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EP4618985A1 - Dual inhibitors of sigma-1 receptor and soluble epoxide hydrolase and their use in the treatment of pain - Google Patents

Dual inhibitors of sigma-1 receptor and soluble epoxide hydrolase and their use in the treatment of pain

Info

Publication number
EP4618985A1
EP4618985A1 EP23806325.9A EP23806325A EP4618985A1 EP 4618985 A1 EP4618985 A1 EP 4618985A1 EP 23806325 A EP23806325 A EP 23806325A EP 4618985 A1 EP4618985 A1 EP 4618985A1
Authority
EP
European Patent Office
Prior art keywords
benzyl
carboxamide
piperidine
alkyl
trifluoromethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23806325.9A
Other languages
German (de)
French (fr)
Inventor
Santiago VÁZQUEZ CRUZ
Eugenia-Alexandra PUJOL BECH
Javier SÁNCHEZ SÁNCHEZ-CORRAL
Celia ESCRICHE MOLINA
Enrique José COBOS DEL MORAL
José Manuel ENTRENA FERNÁNDEZ
María del Carmen RUIZ CANTERO
Emanuele AMATA
Maria DICHIARA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universidad de Granada
Universitat de Barcelona UB
Universita degli Studi di Catania
Original Assignee
Universidad de Granada
Universitat de Barcelona UB
Universita degli Studi di Catania
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidad de Granada, Universitat de Barcelona UB, Universita degli Studi di Catania filed Critical Universidad de Granada
Publication of EP4618985A1 publication Critical patent/EP4618985A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

  • the present invention relates to the field of medicine, particularly to the field of analgesia. Concretely, the present invention provides compounds and pharmaceutical compositions, as well as their use in the treatment or prevention of pain.
  • Pain is defined by the International Association for the Study of Pain (I ASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. (I ASP Pain Terminology, https://www.iasp-pain.org/resources/terminology/).
  • the IASP recommends using specific features to describe a patient's pain: (a) region of the body involved (e.g., abdomen, lower limbs), (b) system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal), (c) duration and pattern of occurrence, (d) intensity, and (e) cause.
  • Pain can be broadly divided into three classes: nociceptive, inflammatory, and neuropathic pain.
  • Nociceptive pain corresponds to the sensation associated with the detection of noxious stimuli able to induce tissue damage
  • inflammatory pain is associated with the milieu of factors released during tissue inflammation
  • neuropathic pain triggers in response to the damage of the nervous system by either trauma or chemical insult (e.g., treatments with antineoplastics) (cf. Woolf, J Clin Invest., 2010, 120(11): 3742-3744).
  • Neuropathic pain is a complex phenomenon with a marked contribution of central mechanisms.
  • the intradermal injection of capsaicin decreases the mechanical pain threshold in the area surrounding the injection even when the area was not stimulated with capsaicin (the so-called area of secondary hypersensitivity).
  • This decrease in the mechanical threshold can be attributed to central sensitization, which is a key feature of neuropathic pain, and in fact, this model is considered a surrogate model of neuropathic pain, since anti-neuropathic drugs show antiallodynic activity in this test in both humans and rodents (cf. Sanchez-Fernandez et al., Adv Exp Med Biol., 2017, 964:109-132).
  • analgesics including opioids, nonsteroidal anti-inflammatory drugs [NSAIDs] and gabapentinoids
  • opioids including opioids, nonsteroidal anti-inflammatory drugs [NSAIDs] and gabapentinoids
  • gabapentinoids show limited efficacy in many pain conditions, or a number of side effects which limit their use.
  • the analgesic effect of NSAIDs is limited and insufficient for the treatment of severe pain states, and they can induce gastrointestinal events or the impairment of renal function, among several other adverse effects (cf. Yaksh et al., FlOOOPrime Rep., 2015, 7, 56).
  • Opioids can induce a much higher analgesic effect, but also constipation, respiratory depression, tolerance, emesis and physical dependence, among other adverse events (cf.
