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Title:
SMALL MOLECULE NON-MORPHINAN OPIOID COMPOSITIONS
Document Type and Number:
WIPO Patent Application WO/2021/067870
Kind Code:
A1
Abstract:
A compound represented by Formula 1 wherein R1 is selected separately from one of methyl, ethyl, n-propyl, i-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, N-isopent-2-enyl; R2 is selected separately from hydrogen, methyl, or ethyl; or R1-N-R2 is 5- or 6-membered non-aromatic ring; R3 is selected from an unsubstituted or substituted 5-or 6-membered aromatic or nonaromatic ring, or an ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, or methylcyclohexyl; R4 is hydrogen, methyl, ethyl, n-propyl, or i-propyl; and R5 is an unsubstituted or substituted 5- or 6- membered aromatic ring alone or fused to a second ring (e.g., R 5 is naphthyl or indole). Methods of treating pain with less risk of dependency include administration of the compound represented by Formula 1 to subjects in need thereof.

Inventors:
KRSTENANSKY JOHN L (US)
ZAMBON ALEXANDER (US)
Application Number:
PCT/US2020/054146
Publication Date:
April 08, 2021
Filing Date:
October 02, 2020
Export Citation:
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Assignee:
KECK GRADUATE INST OF APPLIED LIFE SCIENCES (US)
International Classes:
C07D489/02; A61K31/485; C07D489/08
Foreign References:
US4346101A1982-08-24
Other References:
HSU ET AL.: "Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human mu-opiate receptor 1 (OPRM1) expressing cells", PHARMACOL RES PERSPECT, vol. 7, no. 5, August 2019 (2019-08-01), pages 10, XP055814199
ELLIOTT ET AL.: "The first reported fatality associated with the synthetic opioid 3,4-dichloro-N- [2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis", DRUG TEST ANAL., vol. 8, no. 8, 2016, pages 875 - 9, XP055814202
DATABASE PubChem 25 November 2010 (2010-11-25), XP055814205, Database accession no. 46980005
FLYNN ET AL.: "Correlation and Prediction of Mass Transport across Membranes I: Influence of Alkyl Chain Length on Flux-Determining Properties of Barrier and Diffusant", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 61, no. 6, 1972, pages 838 - 852
Attorney, Agent or Firm:
BALLEW CHANG, Nicole et al. (US)
Download PDF:
Claims:
CLAIMS

What is claimed is:

1. A compound represented by Formula 1 wherein:

R1 is selected separately from one of methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, N-isopent-2-enyl;

R2 is selected separately from hydrogen, methyl, or ethyl; or R N-R2 is 5- or 6-membered non-aromatic ring;

R3 is selected from an unsubstituted or substituted 5-or 6-membered aromatic or nonaromatic ring, or an ethyl, «-propyl, /-propyl, cyclopropyl, «-butyl, /-butyl, /-butyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, or methylcyclohexyl;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted 5- or 6-membered aromatic ring alone or fused to a second ring.

2. The compound of claim 1, wherein R5 is naphthyl or indole.

3. The compound of claim 1, wherein R1 is selected from hydrogen, methyl, ethyl, «-propyl, /- propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl;

R2 is selected from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is an unsubstituted or substituted 5-or 6-membered aromatic or non-aromatic ring;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted phenyl or thienyl or is napthyl or indole.

4. The compound of claim 1, wherein R1 is selected from hydrogen, methyl, ethyl, «-propyl, /- propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl;

R2 is selected from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is an unsubstituted or substituted 5-or 6-membered aromatic ring;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted phenyl or thienyl.

5. The compound of claim 1, wherein R1 is selected from hydrogen, methyl, ethyl, «-propyl, /- propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl;

R2 is selected from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is an unsubstituted phenyl;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and R5is 3,4-dichlorophenyl.

6. The compound of claim 1, wherein R1 is methyl, R2 is methyl, R3 is an unsubstituted phenyl, R4 is hydrogen, and R5 is 3, 4-dichlorophenyl.

7. The compound of claim 1, wherein the compound is selected from any one of Compounds 1 to 13, wherein Compound 1 is 3,4-dichloro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 2 is 4-chloro-N-((l-(dimethylamino-)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 3 is 4-fluoro-N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 4 is 4- trifluoromethyl-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 5 is 4-methoxy-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 6 is 3,4-difluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 7 is N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 8 is 4-bromo-N-((l-(dimethylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 9 is 3-chloro-N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 10 is 3- fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride;

Compound 11 is 3,4-dichloro-N-((l-(benzyl(methyl)amino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 12 is 3,4-dichloro-N-((l-(methylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; and Compound 13 is 3,4-dichloro-N-((l- (dimethylamino)-4-/-butyl-cyclohexyl)methyl)-benzamide hydrochloride.

