.5 Hz, 1 H), 2.20 (dt, 7= 2.6, 11.7 Hz, 1 H), 1.93 (q, J= 1.5 Hz, 2 H), 1.87 - 1.75 (m, 2 H), 1.51 - 1.30 (m, 2 H), 1.01 (t, 7= 7.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCb) d = 173.5, 138.9, 130.3, 129.4, 128.4, 128.3, 128.2, 128.2, 128.1,

111.4, 111.2, 103.7, 103.4, 103.1, 64.2, 62.8, 54.9, 52.0, 51.1, 30.9, 30.4, 28.5, 9.6. ¹⁹F NMR (376 MHz, CDCb) 5 = -112.15, -116.46.

/V-{l-[2-(2,4-difluorophenyl)-2-fluoroethyl]piperidin-4-yl}-/V-phenylpropanamide

To an oven dried 20 mL scintillation vial with a stir bar was added Sll (39 mg, 0.100 mmol).

The vial was sealed and flushed with nitrogen gas for 5 min and to this was syringed anhydrous DCM (10 mL). The solution was cooled to -78 °C in an acetone/dry ice bath and to this was syringed Triethylamine trihydrofluoride (60.0 pL, 0.368 mmol) and DAST (30.0 pL, 0.227 mmol), respectively. The reaction stirred at -78 °C for 4 h, and then allowed gradually warm up to room temperature overnight. A sample aliquot was taken from the reaction, diluted with EtOAc in a microtube, and washed with half-saturated Na2CCb. The organic layer was separated and analyzed by TLC to confirm reaction completion. The reaction was quenched with half- saturated aq. Na2CCb (6 mL) and allowed to vigorously stir for 10 min. The reaction mixture was then transferred to a separatory funnel and diluted with EtOAc (30 mL), washed with half- saturated aq. Na2C03 (2 x 15 mL), dried over with Na2S0₄, filtered, and concentrated under reduced pressure to give crude product. The crude product was dissolved in a minimal amount of DCM, loaded onto a 10 g silica column, and purified with flash chromatography (10 g S1O2; 0- 6% MeOH/DCM) to give S12 as a clear yellow oil (11 mg, 28%). TLC: mobile phase

EtAOc:hexanes (50:50), Rf = 0.38; LC/MS tR = 3.96 min (Characterization Method A); m/z = 391.35 (M + H); ¹H NMR (400 MHz, CD2CI3) d =7.44 - 7.32 (m, 4 H), 7.12 - 7.03 (m, 2 H),

6.93 - 6.72 (m, 2 H), 5.90 - 5.71 (m, 1 H), 4.68 (tt, J= 3.9, 12.2 Hz, 1 H), 3.01 (t, J= 9.7 Hz, 2 H), 2.84 (ddd, J= 8.9, 14.4, 18.1 Hz, 1 H), 2.65 - 2.46 (m, 1 H), 2.40 - 2.24 (m, 2 H), 1.92 (q, J = 7.4 Hz, 2 H), 1.84 - 1.73 (m, 2 H), 1.45 (dquin, J= 3.8, 12.1 Hz, 2 H), 1.01 (t, J= 7.4 Hz, 3 H). ¹⁹F NMR (376 MHz, CDCb) d = -109.82, -114.74, -182.83- -183.10 (ddd, 1 Hz)