  • Gabapentinoids are used in neuropathic pain patients, but induce dizziness, somnolence, peripheral edema, ataxia or gait disturbance and diarrhea (cf. Meng et al., Minerva Anestesiol., 2014, 80(5): 556-67).
  • the sigma-1 receptor (S1 R) is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system (cf. Ruiz-Cantero et al., Pharmacol Res., 2021 , 163:105339).
  • S1 R antagonists modify the chaperoning activity of S1 R by increasing opioid signalling and decreasing N-methyl-D-aspartate receptor (NMDAR) responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions.
  • NMDAR N-methyl-D-aspartate receptor
  • S1 R antagonists in the absence of opioids have been shown to exert antinociceptive effects in preclinical models of neuropathic pain induced by nerve trauma or chemical injury (e.g., the antineoplastic paclitaxel), and more recently in inflammatory pain. Although most studies attributed the analgesic properties of S1 R antagonists to their central actions, it is now known that peripheral S1 R also participate in their effects (cf. Ruiz-Cantero et al., 2021 , supra).
  • EETs epoxyeicosatrienoic acids
  • sEH soluble epoxide hydrolase
  • the inventors of the present invention have designed, for the first time, molecules of formula (I) efficiently acting on S1 R as well as on sEH.
  • Phenytoin potentiates the receptor binding affinity of S1 R agonists (ratios of K without phenytoin/with phenytoin >1); however, it produces no effects or slightly reduces receptor binding affinity for S1 R antagonists (ratios of K without phenytoin/with phenytoin ⁇ 1).
  • the administration of the compound of the invention was able to induce a marked antiallodynic effect in capsaicin-induced mechanical hypersensitivity (FIG. 1 and 2) and during postoperative pain (FIG. 3 and 4) were determined.
  • this effect was reversed when either PRE-084 (S1 R agonist) or MS- PPOH (a CYP450 epoxygenase inhibitor) were associated (FIG. 2 and 4), confirming that both S1 R antagonism and EET accumulation (due to the inhibition of sEH) participate in the antiallodynic effect of the compounds of the invention.
  • the compounds of formula (I) mean a great advance in the efficient management of pain, simplifying the management of pain with molecules having a broader analgesic effect by acting on two targets.
  • the present invention provides compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treatment or prevention of pain, wherein: R 1 is selected from the group consisting of: CN, halogen, (C 1 -C 10 )haloalkyl, -O-(C 2- C 10 )alkyl, and -0-(C 1 -C 10 )haloalkyl;
  • R2 to R4 are the same or different and are independently selected from the group consisting of: H; CN; halogen; (C 1 -C 10 )alkyl; (C 2- C 10 )alkenyl; (C 2- C 10 )alkynyl; (C 1- C 10 )alkyl substituted with one or more substituents Sui; (C 2- C 10 )alkenyl substituted with one or more substituents SU2; (C 2- C 10 )alkynyl substituted with one or more substituents Sus; -O-(C 1 -C 10 )alkyl; -O-(C 1 -C 10 )alkyl substituted with one or more substituents SU4; -O- (C 1 -C 10 )haloalkyl; -O-(C 1 -C 10 )haloalkyl substituted with one or more substituents Sus; - SFs, -S(O)2R9; -NR10R
  • R 5 is CRxR’x, being R x and R’ x the same or different and are independently selected from -H, (C 1 -C 5 )alkyl or (C 1 -C 5 )haloalkyl; or, alternatively, R x and R’ x together with the C atom to which they are attached, form a ring having from 3 to 6 members;
  • R 6 is an aromatic known ring system, which is selected from the group consisting of: an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CR y , and N; R y being selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )alkyl; (C 2- C 10 )alkenyl; (C 2- C 10 )alkynyl; (C 1 -C 10 )alkyl substituted with one or more substituents Sue; (C 2- C 10 )alkenyl substituted with one or more substitu
  • R? is CRvR’v, being R v and R’ v the same or different and are independently selected from H, (C 1 -C 5 )alkyl, or (C 1 -C 5 )haloalkyl; or, alternatively, R v and R’ v together with the C atom to which they are attached, form a ring having from 3 to 6 members;