8. A method of binding the human m-opioid receptor (OPRM1), comprising: providing a compound represented by Formula 1 Formula 1 to OPRM1 -expressing cells, wherein: wherein: R1 is selected separately from one of methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, N-isopent-2-enyl;

R2 is selected separately from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is selected from an unsubstituted or substituted 5-or 6-membered aromatic or nonaromatic ring, or an ethyl, «-propyl, /-propyl, cyclopropyl, «-butyl, /-butyl, /-butyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, or methylcyclohexyl;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted 5- or 6-membered aromatic ring alone or fused to a second ring.

9. The method of claim 8, wherein the providing occurs in vitro or in vivo.

10. The method of claim 8, wherein R1 is methyl, R2 is methyl, R3 is an unsubstituted phenyl, R4 is hydrogen, and R5 is 3, 4-dichlorophenyl.

11. The method of claim 8, wherein the compound represented by Formula 1 is selected from any one of Compounds 1-13, wherein Compound 1 is 3,4-dichloro-N-((l-(dimethylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 2 is 4-chloro-N-((l- (dimethylamino-)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 3 is 4- fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 4 is 4-trifluoromethyl-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 5 is 4-methoxy-N-((l-(dimethylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 6 is 3,4-difluoro-N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 7 is N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 8 is 4- bromo-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 9 is 3-chloro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 10 is 3-fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 11 is 3,4-dichloro-N-((l-(benzyl(methyl)amino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 12 is 3,4-dichloro-N-((l- (methylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; and Compound 13 is 3,4- dichloro-N-((l-(dimethylamino)-4-/-butyl-cyclohexyl)methyl)-benzamide hydrochloride.

12. A method of treating or alleviating pain in a subject, comprising administering to the subject having pain an effective amount of a compound of Formula 1 for a period to time, wherein:

R1 is selected separately from one of methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, N-isopent-2-enyl;

R2 is selected separately from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is selected from an unsubstituted or substituted 5-or 6-membered aromatic or nonaromatic ring, or an ethyl, «-propyl, /-propyl, cyclopropyl, «-butyl, /-butyl, /-butyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, or methylcyclohexyl;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted 5- or 6-membered aromatic ring alone or fused to a second ring.

13. The method of claim 12, wherein R5 is naphthyl or indole.

14. The method of claim 12, wherein R1 is selected from hydrogen, methyl, ethyl, «-propyl, /- propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl; R2 is selected from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is an unsubstituted or substituted 5-or 6-membered aromatic or non-aromatic ring;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted phenyl or thienyl or is napthyl or indole.

15. The method of claim 12, wherein R1 is selected from hydrogen, methyl, ethyl, «-propyl, /- propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl;

R2 is selected from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is an unsubstituted or substituted 5-or 6-membered aromatic ring;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R5 is an unsubstituted or substituted phenyl or thienyl.

16. The method of claim 12, wherein R1 is selected from hydrogen, methyl, ethyl, «-propyl, /- propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl;

R2 is selected from hydrogen, methyl, or ethyl; or R'-N-R2 is 5- or 6-membered non-aromatic ring;

R3 is an unsubstituted phenyl;

R4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and R5 is 3,4-dichlorophenyl.

17. The method of claim 12, wherein R1 is methyl, R2 is methyl, R3 is an unsubstituted phenyl, R4 is hydrogen, and R5 is 3, 4-dichlorophenyl.

18. The method of claim 12, wherein the compound represented by Formula 1 is selected from any one of Compounds 1-13, wherein Compound 1 is 3,4-dichloro-N-((l-(dimethylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 2 is 4-chloro-N-((l- (dimethylamino-)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 3 is 4- fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 4 is 4-trifluoromethyl-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 5 is 4-methoxy-N-((l-(dimethylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 6 is 3,4-difluoro-N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 7 is N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 8 is 4- bromo-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 9 is 3-chloro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 10 is 3-fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride; Compound 11 is 3,4-dichloro-N-((l-(benzyl(methyl)amino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride; Compound 12 is 3,4-dichloro-N-((l- (methylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride; and Compound 13 is 3,4- dichloro-N-((l-(dimethylamino)-4-/-butyl-cyclohexyl)methyl)-benzamide hydrochloride.

19. The method of any one of claims 12-18, wherein after the period of time, the method further comprises no longer administering the compound of Formula 1, and the subject experiences decreased or no withdrawal symptoms.

20. The method of claim 19, wherein the decreased or no withdrawal symptoms of the compound of Formula 1 are relative to a biased opioid agonist or a morphinan opioid agonist.

21. The method of any one of claims 12-18, wherein the period of time is from 1 day up to 3 months.

22. A method of treating dependency to a biased opioid agonist compound or a morphinan opioid agonist compound in a subject, the method comprising administering to the subject suffering from dependency an effective amount of a compound of Formula 1 of any one of claims 1 to 7 for a period of time.

23. The method of claim 22, wherein the period of time is from 1 day up to 6 months.

24. The method of claim 22 or claim 23, wherein the administering further comprises the effective amount of the compound of Formula 1 together with the biased opioid agonist compound or the morphinan opioid agonist compound for a first period of time.

25. The method of claim 24, wherein after the first period of time, the method further comprises administering an effective amount of a compound of Formula 1 for a second period of time without the biased opioid agonist compound or the morphinan opioid agonist compound.

