Substituted 1-arylethyl-4-acylaminopiperidine derivatives as opioid/alpha-adrenoreceptor modulators and method of their preparation

Abstract

The invention provides compounds that bind with high affinities to the μ-, δ- and κ-opioid receptors and α.sub.2-adrenoreceptor. In addition to providing these compounds with novel pharmacological binding properties, the invention also describes detailed novel methods for the preparation of representative compounds and a scheme for the synthesis of related compounds that bind to the opioid receptors and/or α.sub.2-adrenoreceptor.

Claims

1. A compound of the formula: ##STR00031## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from the group consisting of optionally substituted C.sub.1-10 alkyl, and optionally substituted furanyl; A is ethylene; and Y is selected from the group consisting of unsubstituted aryl, optionally substituted thiophenyl, or a moiety of the formula —C(═O)—X.sup.1, wherein X.sup.1 is —OR.sup.5 or —NR.sup.6R.sup.6, wherein each of R.sup.5 and R.sup.6 is H or C.sub.1-10 alkyl.

2. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of ethyl, 7-bromoheptyl, fur-2-yl, and fur-3-yl.

3. The compound of claim 1, wherein Y is selected from the group consisting of phenyl, thiophen-2-yl, and a moiety of the formula —C(═O)—OR.sup.5, wherein R.sup.5 is C.sub.1-10 alkyl.

4. The compound of claim 1 selected from the group consisting of: N-(1-phenethylpiperidin-4-yl)propionamide; methyl 3-(4-propionamidopiperidin-1-yl)propanoate; N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide; N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide; N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide; and 8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide.

5. A method of treating a condition selected from opioid tolerance and dependence, opioid-induced constipation, alcohol abuse, opioid abuse, cocaine abuse, depression, opioid induced immune response depression, opioid-overdose-induced respiratory depression, nicotine withdrawal symptoms, obesity, psychosis, dyskinesia associated with Parkinson's disease, Raynaud's disease, hypertension, scleroderma or a combination thereof, said method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need of such a treatment.

6. The method claim 5, wherein said clinical condition is dyskinesia associated with Parkinson's disease.

7. A compound of the formula: ##STR00032## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from the group consisting of optionally substituted C.sub.1-10 alkyl, and optionally substituted furanyl; A is C.sub.1-10 alkylene; and Y is selected from the group consisting of phenyl, thiophen-2-yl, and a moiety of the formula —C(═O)—OR.sup.5, wherein R.sup.5 is C.sub.1-10 alkyl.

8. The compound of claim 7, wherein R.sup.1 is selected from the group consisting of ethyl, 7-bromoheptyl, fur-2-yl, and fur-3-yl.

9. The compound of claim 8, wherein R.sup.1 is ethyl.

10. The compound of claim 7, wherein A is ethylene.

11. The compound of claim 10, wherein Y is phenyl.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) These and other embodiments, features and advantages of the present invention will become more fully apparent when read in conjunction with the following detailed description taken in conjunction with the accompanying drawings, wherein

(2) FIG. 1 is a (LC/MS) plot of a preferred compound designated HVC-3.

DETAILED DESCRIPTION OF THE INVENTION

(3) For the purposes of this disclosure, a “salt” is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including but not limited to, halogenic acid salts such as hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic or glutamic acid salt. The acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid salt. In all cases, the acid addition salt is used as an achiral reagent which is not selected on the basis of any expected or known preference for interaction with or precipitation of a specific optical isomer of the products of this disclosure.

(4) “Pharmaceutically acceptable salt” is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient 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. (1977) J. Pharm. Sciences, vol. 6. 1-19, which is hereby incorporated by reference in its entirety, describes pharmaceutically acceptable salts in detail.

(5) “Modulation” is meant to refer to the binding activity of a compound with respect to a particular receptor. The binding activity of the compound, or “modulator,” may be that of an agonist, inverse agonist, antagonist, allosteric regulator, positive allosteric modulator, negative allosteric modulator, or any other type of ligand-receptor interaction that is known in the art.

(6) In this invention we disclose a new class of molecules that simultaneously bind with high affinity to opioid μ-, δ-, κ-receptors and also to α-adrenoreceptors, thereby exhibiting modulation-type interactions with those receptors. The interaction of the molecules with μ-receptors is believed to have the character of antagonist action, based at least in part on the observed high affinity binding of the molecules with respect to the μ-receptors.