  • Rs and R’s are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C 8 )cycloalkyl; aryl; and heteroaryl;
  • Rg, R13, R17 and Rtw are selected from the group consisting of: (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; aryl; and heteroaryl;
  • R10 and R11 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C8)cycloalkyl;
  • R12 and R’12 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; and (C 3- C8)cycloalkyl;
  • R14 and R15 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C8)cycloalkyl; and -S(O)2R2i ;
  • R16 and R’16 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; and (C 3- C8)cycloalkyl;
  • R 1 s and R19 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C8)cycloalkyl; and -S(O)2R22;
  • R’18 and R’19 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; (C 1 -C 10 )haloalkyl; and -S(O)2R23;
  • Rtw and R’tw are the same or different and are selected from the group consisting of: - H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; (C 1 -C 10 )haloalkyl; and -S(O)2Rti3;
  • R21 to R23 and Rti3 are selected from the group consisting of (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; or (C 1 -C 10 )haloalkyl;
  • R24, R25, and R’n2 are selected from the group consisting of -H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; and (C 1 -C 10 )haloalkyl; m is an integer value selected from 0, 1 or 2; n is an integer value selected from 1 or 2;
  • aryl means an aromatic ring system comprising 6 CR c members, being R c selected from H, halogen, cyano, nitro, (C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, -O-(C 1 -C 5 )alkyl, or -O-(C 1- Cs)haloalkyl;
  • heteroaryl means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, cyano, nitro, (C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, -O-(C 1 -C 5 )alkyl, -O-(C 1 -C 5 )haloalkyl;
  • Sui to Su 8 are independently selected from the group consisting of: halogen, cyano, nitro, (C 1- C 6 )haloalkyl, (C 1- C 6 )alkyl, (C 1- C 6 )hydroxyalkyl, (C 1- C 6 )alkoxy, (C 1- C 6 )alkylsulfinyl, (C 1- C 6 )alkylsulfonyl, (C 1- C 6 )alkylcarbonyl, (C 1- C 6 )alkoxycarbonyl, carbamoyl, N-(C 1- C 4 )alkylcarbamoyl, N,N-di-(C 1- C 4 )alkylcarbamoyl, (C 1- C 6 )alkylcarbonyloxy, (C 3- C 6 )cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto,
  • This aspect can alternatively be defined as the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, solvate or prodrug, in the manufacture of a medicament for the treatment or prevention of pain.
  • This aspect can alternatively be defined as a method for the treatment or prevention of pain, the method comprising the step of administering a therapeutically effective amount of the compound of formula (I) as defined above, a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof.
  • the present invention provides a compound selected from the group consisting of: a compound of formula (I’): is) or a pharmaceutically salt thereof, solvate or prodrug thereof, wherein
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof, as defined in the second aspect of the invention, together with one or more pharmaceutically acceptable salts.
  • the present invention provides the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof for use in therapy.
  • the present invention provides processes for preparing compounds of formula (I), (I’) and (Ibis).
  • the present invention provides a process for preparing a compound of formula (I), (I’) or (Ibis) as defined in any of the above aspects, wherein the process comprises the coupling reaction between:
  • the invention provides a further process for preparing a compound of formula (I), (I’) and (Ibis) as defined in any of the preceding aspects, which comprises the step of subjecting a compound of formula (X): to a reductive alkylation with a benzaldehyde of formula (XI), in the presence of a reductor agent; or, alternatively, to a nucleophilic substitution with a compound of formula (XII) in the presence of a base,
  • FIG. 2 represents the antiallodynic effect of COMPOUND OF EXAMPLE 2 (compound of the invention, Ex. 2) in capsaicin-treated mice through both S1 R antagonism and sEH inhibition.
  • B % Antiallodynic effect.