26. The method of any one of claims 24 or 25, wherein the first period of time is from 1 day up to about 4 weeks.

27. The method of any one of claims 25 or 26, wherein the second period of time is from 1 day up to about 6 months.

Description:
SMALL MOLECULE NON-MORPHINAN OPIOID COMPOSITIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 62/909, 605filed on October 2, 2019, the entire content of which is incorporated herein by reference.

[0002] This invention was made with government support under NIJ 2016-R2-CX-0059 awarded by the National Institute of Justice. The government has certain rights in the invention.

Field of the Invention

[0003] The field of the invention is a class of 4-substituted-l-(benzamidomethyl)cyclohexyl- dialkylamine opioid analogs.

Background

[0004] The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0005] All publications identified herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0006] Opioid therapeutics are excellent analgesics whose utility is compromised by dependence and other adverse effects such as respiratory depression and constipation. Morphine and its clinically relevant derivatives such as OxyContin®, Vicodin®, and Dilaudid® are “biased” agonists at the human m-opioid receptor (OPRM1) where they engage G-protein signaling but poorly bind the k-opioid receptor and thereby poorly engage the corresponding b -arrestin pathway and the endocytic machinery. In contrast, endorphins which are the endogenous peptide agonists for opioid receptors (ORs), are potent analgesics that show reduced liability for tolerance and dependence and engage both G protein and b -arrestin pathways as “balanced” agonists which are capable of binding both the mu (m-) and kappa (K-) opioid receptors.

[0007] As balanced opioid agonists have been reported to ameliorate the side effects of tolerance and dependence associated with long-term opioid use, there is a need to identify additional balanced opioid agonists with a signaling profile comparable to the endorphins.

Summary of The Invention

[0008] The inventive subject matter provides compositions and methods of compounds represented by Formula 1 Formula 1 wherein:

R 1 is selected separately from one of methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, N-isopent-2-enyl;

R 2 is selected separately from hydrogen, methyl, or ethyl; or R'-N-R 2 is 5- or 6-membered non-aromatic ring;

R 3 is selected from an unsubstituted or substituted 5-or 6-membered aromatic or nonaromatic ring, or an ethyl, «-propyl, /-propyl, cyclopropyl, «-butyl, /-butyl, /-butyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, or methylcyclohexyl;

R 4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and

R 5 is an unsubstituted or substituted 5- or 6-membered aromatic ring alone or fused to another ring, for example, naphthyl or indole. [0009] In additional embodiments, a compound represented by Formula 1, is as defined above, wherein for one or more of the possible hydrogens is replaced with deuterium or fluorine. In typical examples, a deuterium or fluorine may be place at the end of an alkyl chain or in an aromatic ring at a position farthest from the point of attachment ( e.g p-F-phenyl).

[0010] In other embodiments, the compound of Formula 1 is defined where wherein R 1 is selected from hydrogen, methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl; R 2 is selected from hydrogen, methyl, or ethyl; or R'-N- R 2 is 5- or 6-membered non-aromatic ring; R 3 is an unsubstituted or substituted 5-or 6-membered aromatic or non-aromatic ring; R 4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and R 5 is an unsubstituted or substituted phenyl or thienyl or is napthyl or indole.

[0011] In other embodiments, the compound of Formula 1 is defined where R 1 is selected from hydrogen, methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N- isopent-2-enyl; R 2 is selected from hydrogen, methyl, or ethyl; or R'-N-R 2 is 5- or 6-membered non-aromatic ring; R 3 is an unsubstituted or substituted 5-or 6-membered aromatic or non aromatic ring; R 4 is hydrogen, methyl, ethyl, «-propyl, or /-propyl; and R 5 is an unsubstituted phenyl or unsubstituted thienyl.

[0012] In still other embodiments, the compound of Formula 1 is defined where R 1 is selected from hydrogen, methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl; R 2 is selected from hydrogen, methyl, or ethyl; or R'-N-R 2 is 5- or 6- membered non-aromatic ring; R 3 is an unsubstituted phenyl; R 4 is hydrogen, methyl, ethyl, «- propyl, or /-propyl; and R 5 is 3,4-dichlorophenyl.

[0013] In specific embodiments, a compound referred to as AP01 (Compound 1) is represented by Formula 1, wherein R 1 is methyl, R 2 is methyl, R 3 is an unsubstituted phenyl, R 4 is hydrogen, and R 5 is 3, 4-dichlorophenyl.

[0014] The compounds represented by Formula 1 as defined herein include agonists of the human m-opioid receptor (OPRM1). In some embodiments, the compounds represented by Formula 1 as defined herein are partial agonists of OPRM1. In some embodiments, a compound represented by Formula 1 as defined herein interacts with OPRM1, but induces minimal or no receptor internalization of OPRM1. Additionally and/or alternatively, compounds represented by Formula 1 as defined herein are balanced agonists of the OPRM1 and engage in both the G- protein and b-arrestin pathways. In specific embodiments, compounds represented by Formula 1 include Compounds 1 to 13 as disclosed herein.