(7) Although not wishing to be bound by theory, it appears that the principal structural change for agonist-antagonist transformation is the removal of a phenyl group from an N-phenylpropionamide fragment of fentanyl. This transformation is depicted below, wherein N-(1-phenethylpiperidin-4-yl)-N-phenylpropionamide (II) is transformed to N-(1-phenethylpiperidin-4-yl)-N-propionamide (I), causing a transformation of μ-agonist properties to μ-antagonist with simultaneous modulation of delta-, kappa- and alpha-receptors:

(8) ##STR00002##

(9) The invention also relates to processes for preparing compounds of general formula III, which are pharmacologically active compounds:

(10) ##STR00003##
Representative compounds of the present invention also include the following compounds, wherein the central nitrogen containing ring is a substituted or unsubstituted 5- to 7-membered heterocyclic ring:

(11) ##STR00004##
These compounds may include the following structural and functional groups: R.sub.1 is H, substituted or unsubstituted C.sub.1-C.sub.10 alkyl, alkenyl, alkynyl, or substituted or unsubstituted aryl or hetaryl; R.sub.2 is H, —CH.sub.2O—C.sub.1-4 alkyl, etc.; COO—C.sub.1-4 alkyl, etc.; —CONR.sub.4 etc.; R.sub.3 is H, substituted or unsubstituted C.sub.1-C.sub.10 alkyl, alkylene, alkynyl, or substituted or unsubstituted aryl or hetaryl; A is substituted or un-substituted C.sub.1-C.sub.10 alkyl, alkylene, alkynyl; Ar or HetAr is substituted or un-substituted monocyclic or polycyclic aromatic or heteroaromatic moiety; and COOR.sub.5, or CON(R.sub.6).sub.2, where R.sub.5 and R.sub.6 are H, substituted or unsubstituted C.sub.1-C.sub.10 alkyl, alkylene, alkynyl, or substituted or un-substituted aryl or hetaryl.

(12) In certain embodiments of the invention, compounds of formula (III) can be prepared according to the following general schemes (wherein PG is a protecting group):

(13) ##STR00005##
As shown above, these schemes generally include transformations of different starting cyclic ketones (e.g., a variety of piperidin-4-ones, pyrrolidin-3-ones and azepan-4-one) to desired compounds of formula (III) via, for example: a) Grignard or Reformatsky type reactions; b) a Strecker type reaction; c) a Ritter type reaction; d) selective carbalkoxy group transformations, deprotection, and further appropriate acylation or alkylation; e) selective carbalkoxy group transformations; or f) deprotection with further appropriate acylation or alkylation.

(14) The process for the preparation of the first example of μ-opioid modulator/α-modulator N-(1-phenethylpiperidin-4-yl)propionamide and its salt is described in the present invention in detail below (Scheme 1):

(15) ##STR00006##

(16) The synthetic procedure starts with the commercially available 1-phenethylpiperidin-4-one (IV) of formula:

(17) ##STR00007##
which may be reacted with hydroxylamine hydrochloride in ethanol in the presence of base, to give 1-phenethylpiperidin-4-one oxime (V) of formula:

(18) ##STR00008##

(19) Reducing the C═N double bond of obtained oxime (V) by the Bouveault-Blanc protocol using iso-amyl alcohol and sodium metal as a hydrogen source, 1-phenethylpiperidin-4-amine (VI) may be obtained:

(20) ##STR00009##

(21) By treating of compound (VI) with propionic acid chloride in chloroform in the presence of triethylamine the desired N-(1-phenethylpiperidin-4-yl)propionamide (I) may be prepared:

(22) ##STR00010##

(23) The obtained N-(1-phenethylpiperidin-4-yl)propionamide (I) may be transformed to oxalate by treating with a molar equivalent of oxalic acid in ethanol:

(24) ##STR00011##

(25) The tables (Tables 1-3) in the attached Appendix 1 incorporated herein by reference include data from binding assays performed with the N-(1-phenethylpiperidin-4-yl)propionamide compound (I). This data demonstrates the high binding affinities of the compounds of the invention for μ-, δ-, and κ-opioid receptors and for α2-adreno-receptors. Table 1 illustrates the results of binding assays performed with the N-(1-phenethylpiperidin-4-yl)propionamide (compounds R1 and R2) and various receptors. As can be seen in the table, at a test concentration of 1.0E-05 M, N-(1-phenethylpiperidin-4-yl)propionamide demonstrated the highest percentage binding inhibition of control specific binding with respect to the α2B adrenoreceptor (74% and 55%); the δ-opioid receptor (44% and 69%); the κ-opioid receptor (107% and 104%); the μ-opioid receptor (98% and 99%). Table 2 contains reference compound data for the various receptors used in the binding assays. Finally, Table 3 provides summary results of the binding assays, showing the receptors from Table 1 for which the test compound demonstrated the highest percentage binding inhibition of control specific binding.

(26) Appendix 2 incorporated herein by reference includes x-ray crystallography data for a representative compound of the invention, N-(1-phenethylpiperidin-4-yl)propionamide oxalate.

(27) Appendix 3 incorporated herein by reference includes data showing that a representative compound of the invention, N-(1-phenethylpiperidin-4-yl)propionamide, conforms to “Lipinski's rule of five,” which provides a general rule of thumb for evaluating the activity of an orally administered drug.