[0070] To a 4 mL vial, N-phenyl-N-(4-piperidyl)propanamide (25.6 mg, 0.11 mmol), K2CO3 (30 mg, 0.22 mmol), KI (9.4 mg, 0.06 mmol) were added with a magnetic stir bar. Acetonitrile (5 ml) was charged to the flask and then (2-bromo-l-fluoroethyl) benzene (37.1 mg, 0.18 mmol) was added. The reaction was allowed to stir at 115 °C for 2 days. A sample aliquot was taken from the reaction, diluted with DCM in a microtube, and washed with half-saturated aq. Na2CCb. The organic layer was separated and analyzed by LCMS to confirm reaction completion. The reaction was concentrated under reduced pressure, and the crude material was dissolved in a minimal amount of DCM and dry loaded on celite. The celite/crude material was loaded onto a 10 g column which was connected to a l2 g Cl8 column and purified by reverse phase chromatography (12 g C18; 0-95% MeOH/water) to give S13 as a clear yellow oil (10 mg, 25%). 0.68; LC/MS tR = 1.42 min (Characterization Method A); m/z = 354.85 (M + H); ¾ NMR (300 MHz, CD2CI3) d = 7.46 - 7.27 (m, 8 H), 7.12 - 7.04 (m, 2 H), 5.69 - 5.44 (m, 1 H), 4.69 (tt, J = 4.0, 12.2 Hz, 1 H), 3.12 - 2.97 (m, 2 H), 2.87 (ddd, J = 9.3, 14.4, 17.2 Hz, 1 H), 2.64 - 2.43 (m, 1 H), 2.39 - 2.20 (m, 2 H), 1.93 (q, J = 7.4 Hz, 2 H), 1.86 - 1.74 (m, 2 H), 1.58 - 1.37 (m, 2 H), 1.02 (t, J = 7.5 Hz, 3 H).

[0071] Racemic or enantioenriched versions of the compounds can be prepared.

[0072] The fluorinated compounds disclosed above may show equal or better differentiation between normal and inflamed tissues than the analog reported by Stein (Science 2017, 355, 966-969). lt may also have advantages that could include improved metabolic stability, ease of synthesis, and different off-target effects.

[0073] Example 2: Method of Making Enantiomers

[0074] Suitable enantiomers of the fluorinated fentanyl derivatives can be made by methods known in the art, for example, via the replacement of the borohydride reductions of Schemes 1 or 2 with an asymmetric ketone hydrogenation method, such as the chiral ruthenium-catalyzed method described for alpha-aminoketones in Tetrahedron: Asymmetry, 20, 1138 (2009), which is incorporated by reference in its entirety. The resulting amino alcohols can be converted to beta-amino fluorides with retention of configuration, as described in the Journal of Fluorine Chemistry, 37, 343 (1987).

[0075] Example 3: Activity of novel fluorinated fentanyl compounds

[0076] The new fluorinated fentanyl compounds were tested for activation of the mu opioid receptor using a cellular cAMP assay (activation of mu opioid receptor leads to subsequent inhibition of cAMP production). The assays were run at two different pHs (6.5 and 7.4) in HEK 293 cells, with the lower pH approximating the conditions of typical damaged tissue. Example 4 provides a table with representative data for the claimed compounds.

[0077] The fluorinated compounds are significantly more potent at pH 6.5 than 7.4. The ratio of potencies is significantly higher than for fentanyl itself, as illustrated in the table, and for certain claimed compounds, e.g. S6, S9, 12, may exceed that of NFEPP (Science 2017, 355, 966).

[0078] Not to be bound by any theory, but this data implies that it may be possible to dose our compounds in a manner which provides maximal analgesic effects in damaged tissues, while significantly decreasing side effects, e.g., CNS side effects, relative to fentanyl.

[0079] Example 4: Testing of Compounds- MOR cAMP assay protocol

[0080] To determine mu opioid receptor (MOR) Gi-mediated cAMP production, Promega’s split luciferase-based GloSensor cAMP biosensor was used. HEK 293T cells were transfected with MOR DNA and GloSensor cAMP DNA constructs overnight, using calcium phosphate transfection method. HEK 293T cells were subcultured into either 10-cm dishes (3 million cells per dish) or 15-cm dishes (8 million cells per dish) and incubated overnight. Alternatively, HEK 293T cells were seeded at a density of 6 million per 10-cm dish 4 hours prior to transfection. For each 10-cm dish of HEK 293T cells, 10 pg receptor DNA construct in 440 pL distilled water is mixed with 60 pL of 2 M CaCh; the DNA/CaCh solution is then added dropwise into 500 pL 2x HBS solution (50 mM HEPES, 280 mM NaCl, 10 mM KC1, 1.5 mM Na2HP0₄, pH 7.00) while shaking. The mixture was incubated at room temperature for 10 min, then added to cells dropwise, which were then incubated overnight. For transfections in 15-cm dishes, reagents and DNA amounts were increased by 2.5 fold per dish. To prepare plates for assays, cells were seeded into PLL-coated 384-well white clear bottom cell culture plates in DMEM supplemented with 1% dFBS at a density of 15-20K cells, in a volume of 40 pL per well. The plates were used for assays after 6 hours or overnight.