[0015] The contemplated subject matter also includes a method of treating or alleviating pain in a subject having pain, the method including administering an effective amount of a compound represented by Formula 1 to the subject having pain. In exemplary embodiments, a method of treating or alleviating pain in a subject having pain includes administering an effective amount of any of Compounds 1 to 13 as disclosed herein to the subject having pain.

[0016] The contemplated subject matter also includes a method of treating or alleviating opioid dependence in a subject suffering from dependence to a biased opioid agonist or morphinan opioid agonist, the method including administering a compound represented by Formula 1 to the subject, wherein the compound represented by Formula 1 is consumed by the subject instead of or together with the opioid compound to which the subject is addicted. For example, a compound of Formula 1 may be consumed by the subject instead of or together with OxyContin® ( i.e ., oxycodone), Vicodin® (i.e., hydrocodone and acetaminophen), Dilaudid®

(i.e., hydromorphone or palladone). The method of treating or alleviating opioid dependence/addition in a subject may include administering a compound represented by Formula 1 to the subject together with the opioid compound to which the subject is addicted for a period of time ( e.g ., 1 day up to 4 weeks), and after the period of time, the method includes administering the compound of Formula 1 to the subject instead of (e.g., without) the subject consuming the opioid compound to which the subject is addicted. In exemplary embodiments, a a method of treating or alleviating opioid dependence in a subject includes administering an effective amount of any of Compounds 1 to 13 as disclosed herein to the subject having an opioid dependence.

[0017] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components. Brief Description of the Drawings

[0018] Fig. la is graph showing percent (%) inhibition of forskolin (FSK) in a FSK-induced cyclic AMP (cAMP) assay as a function of concentration of AH-7921 (A01).

[0019] Fig. lb is graph showing percent (%) inhibition of FSK response in a cAMP assay as a function of concentration of AP01.

[0020] Fig. 2 is a graph of percent of the human m-opioid receptor (OPRM1) internalization for the indicated opioid analogs and control compounds.

[0021] Fig. 3 is a schematic of an exemplary compound represented by Formula 1, according to embodiments of the present disclosure.

Detailed Description

[0022] Morphinan opioid compounds derived from the scaffold of morphine selectively bind the human m-opioid receptor (OPRM1) where they engage G-protein signaling, thereby rendering a signaling bias toward the G-protein pathway having the well known analgesic and addictive effects. In contrast to these biased opioid agonists, the presently disclosed subject matter includes non-morphinan opioid compounds that are capable of binding to both the m- and k-opioid receptors, having a partial or “balanced” engagement of G-protein and b-arrestin effectors that is promoted by the endorphins. The small-molecule agonists of Formula 1 as disclosed herein are structurally distinct from morphine and have a signaling profile somewhere between that of the morphinan and endorphin chemotype. The balanced opioid agonist compounds of Formula 1 are safer, yet effective analgesic agents. Notably, partial or “balanced” agonists have a utility of their own with the potential for use in treatment of opioid use disorder.

[0023] The compounds represented by Formula 1 as defined herein include agonists of the human m-opioid receptor (OPRM1). Typically, the compounds represented by Formula 1 as defined herein are partial agonists of OPRM1. More typically, a compound represented by Formula 1 as defined herein interacts with OPRM1, but induces decreased, minimal, or no receptor internalization of OPRM1 compared to morphinan opioid compounds. Additionally and/or alternatively, compounds represented by Formula 1 as defined herein are balanced agonists of the OPRM1 and engage in both the G-protein and b-arrestin pathways. [0024] Advantageously, the contemplated subject matter includes a class of 4-substituted-l- (benzamidomethyl)-cyclohexyldialkylamine balanced analogs represented by Formula 1: Formula 1 where:

R 1 is selected separately from hydrogen, methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, and N-isopent-2-enyl;

R 2 is selected separately from hydrogen, methyl, or ethyl; or R'-N-R 2 is 5- or 6-membered non-aromatic ring;

R 3 is selected separately from an unsubstituted or substituted 5-or 6-membered aromatic or nonaromatic ring, or is selected separately from ethyl, «-propyl, /-propyl, cyclopropyl, «-butyl, /- butyl, /-butyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, and methylcyclohexyl;

R 4 is selected separately from hydrogen, methyl, ethyl, «-propyl, or /-propyl; and R 5 is an unsubstituted or substituted 5- or 6-membered aromatic ring by itself or fused to another ring (e.g, naphthyl, indole).

[0025] Advantageously, the compounds of Formula 1 as disclosed herein, are balanced opioid agonists that confer an analgesic effect upon administration to a subject experiencing pain with decreased or without dependency (addiction) to the compound compared to biased opioid agonist compounds or morphinan opioid agonist compounds as detailed herein.

[0026] In additional embodiments, a compound represented by Formula 1 is as defined above, wherein for one or more of the possible hydrogens is replaced with deuterium or fluorine. In typical examples, a deuterium or fluorine may be place at the end of an alkyl chain or in an aromatic ring at a position farthest from the point of attachment ( e.g p-F-phenyl).