  • the data shown represent the effect of the subcutaneous (s.c.) administration of Ex. 2 (2.5 mg/kg), alone or associated with the S1 R agonist PRE-084 (32 mg/kg, s.c.) or the CYP450 epoxygenase inhibitor MS-PPOH (20 mg/kg, s.c.), on paw withdrawal latency in mice treated intraplantarly with capsaicin (1 pg).
  • N 8-11.
  • FIG. 3 represents the time course of the effect on postoperative pain of the association of the dual S1 R antagonist/sEH I COMPOUND OF EXAMPLE 2 (Ex. 2).
  • F von Frey threshold (g).
  • T Time after treatment (min).
  • L 2.5 h after laparotomy.
  • the data shows that the subcutaneous (s.c.) administration of Ex. 2 (10-40 mg/kg) induces a prominent relief of sensory hypersensitivity in laparotomized mice, in particular at 120 min after drug administration.
  • the present invention provides the use of compounds of formula (I) in the treatment or prevention of pain.
  • alkyl refers to a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond.
  • Typical alkyl groups have from 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e.g., methyl, ethyl, n-propyl, /-propyl, n-butyl, f-butyl, n- pentyl, etc. If substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropyl methyl.
  • Typical alkenyl radicals have from 2 to about 10, 2 to about 8 or 2 to about 6 carbon atoms.
  • the alkenyl group is vinyl, 1-methyl-ethenyl, 1 -propenyl, 2- propenyl, or butenyl.
  • hydroxyalkyl refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogens are replaced by -OH.
  • Illustrative non-limitative examples of hydroxyalkyl are methanol, ethanol, isopropanol, isobutanol or f-butanol, among others.
  • alkoxy refers to a -O-alkyl, wherein “alkyl” is as defined above.
  • Illustrative non-limitative examples of hydroxyalkyl are methoxy, ethoxy, or f-butoxy, among others.
  • alkylsulfinyl refers alkyl-SO-, being “alkyl” as defined above.
  • alkylsulfonyl refers to alkyl-SCh-, being “alkyl” as defined above.
  • Representative alkylcarbonyl groups include methylcarbonymethyl, ethylcarbonylmethyl, methylcarbonylethyl, (2-methylpropyl)carbonylmethyl, and the like.
  • carbamoyl refers to -C(O)NH2.
  • alkylcarbonyloxy refers to -C(O)-O-alkyl, being alkyl as defined above.
  • sulfamoyl refers to -S(O)2NH2.
  • halogen refers to bromo, chloro, iodo or fluoro.
  • haloalkyl refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogen atoms are replaced by halogen.
  • Illustrative non-limitative examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like.
  • the ring is saturated.
  • the ring is a cyclopropyl.
  • R 6 represents an aromatic ring system as defined in the first aspect of the invention.
  • R 6 includes one or more heteroatoms.
  • Illustrative non-limitative examples of R 6 aromatic ring systems including one or more heteroatoms include:
  • the term "salt” must be understood as any form of a compound used in accordance with this invention in which said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution.
  • This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly, complexes formed via ionic interactions.
  • the definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or “pharmaceutically acceptable salts”.
  • the term "pharmaceutically acceptable salts” means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly, as a result of the counter-ion) when used in an appropriate manner for a treatment, applied or used, particularly, in humans and/or mammals.
  • physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention -normally an acid (deprotonated)- such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used in humans and/or mammals.
  • Salts with alkali and alkali earth metals are preferred particularly, as well as those formed with ammonium cations (NH 4 + ).
  • Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium.
  • These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals.
  • This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e., salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals.
  • a physiologically tolerated acid i.e., salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals.
  • this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
  • solvate should be understood as meaning any form a compound in accordance with the invention in which said compound is bonded by a non-covalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates, like for example, methanolate.
  • a preferred solvate is the hydrate.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention.
  • prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (I) that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
  • the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
  • Prodrugs can typically be prepared using well-known methods.
  • any compound of formula (I) referred to herein is intended to represent such specific compound as well as certain variations or forms.
  • compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms.
  • any given compound of formula (I) referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof.
  • stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers).
  • each double bond will have its own stereoisomerism, that could be the same as, or different to, the stereoisomerism of the other double bonds of the molecule.
  • compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
  • any compound of formula (I) referred to herein may exist as tautomer.
  • tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another.
  • R y is selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )alkyl; (C2- C 10 )alkenyl; (C 2- C 10 )alkynyl; (C 1 -C 10 )alkyl substituted with one or more halogen, cyano, nitro, (C 1- C 6 )haloalkyl, (C 1- C 6 )alkyl, (C 1- C 6 )hydroxyalkyl, (C 1- C 6 )alkoxy, (C 1- Ce)alkylsulfinyl, (C 1- C 6 )alkylsulfonyl, (C 1- C 6 )alkylcarbonyl, (C 1- C 6 )alkoxycarbonyl, carbamoyl, N-(C 1- C 4 )alkylcarbamoyl, N,N-di-(C 1- C 4 )alkylcarbamoyl, (C 1- C 6 )
  • R’P is selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )haloalkyl; -O- (C 1 -C 10 )alkyl; -0-(C 1 -C 10 )haloalkyl; SF5; S(O)2R’I?; NR’isR’ig; and COOR25;
  • R z is selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )haloalkyl; -O- (C 1 -C 10 )alkyl; -0-(C 1 -C 10 )haloalkyl; SF5; S(O)2RI?; NR18R19; and COOR24;
  • R9, R13, and R17 represent (C 1 -C 10 )alkyl; and (C 3- C8)cycloalkyl;
  • R 1 s and R19 are the same or different and are selected from the group consisting of: H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; and (C 1 -C 10 )haloalkyl;
  • R’18 and R’19 are the same or different and are selected from the group consisting of: H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; and (C 1 -C 10 )haloalkyl; and
  • R23 and R24 are selected from the group consisting of H, and (C 1 -C 10 )alkyl; and (C 3- C8)cycloalkyl.
  • the compound is one of formula (Ibis): wherein R 1 to R3 and R 6 and n are as defined in the first aspect of the invention.
  • R1 is selected from the group consisting of: halogen; -O-(C 1 -C 10 )haloalkyl; and (C 1 -C 10 )haloalkyl.
  • R2 is selected from the group consisting of: H, CN; halogen; -0-(C 1 -C 10 )alkyl; -O-(C 1 -C 10 )haloalkyl; and (C 1- C 10 )haloalkyl.
  • R3 is selected from the group consisting of: H; CN; halogen; -0-(C 1 -C 10 )alkyl; -O-(C 1 -C 10 )haloalkyl; SF5; S(O)2Rg, wherein R9 is as defined above; particularly R9 is selected from (C 1 -C 10 )alkyl or aryl; particularly R9 is selected from (C 1 -C 10 )alkyl.
  • R3 is selected from the group consisting of: CN; halogen; -0-(C 1 -C 10 )alkyl; -O-(C 1 -C 10 )haloalkyl; and SF5.
  • R 6 is an aromatic 5- or 6-membered ring system, as defined in the first aspect of the invention.
  • R26 is selected from the group consisting of: (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; (C2- C 10 )alkenyl; (C 2- C 10 )alkynyl; aryl; and heteroaryl; and
  • Su 8 to Suw are independently selected from the group consisting of: halogen, cyano, nitro, (C 1- C 6 )haloalkyl, (C 1- C 6 )alkyl, (C 1- C 6 )hydroxyalkyl, (C 1- C 6 )alkoxy, (C 1- Ce)alkylsulfinyl, (C 1- C 6 )alkylsulfonyl, (C 1- C 6 )alkylcarbonyl, (C 1- C 6 )alkoxycarbonyl, carbamoyl, N-(C 1- C 4 )alkylcarbamoyl, N,N-di-(C 1- C 4 )alkylcarbamoyl, (C 1- Ce)alkylcarbonyloxy, (C 3- C 6 )cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenyl
  • R 6 is an aromantic 5-membered ring system of formula (IV):
  • R 3 represents -H.