(28) The compounds of the present invention may be utilized in various pharmaceutical and medical applications in which the use of a compound exhibiting high binding affinities for μ-, δ- or κ-opioid receptors and/or α2-adreno-receptors is indicated. The compounds may be of particular use in applications in which the use of a μ-, δ- or κ-opioid receptor modulator, including particularly a μ-opioid receptor antagonist, and/or an α2-adrenoreceptor modulator is indicated. Accordingly, in certain embodiments, the present invention also includes salts, and particularly pharmaceutically acceptable salts, of the disclosed compounds, as well as processes for preparing the salt forms of the disclosed compounds.

EXAMPLES

(29) The following examples illustrate the preparation of N-(1-phenethylpiperidin-4-yl)propionamide and its oxalate salt form, N-(1-phenethylpiperidin-4-yl)propionamide oxalate, in accordance with the present disclosure.

Example 1

1-Phenethylpiperidin-4-one oxime (Compound V)

(30) 1-Phenethylpiperidin-4-one (10.15 g (0.05 mol) dissolved in 60 mL of ethanol) was added drop-wise at 0° C. to a solution of hydroxylamine in water. The water solution of hydroxylamine was preliminarily prepared by adding at 0° C. in portions 13.8 g (0.1 mol) of K.sub.2CO.sub.3 to the solution of 6.95 g (0.1 mol) hydroxylamine hydrochloride in 50 mL of water. The mixture was set aside for a night. Ethanol was evaporated under slight vacuum. Water (˜100 mL) was added, and the mixture was stirred on ice bath for an hour. The separated solid product was filtered, washed with water and allowed to air-dry. The crude oxime (10.71 g (98.25%), m.p. 132-134° C.) was reserved for use in the next reaction without further purification. Analysis with electrospray ionization mass spectrometry (MS (ESI)) resulted in a peak at 219.1 (MH+).

Example 2

1-Phenethylpiperidin-4-amine (Compound VI)

(31) 1-Phenethylpiperidin-4-one oxime (6.54 g (0.03 mol)) was dissolved in 100 mL of dry i-AmOH on heating. A ten-fold excess of sodium (6.9 g (0.3 mol)) was slowly (1 hour) added to the stirred solution in small pieces, while the temperature was maintained around 110°. The solution was stirred on heating at 110° for two hours and left to cool to room temperature. 150 mL of ether, followed by 75 mL of water, was then added to the solution. The organic layer was separated and dried on MgSO.sub.4. After evaporation of solvents under slight vacuum, the product was distilled to give 4.3 g (70%) of 1-phenethylpiperidin-4-amine (VI) with a boiling point of 138-142°/1.5 mm. MS (ESI): 205.0 (MH+).

Example 3

N-(1-Phenethylpiperidin-4-yl)propionamide (Compound I)

(32) Propionyl chloride (2.775 g (0.03 mol)) in 5.55 mL of CHCl.sub.3 was added drop-wise on stirring to the cooled (0° C.) solution of 4.08 g (0.02 mol) 1-phenethylpiperidin-4-amine and 3.03 g (0.03 mol) of Et.sub.3N in 30 mL of CHCl.sub.3. The mixture was left to come to room temperature and stirred overnight. After working up with 5% solution of NaHCO.sub.3 (2.52 g (0.03 mol)) in 47.88 H.sub.2O, the organic layer was separated, washed with water and dried on MgSO.sub.4. After evaporation of solvents under slight vacuum, the residue was crystallized from hexane to give 4.9 g (94%) of

(33) N-(1-phenethylpiperidin-4-yl)propionamide (I) with m.p. 134-135°. MS (ESI): 261.2 (MH+).

(34) The results of proton NMR spectroscopy were as follows:

(35) .sup.1H NMR (600 MHz, CDCl.sub.3): δ 7.27 (t, J=7.4 Hz, 2H), 7.19 (m, 3H), 5.32 (d, J=7.4 Hz, 1H), 3.82 (qt, J=7.8, 4.2 Hz, 1H), 2.92 (dt, J=11.8, 3.4 Hz, 2H), 2.79 (m*, 2H), 2.59 (m*, 2H), 2.19 (q, J=7.5 Hz, 2H), 2.18 (m, 2H), 1.95 (dtd, J=12.4, 4.4, 1.7 Hz, 2H), 1.46 (qd, J=11.7, 3.8 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H).