[0027] In some embodiments of the inventive subject matter, the compound of Formula 1 is defined where R 1 is selected from hydrogen, methyl, ethyl, «-propyl, /-propyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or N-isopent-2-enyl; R 2 is selected from hydrogen, methyl, or ethyl; or R'-N-R 2 is 5- or 6-membered non-aromatic ring; R 3 is an unsubstituted or substituted 5-or 6-membered aromatic or non-aromatic ring; R 4 is hydrogen, methyl, ethyl, n- propyl, or /-propyl; and R 5 is an unsubstituted phenyl or unsubstituted thienyl.

[0028] In some embodiments, the compounds of Formula 1 have an increased potency compared to other known opioid analogs. For example, the compounds of Formula 1 have an increased potency compared to the opioid analog AH-7921 (referred to herein as A01), which is l-(3,4- di chi orobenzamidomethylj-cyclohexyl -dim ethyl a ine.

[0029] In an exemplary embodiment, a compound represented by Formula 1 is defined wherein R 1 is methyl, R 2 is methyl, R 3 is an unsubstituted phenyl, R 4 is hydrogen, and R 5 is 3, 4- dichlorophenyl. This specific compound is referred to herein as AP01 (i.e., 3,4-dichloro-N-((l- (dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride as set forth in Example 1) .

[0030] With reference to Figs. 1A and IB, human m-opioid receptor OPRM1 -expressing cells were incubated with A01 or AP01, followed by incubation with forskolin (FSK) prior to measuring the amount of cyclic adenine monophosphate (cAMP) levels. As FSK induces cAMP accumulation in OPRM1 -expressing cells, a decrease in an FSK response indicates that the opioid analog compound interacts with the OPRM1 receptor. Accordingly, AP01 (Fig. 1A) is a more potent OPRM1 agonist than A01 (Fig. IB). In particular, AP01 (i.e., Compound 1 of Example 1) has a potency that is 142 times greater than the potency of A01. Without being bound by any one theory or mechanism of action, APOlbinds to m- and k-opioid receptors in the low nM range, while affinity for the d-opioid is 10-fold weaker. In another example, AbOl (Compound 13 of Example 13) also binds to m- and k-opioid receptors in the low nM range, while the affinity of AbOl for the d-opioid receptor is approximately 100-fold weaker than the m- opioid receptor affinity. [0031] With reference to Fig. 2, OPRM1 receptor internalization of the AP01 was assayed with the indicated analogs. Specifically, in addition to AP01 as disclosed herein, the opioid analogs assayed were DAMGO, morphine, AH-7921 (A01), A02, U01, U04, UdesOl, and AS01 as described in U.S. PatentNo, 4,346,101 and/or Hsu et al., 2019, Pharmacol. Res. Perspect., e00511. https://doi.org/10.1002/prp2.511. While A01 and AP01 appear to demonstrate similar levels of receptor internalization (an indicator of ligand bias), modifications of the aromatic substitution, amide substitution, or the 4 position of the cyclohexyl ring appear to alter the level of internalization.

[0032] In additional exemplary embodiments, a compound represented by Formula 1 is one of Compounds 2-13, as set forth below and in Examples 2-13.

[0033] Compound 2: 4-chloro-N-((l-(dimethylamino-)-4-phenylcyclohexyl)methyl)-b enzamide hydrochloride.

[0034] Compound 3: 4-fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-be nzamide hydrochloride.

[0035] Compound 4: 4-trifluoromethyl-N-((l-(dimethylamino)-4-phenylcyclohexyl)m ethyl)- benzamide hydrochloride.

[0036] Compound 5: 4-methoxy-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride.

[0037] Compound 6: 3,4-difluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl )- benzamide hydrochloride.

[0038] Compound 7: N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride.

[0039] Compound 8: 4-bromo-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-ben zamide hydrochloride.

[0040] Compound 9: 3-chloro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-be nzamide hydrochloride. [0041] Compound 10: 3-fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-be nzamide hydrochloride.

[0042] Compound 11: 3,4-dichloro-N-((l-(benzyl(methyl)amino)-4-phenylcyclohexyl) methyl)- benzamide hydrochloride.

[0043] Compound 12: 3,4-dichloro-N-((l-(methylamino)-4-phenylcyclohexyl)methyl)- benzamide hydrochloride.

[0044] Compound 13: 3,4-dichloro-N-((l-(dimethylamino)-4-/-butyl-cyclohexyl)meth yl)- benzamide hydrochloride.

[0045] This invention also relates to compositions having a compound represented by Formula 1 as an active ingredient in a pharmaceutical carrier. The compositions are useful in pharmaceutical dosage unit forms of the Formula I compounds ( e.g Compounds 1-13) for systemic administration (oral, rectal and parenteral administration form) in therapy for treating and alleviating pain in humans and valuable animals, including dogs, cats and other commercially valuable and domestic animals.