  • R 1 is selected from the group consisting of halogen, CN, -0-(C 1 -C 10 )alkyl, (C 1- C 10 )haloalkyl, and -O-(C 1 -C 10 )haloalkyl;
  • R2 represents H
  • R3 is selected from the group consisting of -CN, halogen, -0-(C 1 -C 10 )alkyl, -O-(C 1- C 10 )haloalkyl, -SF5, and -S(O)2Rg; and R 6 is selected from the group consisting of:
  • each R y is independently selected from the group consisting of: H; halogen; nitro; CN; (C 1 -C 5 )alkyl; (C 1 -C 5 )alkyl substituted with one or more halogens; -O-(C 1 -C 5 )alkyl; -O-(C 1 -C 5 )haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each R y is independently selected from the group consisting of: H; halogen; (C 1 -C 5 )alkyl; -O-(C 1 -C 5 )alkyl; and -COOH;
  • R1 is selected from the group consisting of halogen; -0-(C 1 -C 10 )alkyl; (C 1 -C 10 )alkyl substituted with one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl; and
  • R3 is selected from the group consisting of CN, -0-(C 1 -C 10 )alkyl, -O-(C 1 -C 10 )haloalkyl, and halogen.
  • R1 is selected from the group consisting of halogen; (C 1 -C 10 )alkyl substituted with one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl;
  • R2 is H; and Rs is selected from the group consisting of CN, -0-(C 1 -C 10 )alkyl, -O-(C 1 -C 10 )haloalkyl, and halogen.
  • R 1 is selected from the group consisting of halogen; (C 1 -C 10 )alkyl substituted by one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl;
  • R2 represents H
  • R3 is selected from the group consisting of -CN, halogen, -O-(C 1 -C 10 )haloalkyl, and -O- (C 1 -C 10 )alkyl; and R 6 is selected from the group consisting of:
  • each R y is independently selected from the group consisting of: H; halogen; nitro; CN; (C 1 -C 5 )alkyl; (C 1 -C 5 )alkyl substituted with one or more halogens; -O-(C 1 -C 5 )alkyl; -O-(C 1 -C 5 )haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each R y is independently selected from the group consisting of: H; halogen; (C 1 -C 5 )alkyl; -O-(C 1 -C 5 )alkyl; and -COOH;
  • R1 is selected from the group consisting of halogen; (C 1 -C 10 )alkyl substituted by one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl;
  • R2 represents H
  • R3 is selected from the group consisting of -CN, halogen, -O-(C 1 -C 10 )haloalkyl, and -O- (C 1 -C 10 )alkyl; and R 6 is a 6-membered aromatic ring system is a ring of formula (II) as defined above, wherein R y is selected from the group consisting of: H; halogen; (C 1 -C 5 )alkyl; (C 1 -C 5 )alkyl substituted with one or more halogens; -O-(C 1 -C 5 )alkyl; -O-(C 1 -C 5 )haloalkyl; and -COOR23; particularly each R y is independently selected from the group consisting of: H; halogen; (C 1 -C 5 )alkyl; -O-(C 1 -C 5 )alkyl; and -COOH;
  • R1 is selected from the group consisting of halogen; (C 1 -C 10 )alkyl substituted by one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl;
  • R2 represents H
  • treatment includes, but is not limited to, alleviating, diminishing or eliminating one or more symptoms of the disorder (i.e. , pain), reducing the degree of the pain, stabilizing (i.e., not worsening) the condition, delaying or slowing the progression of the pain, alleviating or improving its condition, and remitting (whether total or partial).
  • prevention refers to preventing the onset of the pain from occurring in a patient who is predisposed, but who does not yet have symptoms of the disease, or when the intervention is done before pain-inducing procedure.
  • pain shall refer to all types of pain.
  • Illustrative non-limitative examples are acute and chronic pains, such as surgical pain, articular pain, neuropathic pain and post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, migraine, angina pain, and genitourinary tract-related pain including cystitis, the term shall also refer to nociceptive pain or nociception.