(36) * these two multiplets arise from two methylene groups that have magnetically inequivalent protons AA′BB′ with .sup.2J.sub.AA′=.sup.2J.sub.BB′12 Hz, .sup.3J.sub.AB=3J.sub.A′B′=11 Hz, .sup.3J.sub.AB′=.sup.3J.sub.A′B=4 Hz, consistent with a preferred anti conformation for the phenyl and piperidine rings

(37) The results of carbon-13 NMR spectroscopy were as follows:

(38) .sup.13C NMR (150 MHz, CDCl.sub.3): δ 173.0, 140.2, 128.6, 128.4, 126.0, 60.4, 52.3, 46.3, 33.7, 32.3, 29.8, 9.9.

Example 4

N-(1-Phenethylpiperidin-4-yl)propionamide oxalate (Compound VII)

(39) Oxalic acid (1 g (0.011 mol)) in 10 mL of ethanol was added drop-wise to the solution of 2.93 g (0.011 mol) of N-(1-phenethylpiperidin-4-yl)propionamide (I) in 29.3 mL of ethanol. The mixture was set aside overnight. The obtained crystals were then separated and dried in a desiccator over P.sub.2O.sub.5 to give 3.5 g of N-(1-phenethylpiperidin-4-yl)propionamide oxalate (VII) with m.p. 216-218 (MS (ESI): 261.2 ([M+H])—see FIG. 1

(40) The compound designated as HCV-3 was then subject to cellular functional assay and results reported below:

(41) TABLE-US-00001 Cellular functional assays Catalog Ref Reference Experimental Client Com Compound Test Conce % of EC.sub.50 Assay Batch Contro % of Agonist Response 1.sup.st 2.sup.nd Mean Ref (M) 27/07/201α HCV-3 1 1000233221.0E−05 7.1 9.2 5.1 7.1 dexmedete 2B (h 1813 1.3E−08 27/07/200 κ HCV-3 1 1000233221.0E−05 −4.2 −10.3 1.8 −4.2 U 50488 (KO 2071 1.6E−09 27/07/201 μ HCV-3 1 1000233221.0E−05 33.5 28.1 38.9 33.5 DAMGO (MOP) 1392 4.2E−09 Catalog Ref Compound Test Conce % Reference Experimental Client Com Inhibition Agonist Response IC50 Ref(N Assay Batch (% of Control) 1.sup.st 2.sup.nd Mean KbRef (M) 27/07/201 HCV-3 1 1000233221.0E−05 −28 116.8 138.7 127.8 yohimine α2B(h 1814 3.7E-07 4.8E−08 27/07/201 κ HCV-3 1 1000233221.0E−05 6 112.4 76.5 94.4 nor-BNI (KO 2072 4.3E-10 7.2E−11 27/07/201 μ HCV-3 1 1000233221.0E−05 −1 100.1 101.8 101.0 CTOP (MOP) 1393 2.1E-07 2.3E−08

(42) Compound HCV-3 also was tested for hERG inhibition. Over the concentration range tested (up to 25 micromolar) no dose-response was obtained. Therefore the inhibition IC.sub.50 was considered as >25 micromolar. There was a hint of some inhibition at the top concentration of 25 micromolar, with 32.5% inhibition observed (insufficient to generate an IC.sub.50 value). As such, this compound is categorised as having weak or no hERG inhibition. The control compounds behaved as expected in the assay.

(43) Compound HCV-3 also was tested for CYP inhibition, and was found to inhibit CYP2D6, and to weakly inhibit CYP2C19. However, with CYP2C19 the inhibition was too weak to generate an IC.sub.50 value, and we observed just 36.4% inhibition at the top concentration of 25 micromolar. With CYP2D6, an IC.sub.50 of 4.2 micromolar was observed. Thus, this compound was considered to be a moderate CYP2D6 inhibitor, and a weak CYP2C19 inhibitor. No inhibition was observed at CYP2B6, CYP2C9, CYP3A4 (with either substrate), CYP2C8 or CYP1A2. The significance of this CYP2D6 inhibition will depend on the levels of the compound in vivo.

(44) Compound HCV-3 also was tested in cellular and nuclear receptor functional assays, and the results reported in Appendix 4, incorporated herein by reference.

(45) Compound HCV-3 was also subjected to AMES testing, and the results reported in Appendix 5, incorporated herein by reference.

(46) In summary, the compound HCV-3 was negative for genotoxicity against both strains used in this assay (TA98 and TA 100) up to a maximum tested concentration of 1 mg/mL, in both the absence and presence of S9 metabolic activation. The assay controls behaved as expected.

(47) Compound HCV-3 also was subjected to in vitro metabolic disposition in mouse, rat, monkey and human microsomes. The test compound was incubated with pooled liver microsomes, since drip stability in liver microsomes can be predictive of drug stability in vivo. Aliquots were taken at 0, 5, 15, 30 and 45 minutes and quenched immediately. The samples were extracted and analyzed by LC-MS/MS. Compound HCV-3 was observed to have low clearance in human, monkey and mouse microsomes, and moderate clearance in rat.