[0046] The term "dosage unit form" as used in this specification and in the claims refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a predetermined quantity of the essential active ingredient compound of this invention calculated to produce the desired effect, in combination with the required pharmaceutical means which adapt the said ingredient for systemic administration. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on the physical characteristics of the essential active ingredient and the particular effect to be achieved in view of the limitations inherent in the art of compounding such an essential active material for beneficial effects in humans and animals. Examples of suitable dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in suitable liquid vehicles, sterile preparations in suitable liquid vehicles for intramuscular and intravenous administration, suppositories, and sterile dry preparations for the extemporaneous preparation of sterile injectable preparations in a suitable liquid vehicle. Suitable solid diluents or carriers for the solid oral pharmaceutical dosage unit forms are selected from the group consisting of lipids, carbohydrates, proteins and mineral solids, for example, starch, sucrose, lactose, kaolin, dicalcium phosphate, gelatin, acacia, com syrup, corn starch, talc and the like. Capsules, both hard and soft, are filled with compositions of these aminoamide active ingredients in combination with suitable diluents and excipients, for example, edible oils, talc, calcium carbonate and the like and also calcium stearate. Liquid preparations for oral administration are prepared in water or aqueous vehicles which advantageously contain suspending agents, for example, methylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like. In the case of injectable forms, the injectable formulation must be sterile and must be fluid to the extent that easy syringeability exists. Such preparations must be stable under the conditions of manufacture and storage, and ordinarily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like. In many cases, it is preferable to include osmotically active agents, for example, sugars or sodium chloride in isotonic concentrations. Carriers and vehicles include vegetable oils, ethanol, polyols, for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like. Any solid preparations for subsequent extemporaneous preparation of sterile injectable preparations are sterilized, preferably by exposure to a sterilizing gas, for example, ethylene oxide. The aforesaid carriers, vehicles, diluents, excipients, preservatives, isotonic agents and the like constitute the pharmaceutical means which adapt the preparations for systemic administration.

[0047] The pharmaceutical dosage unit forms are prepared in accordance with the preceding general description to provide from about 0.5 to about 250 mg of the essential active ingredient per dosage unit form, divided if desired in dosages of from 1 to 4 times per day, not to exceed about 250 mg per day; the preferred dosage is 1 to 150 mg per day, which, as aforesaid, may be in the form of a semi-solid, oral, or rectal preparation, a liquid oral preparation, an injectable preparation including liquid preparations and solid dry preparations for extemporaneous reconstitution to a liquid injectable preparation. The amount of the essential active ingredient provided in the pharmaceutical dosage unit forms is that amount sufficient to obtain analgesic effects within the aforesaid effective non-toxic range. Expressed otherwise, when used systemically, an amount of the essential active ingredient is provided to a recipient within a range from about 0.01 mg per kg to about 4 mg per kg of body weight of the recipient depending upon the age, weight, condition of the patient or other factors of concern to the physician. Preferred dosages for most applications are about 0.03 to 1.5 mg per kg of body weight.

[0048] The useful pharmaceutical dosage unit forms of these compounds in pharmaceutical formulations is preferably adapted for systemic administration to obtain analgesic effects comprising an effective, non-toxic amount of a compound according to Formula 1 ( e.g ., Compounds 1-13) or as its pharmacologically acceptable salt.

[0049] Advantageously, methods of treating a subject in pain, includes administering a compound of Formula 1 (e.g., Compounds 1-13) to the subject in pain. These methods include obtaining analgesic effects in subjects which include mammals, for example, humans and valuable warm-blooded animals such as dogs, cats, horses and other commercially valuable animals, by administering systemically to the mammals the aforesaid pharmaceutical dosage unit forms of a compound of Formula 1 for supplying an effective, non-toxic amount for analgesic effects. These compounds have an advantage, to a greater or lesser extent, depending upon the particular compound, of having analgesic activity (lower EDso numbers) with less dependence (e.g, decrease in symptoms/feelings of withdrawal in the subject compared to morphinan compounds or biased opioid agonists when the compound is no longer consumed by the subject. Additionally or alternatively, the compounds confer analgesic activity with decreased euphoria compared to morphinan opioid compounds. As used herein, dependency or addiction include symptoms and/or feelings of withdrawal when the opioid compound is no longer administered or consumed. These symptoms or feelings of withdrawal associated with dependency/addiction include one or more of agitation, shakiness in any part of or throughout the subject’s body, having a need to feel differently, feeling depressed and incapable of self-regulating any feelings, headache, nausea, lethargy, and fatigue.

[0050] Notably, the contemplated subject matter also includes a method of treating or alleviating pain in a subject (e.g, a mammal as disclosed herein) having pain, the method including administering an effective amount of a compound represented by Formula 1 (e.g, Compounds 1- 13) to the subject having pain. Administering includes any suitable means of administration as disclosed herein. For example, the compounds of Formula 1 may be orally administered as whole tablets, capsules, or in powder form. In another example, the compound of Formula 1 may be dissolved and intravenously or subcutaneously injected. Oral administration may be self-administered or may be carried out by another person assisting the subject in pain. Administration of the compound of Formula 1 to the patient may occur on a daily basis for a period of time including 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or for as long the pain persists.