[0081] On the day of assay, cells were removed from culture medium and receive 20 pL/well of assay buffer (20 mM HEPES, lx HBSS, pH 7.40), followed by addition of 10 pL of 3x drug solutions for 15 min at room temperature. To measure agonist activity for Gi- coupled receptors (such as MOR), 10 pL of 4 mM luciferin supplemented with isoproterenol at a final concentration of 200 nM was added, and luminescence counting was done after 15 min. Eight-point concentration-response curves were performed in duplicate twice on two separate lots of cells. For each compound, the results from the four replicates were averaged and ECso values were calculated by non-linear regression using the 4-parameter logistic equation.

[0082] Representative data is included in the table below for the compounds described in the examples above. The ratio of ECso at pH 7.4 to ECso at pH 6.5 in the MOR cAMP assay provides a measure of the pH-sensitivity of the compounds, which may be correlated with their selectivity for inflamed tissue at lower pH.

[0083] As can be appreciated, the results described in the above examples support the utility of the materials and methods described and claimed herein. Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration from the specification and practice of the invention disclosed herein. All references cited herein for any reason, including all journal citations and U.S. /foreign patents and patent applications, are specifically and entirely incorporated herein by reference. lt is understood that the invention is not confined to the specific materials, methods, formulations, reaction/assay conditions, etc., herein illustrated and described, but embraces such modified forms thereof as come within the scope of the following claims.

Claims

CLA1MS

1. A compound of formula 11, salts or enantiomer thereof,

(P]

i

wherein

R¹ is a C1-C12 alkyl group

R² is selected from the group consisting of:

(i) (ii) and (in)

Ar¹ is selected from the group consisting of: Ar¹

, and

2. The compound of claim 1, wherein R¹ is ethyl.

3. The compound of claim 1, wherein R¹ is ethyl, R² is (i), and Ar¹ is a fluorinated phenyl.

4. The compound of claim 1, wherein the compound is formula 1, salts or enantiomer thereof,

wherein

R¹ is a C1-C12 alkyl group,

Ar¹ is selected from the group consisting of:

Ar¹

Ar² is

wherein each X and Y are independently selected from H, F and Cl, and wherein Ar¹ and Ar² are not both phenyl.

5. The compound of claim 4, wherein the compound is:

6. The compound of claim 5, wherein Ar is , and at least one of X and Y is F.

7. The compound of claim 5, wherein the compound is selected from the group consisting of

, salts or an enantiomer thereof.

8. The compound of claim 1, wherein the compound is formula (111), salts or enantiomer thereof:

(111)

wherein ArUs selected from the group consisting of:

Ar² is , and each X and Y are independently selected from H, F and Cl.

9. The compound of claim 1, wherein the compound is formula (IV), salts or

enantiomer thereof:

wherein ArUs selected from the group consisting of:

Ar¹

Ar² is , and each X and Y are independently selected from H, F and Cl.

10. The compound of claim 1, wherein R¹ is ethyl, R² is (i), and Ar² is , and wherein at least one of X and Y is F.

11. The compound of any one of the preceding claims, wherein both X and Y are F.

12. A composition comprising the compound of any one of claims 1-11 and a

pharmaceutically acceptable carrier.

13. The composition of claim 12, wherein the composition is formulated for parenteral administration.

14. The composition of claim 12, wherein the composition is formulated for injection or infusion.

15. The composition of claim 12, wherein the composition is formulated for

transdermal administration.

16. The composition of claim 12, wherein the composition is formulated for buccal administration.

17. A method of treating chronic or acute pain, the method comprising administering an effective amount of the compound of any one of claims 1-11 or the composition of any one of claims 12-16.

18. The method of claim 17, wherein the subject is a human.

19. The method of claim 17, wherein the administration is characterized by the reduction of one or more side effects observed with use of fentanyl.

20. A method of providing analgesic and/or sedation to a patient during surgery, the method comprising administering an effective amount of the fluorinated compound of any one of claims 1-11 or the composition of any one of claims 12-16.