(48) Compound HCV-3 also was subjected to MDCK permeability assay. The compound was observed to be highly permeable in the MDCK assay. There was a slight difference between the plus and minus inhibitor data in terms of the efflux ratio obtained (1.48 minus inhibitor, versus 0.929 plus inhibitor). A ratio of greater than 2 generally indicates that efflux, i.e., blood brain barrier permeability, is occurring. The control compounds behaved as expected, with prazosin (a P-gp substrate) showing efflux in the absence of Cyclosporin A, which was inhibited in its presence.

(49) Various derivatives of the above compounds with potential opiod and alpha antagonist activity were prepared as follows, and characterized by NMR and mass-spec as reported below.

Protocols for the synthesis of substituted 1-arylethyl-4-acylaminopiperidine derivatives

Synthesis of 1-benzylpiperidin-4-one oxime

(50) ##STR00012##
28.35 g (1 equiv., 0.15 mol) of 1-benzylpiperidin-4-one was dissolved in 60 mL of EtOH and then cooled to 0° C. using an ice bath. A solution containing 20.85 g (2 equiv., 0.30 mol) of hydroxylamine hydrochloride dissolved in 75 mL of H.sub.2O was prepared and then added dropwise to the reaction mixture followed by dropwise addition of a solution containing 20.7 g (1 equiv., 0.15 mol) of K.sub.2CO.sub.3 dissolved in 75 mL of H.sub.2O. The reaction mixture was then brought to room temperature and stirred overnight. The EtOH was then removed via rotary evaporation and the reaction mixture was then cooled in an ice bath to allow the product to crystallize out of solution. The product was filtered and washed several times with H.sub.2O and recrystallized in EtOH. Yield: 27.78 g (70.17%).

Synthesis of 1-benzylpiperidin-4-amine

(51) ##STR00013##
A solution containing 6.12 g (1 equiv., 0.03 mol) of 1-benzylpiperidin-4-one oxime dissolved in 90 mL of iso-amyl alcohol was prepared and heated to approximately 110° C. 6.9 g (10 equiv., 0.3 mol) of Na metal was then added slowly to the reaction mixture. After addition of Na, the reaction mixture was allowed to cool to room temperature and stirred until the reaction mixture turned into a thick slurry. The slurry was dissolved in 50 mL of ethyl acetate and 25 mL of H.sub.2O. The organic layer was separated and washed with H.sub.2O (2×20 mL) followed by drying over anhydrous magnesium sulfate. The solvent was removed via rotary evaporation, resulting in a yellow oil. The crude product was purified via column chromatography utilizing silica gel and a DCM:MeOH solvent system in a ratio of 4:1 with an additional 1% of Et.sub.3N. Yield: 3.7 g (64%).

Synthesis of N-(1-benzylpiperidin-4-yl)propionamide

(52) ##STR00014##
A solution of 3.7 g of 1-benzylpiperidin-4-amine (1 equiv., 0.019 mol) dissolved in 45 mL of dry dichloromethane was prepared followed by the addition of 5 mL of Et.sub.3N (2.6 equiv., 0.05 mol). The reaction mixture was then cooled to 0° C. using an ice bath, and then 2.17 mL (1.3 equiv., 0.025 mol) of propionyl chloride dissolved in 10 mL of dry dichloromethane was added dropwise to the reaction mixture. The reaction mixture was then warmed to room temperature and stirred overnight. Once the reaction was complete, 4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added to the reaction mixture. The organic layer was separated, and the aqueous layer was washed with dichloromethane (3×20 mL) followed by NaHCO.sub.3 solution and brine. The organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed via rotary evaporation, resulting in a white solid. The product was washed with hexanes to obtain an analytically pure sample. Yield: 2.8 g (72%)

Synthesis of N-(piperidin-4-yl)propionamide

(53) ##STR00015##
0.7 g of N-(1-benzylpiperidin-4-yl)propionamide (1 equivalent, 0.003 moles) were added to a parr hydrogenation flask and dissolved in 30 mL of EtOH. The solution was then degassed with argon for 30 min followed by the addition of 0.07 g of 10% Pd/C (0.2 equiv., 6.58×10.sup.−4 mol) and 0.07 g of 20% Pd(OH).sub.2 (0.17 equiv., 4.98×10.sup.−4 mol). The black solution was then degassed with argon for an additional 15 min. The reaction mixture was then charged with 50 psi of H.sub.2 gas and shaken for 24 h. The product was filtered through celite and the solvent was removed via rotary evaporation. No further purification was required. Yield: 0.467 g (99%)

Synthesis of methyl 3-(4-propionamidopiperidin-1-yl)propanoate (CRA5)