[0051] The contemplated subject matter also includes a method of treating or alleviating opioid dependence in a subject suffering from dependence to opioids, the method including administering by any suitable method disclosed herein, a compound represented by Formula 1 (e.g, Compounds 1-13) to the subject, wherein the compound represented by Formula 1 is consumed by the subject instead of or together with the opioid compound to which the subject is addicted. For example, a compound of Formula 1 may be consumed by the subject instead of or together with an opioid biased agonist or a morphinan opioid agonist. Examples of morphinan opioid agonist include morphine, OxyContin® ( i.e oxycodone), Vicodin® (i.e., hydrocodone and acetaminophen), Dilaudid® (i.e., hydromorphone or palladone).

[0052] In additional embodiments, the method of treating or alleviating opioid dependence/addition in a subject may include administering a compound represented by Formula 1 (e.g, Compounds 1-13) to the subject together with the opioid compound (e.g., biased opioid agonist or morphinan opioid agonist) to which the subject is addicted for a period of time including 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks, wherein the total daily amount of the biased opioid agonist or morphinan opioid agonist and the compound of Formula 1 does not exceed the amount the total daily amount the subject had been taking of the biased opioid agonist or morphinan opioid agonist to which they were addicted. Typically, the period of time that the compound of Formula 1 and the biased opioid agonist or morphinan opioid agonist are administered together to the subject is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week, followed by a second period of time of administering the compound of Formula 1 to the subject instead of (e.g, without) the subject consuming the opioid compound to which the subject is addicted. This second period of time may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer as necessary. Typically, this second period of time is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month, [0053] The method of treating or alleviating opioid dependence/addition in a subject may include administering the compound of Formula 1 ( e.g ., Compounds 1-13) to the subject instead of (e.g., without) the subject consuming the opioid compound to which the subject is addicted. The subject may be treated with the compound of Formula 1 for any effective period of time. An effective period of time is defined as a period of time necessary for the subject to be free of pain and have minimal feelings/symptoms of withdrawal as disclosed herein when not consuming the compound of Formula 1. For example, the effective period of time may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer as necessary. Typically, this second period of time is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month,

[0054] The present disclosure provides exemplary embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements.

Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0055] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. [0056] Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints and open-ended ranges should be interpreted to include only commercially practical values. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.

[0057] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.

[0058] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value with a range is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0059] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0060] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims refers to at least one of something selected from the group consisting of A, B, C ... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

[0061] Examples

[0062] This invention is illustrated by the following, nonlimiting examples.

[0063] Example 1. Preparation of 3,4-dichloro-N-((l-(dimethylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride (APOl). The 4-phenylcyclohexanone (10.48g; 60.1mmol), dimethylamine hydrochloride (4.91g; 60.2mmol), and 15mLwater were stirred in a round bottom fitted with a condenser. Potassium cyanide (4.05g; 62.2mmol) in 15mL water was added gradually over 5 minutes time. The mixture was then stirred overnight at room temperature. The reaction mixture can be extracted three times with 50mL dichloromethane, the combined organic washes dried over anhydrous sodium sulfate, and evaporated in vacuo to give l-dimethylamino-4-phenylcyclohexane-l-carbonitrile (13.63g; 59.7mmol; 99.2% yield). Without further purification, the nitrile derivative (8.09g; 34.9mmol) was dissolved in 35mL diethyl ether and added in portions to a stirred solution of 70mL 1M LiAlEE in diethyl ether in a round-bottom flask, cooled in an ice-water bath and fitted with a condenser. Upon complete addition, the cooling bath was removed and the mixture stirred overnight at room temperature with a drying tube fitted atop the condenser. The mixture was then cooled in an ice-water bath and 9mL water was added to the reaction mixture slowly followed by 7mL 30% aqueous potassium hydroxide solution followed by 17mL water. The diethyl ether was decanted from the clumped white solid in the reaction flask. The white solid was washed three times with 50mL diethyl ether. The combined organic layer and washes were dried over anhydrous sodium sulfate and evaporated in vacuo to give l-aminomethyl-l-dimethylamino-4-phenylcyclohexane. The final step was the acylation of the amine. This was performed by either of two methods. In the first method, 1.41g of 3,4-dichlorobenzoyl chloride was added to a stirred lOmL solution of 1.47g 1-aminom ethyl- 1- dimethylamino-4-phenylcyclohexane in pyridine. The solution was warmed on a hot plate until a solid appeared in the solution, at which time the solution was allowed to stand overnight. The mixture was gravity filtered and washed with toluene followed by n-hexane. After drying the solid was recrystallized from hot methanol with the addition of an equal volume of diethyl ether as the methanol cooled. Two crops of product were obtained from this solution for a total of 1.8 lg (61.6% yield). An alternative acylation method without the use of pyridine is as follows. 3,4-dichlorobenzoyl chloride (1.05 eq) was added to a solution of 1-aminom ethyl- 1- dimethylamino-4-phenylcyclohexane (1.0 eq) and triethylamine (1.0 eq) in 5 mL of dry diethyl ether and stirred at room temperature overnight. The reaction mixture was extracted three times with ethyl acetate, the combined organic layers washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude product was recrystallized from dichloromethane or precipitated with ethyl acetate upon sonication to give desired product as a solid. Conversion to the hydrochloride salt of final compounds were made using 2.0 N HC1 in diethyl ether solution. ¾NMR (400 MHz, METHANOL-^) d ppm 1.85 - 2.10 (m, 6 H), 2.0 (br d, 2 H), 2.55-2.70 (m, 1 H), 2.92 (s, 6H), 4.06 (s, 2 H), 7.20-7.35 (m, 5 H), 7.58 (d, 1 H), 7.98 (dd, 1 H), 8.19 (d, 1 H). mp = 234.3 + 0.21°C. The X-ray crystallographic structure is shown in Figure 3.