(54) ##STR00016##
0.1 g of N-(piperidin-4-yl)propionamide (1 equiv., 5.26×10.sup.−4 moles) was dissolved in 2 mL of dry acetonitrile followed by the addition of 0.071 mL of methyl acrylate (1.5 equiv., 7.89×10.sup.−4 mol). The reaction mixture was refluxed overnight. The solvent was removed via rotary evaporation. The crude product was purified by washing with hexanes followed by drying under high vacuum. Yield: 0.90 g (71%)

Synthesis of N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide (CRAS1)

(55) ##STR00017##
0.1 g of N-(piperidin-4-yl)propionamide (1 equiv., 6.40×10.sup.−4 mol), 0.145 g of 2-(thiophen-2-yl)ethyl methanesulfonate (1.1 equiv., 7.04×10.sup.−4 moles), 0.097 g of K.sub.2CO.sub.3 (1.1 equiv., 7.04×10.sup.−4 mol), 0.032 g of KI (1.92×10.sup.−4 mol), and 0.178 mL of Et.sub.3N (2 equiv., 1.28×10.sup.−3 mol) were added to a round bottom flask and dissolved in 5 mL of dry acetonitrile. The reaction mixture was stirred and refluxed overnight. The solvent was then removed via rotary evaporation followed by the addition of H.sub.2O. The mixture was extracted with ethyl acetate (3×5 mL), and the organic extracts were combined and dried over anhydrous magnesium sulfate. The solvent was removed via rotary evaporation. The crude product was washed with hexanes to obtain an analytically pure sample. Yield: 0.101 g (60%).

Synthesis of 1-phenethylpiperidin-4-one oxime

(56) ##STR00018##
28.35 g (1 equivalent, 0.14 mol) of 1-benzylpiperidin-4-one were dissolved in 60 mL of EtOH and then cooled to 0° C. using an ice bath. A solution containing 19.46 g (2 equivalents, 0.28 mol) of hydroxylamine hydrochloride dissolved in 75 mL of H.sub.2O was prepared and then added dropwise to the reaction mixture followed by dropwise addition of a solution containing 19.35 g (1 equivalent, 0.14 mol) of K.sub.2CO.sub.3 dissolved in 75 mL of H.sub.2O. The reaction mixture was then brought to room temperature and stirred overnight. The EtOH was then removed via rotary evaporation and the reaction mixture was then cooled in an ice bath to allow the product to crystallize out of solution. The product was filtered and washed several times with H.sub.2O and recrystallized in EtOH. Yield: 25.60 g (83.77%).

Synthesis of 1-phenethylpiperidin-4-amine

(57) ##STR00019##
A solution containing 6.00 g (1 equiv., 0.027 mol) of 1-phenethylpiperidin-4-one oxime dissolved in 90 mL of iso-amyl alcohol was prepared and heated to approximately 110° C. 6.21 g (10 equiv., 0.27 mol) of Na metal was then added slowly to the reaction mixture. After addition of Na, the reaction mixture was allowed to cool to room temperature and stirred until the reaction mixture turned into a thick slurry. The slurry was dissolved in 50 mL of ethyl acetate and 25 mL of H.sub.2O. The organic layer was separated and washed with H.sub.2O (2×20 mL) followed by drying over anhydrous magnesium sulfate. The solvent was removed via rotary evaporation, resulting in a yellow oil. The crude product was purified via column chromatography utilizing silica gel and a DCM:MeOH solvent system in a ratio of 4:1 containing an additional 1% of Et.sub.3N.

Synthesis of N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide (CRA8)

(58) ##STR00020##
A solution of 0.1 g of 1-phenethylpiperidin-4-amine (1 equiv., 4.89×10.sup.−4 mol) dissolved in 2 mL of dry dichloromethane was prepared followed by the addition of 0.178 mL (2.6 equiv., 1.27×10.sup.−3 moles) of Et.sub.3N. The reaction mixture was then cooled to 0° C. using an ice bath, and then 0.063 mL (1.3 equiv., 6.36×10.sup.−4 mol) of 2-furoyl chloride dissolved in 0.25 mL of dry dichloromethane was added dropwise to the reaction mixture. The reaction mixture was then warmed to room temperature and stirred overnight. Once the reaction was complete, 4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added to the reaction mixture. The organic layer was separated, and the aqueous layer was washed with dichloromethane (3×5 mL) followed by NaHCO.sub.3 solution and brine. The organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed via rotary evaporation, resulting in a white solid. The product was washed with hexanes to obtain an analytically pure sample. Yield: 0.0845 g (58.3%).