[0064] In the same manner as Example 1, the following Examples 2-13 were prepared.

[0065] Example 2. 4-chloro-N-((l-(dimethylamino-)-4-phenylcyclohexyl)methyl)-b enzamide hydrochloride (1.76g; 65.1% yield) was obtained by the method described in Example 1 using the pyridine acylation method mp = 235.8 + 0.67°C.

[0066] Example 3. 4-fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-be nzamide hydrochloride (1.84g; 70.7% yield) was obtained by the method described in Example 1 using the pyridine acylation method mp = 253.9 + 0.68°C.

[0067] Example 4. 4-trifluoromethyl-N-((l-(dimethylamino)-4-phenylcyclohexyl)m ethyl)- benzamide hydrochloride (0.70g; 69.6% yield) was obtained by the method described in Example 1 using the non-pyridine acylation method mp = 232.8 + 0.36°C. [0068] Example 5. 4-methoxy-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-b enzamide hydrochloride (0.71g; 77.5% yield) was obtained by the method described in Example 1 using the non-pyridine acylation method mp = 217.8 + 0.64°C.

[0069] Example 6. 3,4-difluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl )-benzamide hydrochloride (0.70g; 75.2% yield) was obtained by the method described in Example 1 using the non-pyridine acylation method mp = 244.6 + 0.12°C.

[0070] Example 7. N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-benzamide hydrochloride (0.55g; 81.4% yield) was obtained by the method described in Example 1 using the non-pyridine acylation method mp = 249.5 + 0.15°C.

[0071] Example 8. 4-bromo-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-ben zamide hydrochloride (2.05g; 68.2% yield) was obtained by the method described in Example 1 using the pyridine acylation method mp = 241.0 + 0.95°C.

[0072] Example 9. 3-chloro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-be nzamide hydrochloride (0.50g; 68.1% yield) was obtained by the method described in Example 1 using the non-pyridine acylation method mp = 231.8 + 0.15°C.

[0073] Example 10. 3-fluoro-N-((l-(dimethylamino)-4-phenylcyclohexyl)methyl)-be nzamide hydrochloride (0.59g; 83.3% yield) was obtained by the method described in Example 1 using the non-pyridine acylation method mp = 240.0 + 0.06°C.

[0074] Example 11. 3,4-dichloro-N-((l-(benzyl(methyl)amino)-4-phenylcyclohexyl) methyl)- benzamide hydrochloride (5.05g; 44.4% yield) was obtained by the non-pyridine acylation method described in Example 1 was followed with the exception that N-benzyl-methylamine hydrochloride was used in place of dimethylamine hydrochloride in the first step. HRMS-ESI (+) calcd m/z for C28H3iCl2N20 + 481.1813 (M+H) + , found 481.1814.

[0075] Example 12. Preparation of 3,4-dichloro-N-((l-(methylamino)-4- phenylcyclohexyl)methyl)-benzamide hydrochloride. 457.7mg (884mmol) of 3,4-dichloro-N- ((l-(benzyl(methyl)amino)-4-phenylcyclohexyl)methyl)-benzami de hydrochloride was dissolved in 55mL THF :water (1:1) containing 12 drops of glacial acetic acid. Using an HCube Mini Plus flow reactor, this solution was pumped through a 10% Pd/C column at 80°C with a flow rate of 1.OmL/min. The eluant solution was evaporated in vacuo to remove the tetrahydrofuran. The pH of the aqueous solution was made basic through the addition of KOH solution and the aqueous solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, decanted from the solid, and evaporated in vacuo. This gave 326.4mg of a white solid (86.3% yield).

[0076] Example 13. 3,4-dichloro-N-(( 1 -(di methyl ami no)-4-/-butyl -cyclohexyl (methyl )- benzamide hydrochloride (AbOl; 3.62g; 42.9% yield) was obtained by the non-pyridine acylation method described in Example 1 was followed with the exception that 4 -t- butylcyclohexanone was used in place of 4-phenylcyclohexanone in the first step. HRMS-ESI (+) calcd m/z for C20H31CI2N2CC385.I8I3 (M+H) + , found 385.1817.