Synthesis of N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide (CRA9)

(59) ##STR00021##
A solution of 0.1 g of 1-phenethylpiperidin-4-amine (1 equiv., 4.89×10.sup.−4 mol) dissolved in 2 mL of dry dichloromethane was prepared followed by the addition of 0.178 mL (2.6 equiv., 1.27×10.sup.−3 mol) of Et.sub.3N. The reaction mixture was then cooled to 0° C. using an ice bath, and then 0.063 mL (1.3 equiv., 6.36×10.sup.−4 mol) of 3-furoyl chloride dissolved in 0.25 mL of dry dichloromethane was added dropwise to the reaction mixture. The reaction mixture was then warmed to room temperature and stirred overnight. Once the reaction was complete, 4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added to the reaction mixture. The organic layer was separated, and the aqueous layer was washed with dichloromethane (3×5 mL) followed by NaHCO.sub.3 solution and brine. The organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed via rotary evaporation, resulting in a white solid. The product was washed with hexanes to obtain an analytically pure sample. Yield: 0.104 g (72%).

Synthesis of 8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide (CRA10)

(60) ##STR00022##
A solution of 0.101 g of 1-phenethylpiperidin-4-amine (1.1 equiv., 4.93×10.sup.−4 mol), 0.1 g of 8-bromooctanoic acid (1.0 equiv., 4.48×10.sup.−4 mol), 0.170 g of HATU (1.0 equiv., 4.48×10.sup.−4 mol), 0.061 g of HOAt (1.0 equiv., 4.48×10.sup.−4 mol), and 0.314 mL of DIEPA (4.0 equiv., 0.0018 mol) in dry DMF was prepared. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 0.5 M KHSO.sub.4 solution followed by the addition of dichloromethane. The organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (3×5 mL) followed by washing with NaHCO.sub.3 solution and Brine. The organic extracts were then dried over anhydrous magnesium sulfate.

Synthesis of N-(1-phenethylpiperidin-4-yl)benzamide (CRA11)

(61) ##STR00023##
A solution of 0.1 g of 1-phenethylpiperidin-4-amine (1 equiv., 4.89×10.sup.−4 mol) dissolved in 2 mL of dry dichloromethane was prepared followed by the addition of 0.178 mL (2.6 equiv., 1.27×10.sup.−3 mol) of Et.sub.3N. The reaction mixture was then cooled to 0° C. using an ice bath, and then 0.074 mL (1.3 equiv., 6.36×10.sup.−4 mol) of 3-furoyl chloride dissolved in 0.25 mL of dry dichloromethane was added dropwise to the reaction mixture. The reaction mixture was then warmed to room temperature and stirred overnight. Once the reaction was complete, 4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added to the reaction mixture. The organic layer was separated, and the aqueous layer was washed with dichloromethane (3×5 mL) followed by NaHCO.sub.3 solution and brine. The organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed via rotary evaporation, resulting in a white solid. The product was washed with hexanes to obtain an analytically pure sample.

Synthesis of 2-(thiophen-2-yl)ethyl methanesulfonate

(62) ##STR00024##
2.6 mL of 2-(thiophen-2-yl)ethanol (1 equiv., 0.023 mol) was dissolved in 45 mL of dry dichloromethane followed by the addition of 3.63 mL of Et.sub.3N (1.13 equiv., 0.026 mol). The reaction mixture was stirred at room temperature for 1 h. It was then cooled to −5° C. using an ice bath and solid NaCl. Once cooled, 1.92 mL of methanesulfonyl chloride was added dropwise over the course of 10 min. The reaction mixture was then warmed to room temperature and stirred for 1 h. Once the reaction was complete, 30 mL of NaHCO.sub.3 solution was added followed by separation of the organic and aqueous layers. The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed via rotary evaporation, resulting in a brown oil. No further purification was required.

NMR (1H & 13C) & Mass-Spec Data of Novel Substituted 1-arylethyl-4-acylaminopiperidine Derivatives (Total Six Compounds)

(63) TABLE-US-00002 Observed Molecular Exact Mass Compound Formula Structure R.sub.f Mass [M + H].sup.+ Yield CRA5 C.sub.12H.sub.22N.sub.2O.sub.3 0.72  (20% MeOH in DCM) 242.16 243.3    90 mg (70.7%) CRA8 C.sub.18H.sub.22N.sub.2O.sub.2 0.825 (4:1 MeOH DCM) 298.17 299.3   84.5 mg (58.3%) CRA9 C.sub.18H.sub.22N.sub.2O.sub.2 0.757 (4:1 MeOH DCM 298.17 299.3  104.3 mg (71.9 %) CRAS1 C.sub.14H.sub.22N.sub.2OS 266.15 267.73 101.4 mg (60%) CRA10 C.sub.21H.sub.33BrN.sub.2O 0.90  408.18 409.19 411.19   262 mg (130%) CRA11 C.sub.20H.sub.24N.sub.2O 0 0.875 308.19 309.2    132 mg (87%)

(64) CRA5 NMR data: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.14 (t, J=7.59, 7.59 Hz, 3H), 1.41 (dtd, J-3.70, 11.10, 11.13, 12.61 Hz, 2H), 1.91 (m, 2H), 2.17 (m, 4H), 2.49 (m, 2H), 2.68 (m, 2H), 2.81 (m, 2H), 3.67 (s, 3H), 3.78 (dddd, J=4.29, 4.36, 11.92, 15.26, 1H), 5.25 (d, J=7.96 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 10.02, 29.99, 32.41, 46.40, 51.76, 52.25, 55.63, 173.14, 174.05.

(65) CRA8 NMR data: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.63 (d, J=11.93 Hz, 2H), 2.05 (d, J=12.33 Hz, 2H), 2.26 (t, J=11.35, 11.35 Hz, 2H), 2.64 (dd, J=6.16, 10.21 Hz, 2H), 2.83 (dd, J=6.12, 10.24 Hz, 2H), 2.99 (d, J=12.01 Hz, 2H), 3.98 (m, 1H), 6.21 (d, J=8.20 Hz, 1H), 6.49 (dd, J=1.79, 3.47 Hz, 1H), 7.10 (dd, J=0.84, 3.47 Hz, 1H), 7.24 (m, 5H), 7.43 (dd, 0.84, 1.77 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 32.67, 34.17, 46.27, 46.61, 52.76, 60.88, 112.60, 114.57, 126.56, 128.87, 129.13, 140.58, 144.16, 148.48, 158.13.

(66) CRA9 NMR data: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.63 (m, 2H), 2.06 (d, J=11.35 Hz, 2H), 2.26 (m, J=11.35, 2H), 2.65 (m, 2H), 2.84 (m, 2H), 3.02 (d, J=11.86 Hz, 2H), 3.99 (m, 1H), 5.65 (d, J=7.99 Hz, 1H), 6.59 (dd, J=0.91, 1.93 Hz, 1H), 7.24 (m, 5H), 7.42 (dd, 1.58, 1.91 Hz, 1H), 7.91 (dd, J=0.90, 1.59 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 32.04, 33.49, 46.43, 52.35, 60.26, 108.25, 122.66, 126.19, 128.46, 128.68, 139.88, 143.72, 144.69, 161.95

(67) CRA1S NMR data: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.15 (t, J=7.58, 7.58 Hz, 3H), 1.47 (m, 2H), 1.95 (m, 2H), 2.18 (m, 4H), 2.64 (dd, J=6.87, 8.62 Hz, 2H), 2.90 (m, 2H), 3.00 (m, 2H), 3.82 (dddd, J=4.20, 8.31, 10.86, 15.17 Hz, 1H), 5.32 (d, J=7.95 Hz, 1H), 6.81 (dq, J=1.02, 1.02, 1.02, 3.20 Hz, 1H), 6.91 (dd, J=3.39, 5.14 Hz, 1H), 7.11 (dd, J=1.21, 5.13 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 10.04, 28.06, 30.03, 32.15, 46.52, 52.42, 59.98, 123.62, 124.71, 126.69, 142.87, 173.15.

(68) CRA10 NMR data: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.32-2.34 (m, 14H), 2.82-3.01 (m, 11H), 3.16 (dd, J=6.53, 10.91 Hz, 1H), 3.49 (d, J=11.91 Hz, 1H), 4.63 (dt, J=5.61, 5.61, 8.76 Hz, 1H), 7.24 (m, 4H), 7.42 (dd, J=4.46, 8.37, 1H), 8.02 (m, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 25.17, 25.45, 27.85, 28.70, 28.75, 31.46, 36.55, 38.61, 81.47, 120.73, 128.66, 128.86, 129.19, 151.29, 162.71, 173.62.

(69) CRA11 NMR data: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.35 (t, J=7.29, 7.29 Hz, 2H), 1.64 (qd, J=3.80, 11.29, 11.29, 11.35 Hz, 2H), 2.08 (m, 2H), 2.27 (td, J=2.57, 11.61, 11.65 Hz, 2H), 2.64 (m, 2H), 2.83 (m, 2H), 3.00 (m, 3H), 4.04 (dddd, J=4.28, 8.29, 10.85, 15.24 Hz, 1H), 6.04 (d, J=7.94 Hz, 1H), 7.25 (m, 5H), 7.44 (m, 3H), 7.75 (m, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 32.22, 33.71, 45.83, 46.97, 52.38, 60.42, 114.25, 126.12, 126.86, 128.42, 128.56, 128.68, 131.42, 134.75, 140.11, 166.88

(70) Many other variations and modifications may be made to the above-described embodiments of the disclosure without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of the present disclosure and protected by the following claims.

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INCORPORATION BY REFERENCE

(72) Each document, patent, patent application or patent publication cited by or referred to in this disclosure is incorporated by reference in its entirety. However, no admission is made that any such reference constitutes prior art, and the right to challenge the accuracy and pertinence of the cited documents is reserved.