  • these embodiments can find use in the treatment of neuropathic pain, and in particular of nervous pain, herpes zoster, desafferentation (phantom member) pain, diabetic neuropathies, and chemotherapy-induced neuropathic pain.
  • the term “animal” shall refer to a vertebrate animal. Such animals include both domestic animals; for example, livestock, laboratory animals and household pets, and non-domestic animals such as wildlife.
  • the animal is a vertebrate.
  • the animal is a domestic mammal or a human.
  • a compound of this invention may be administered as a feed additive.
  • the second aspect of the invention also provides a compound of formula (Ibis) as defined above. All the embodiments provided for the compound of formula (Ibis) in the context of the first aspect are also embodiments of the compound in the context of the second aspect of the invention, applying the corresponding provisos pointed out above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the invention (Ibis) or (I’) or a pharmaceutical salt thereof, as defined above.
  • terapéuticaally effective amount it is understood the amount of the compound(s) that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • the precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the invention, may depend on several variables. Some of these would be: route of administration, time of drug release (e.g., instant or extended), administration schedule, pain severity, condition of the patient, and the like.
  • compositions can be prepared as a liquid, semi-solid or solid dosage form, for example in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pills or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, or administered as such.
  • compositions can be prepared with the aid of conventional means, devices, methods or processes known in the art.
  • pharmaceutically acceptable refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio in animals and, particularly, in humans.
  • physiologically compatible adjuvants or the number of adjuvants to be used depends on the form of administration of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, otic or intratympanic.
  • the active drug components can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatine, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.
  • the dosage administered of the pharmaceutical composition will, of course, vary depending on the use and known factors such as the age, health, and weight of the recipient; nature and extent of symptoms, concurrent treatments, if any, frequency of treatment, and the effect desired.
  • the recipient may be any type of mammal, but is preferably a human.
  • the compounds of formula (I) may be prepared by reacting the amine of formula (VIII), either as free base or in the form of a salt such as the hydrochloride, with the carboxylic acid of formula (IX) (such as 1- benzylpiperidine-4-carboxylic acid and N-boc-piperidine-4-carboxylic acid) in the presence of a coupling agent such as EDCI or HOBt or using an acyl chloride in the presence of a base, such as triethylamine, in an organic solvent such as ethyl acetate.
  • a coupling agent such as EDCI or HOBt
  • acyl chloride such as triethylamine
  • the compounds of formula (I) may also be prepared following the three-step reaction scheme shown below:
  • Compounds of formula (I) may be prepared by reacting the amine of formula (VIII), preferably in the form of a salt such as the hydrochloride, with a carboxylic acid of formula (XIII), wherein PG is a protecting group (e.g., a Boc group), in the presence of a coupling agent such as EDCI or HOBt or using an acyl chloride in the presence of a base, such as triethylamine, in an organic solvent such as ethyl acetate.
  • a coupling agent such as EDCI or HOBt
  • a base such as triethylamine
  • the protected compound of formula (XIV) may be deprotected using a standard procedure (e.g., HCI/dioxane in an organic solvent) to synthesize an amide of formula (X), followed by conventional alkylation reactions, such as a reductive alkylation with benzaldehydes of general structure (XI) and a suitable reductor agent, such as NaBHsCN or a nucleophilic substitution reaction with the appropriate halide compound of formula (XII) in the presence of a base, such as Na2COa, in an organic solvent as acetonitrile, at 80 °C.
  • a standard procedure e.g., HCI/dioxane in an organic solvent
  • conventional alkylation reactions such as a reductive alkylation with benzaldehydes of general structure (XI) and a suitable reductor agent, such as NaBHsCN or a nucleophilic substitution reaction with the appropriate halide compound of formula (XII) in the presence
  • the amines of formula (VIII) are commercially available or may be obtained using a range of different reactions already disclosed in the literature (see for example WO 2009/049157 A1 ; WO 2007/098352; WO 2010/096722 A1 ; Bioorg Med Chem. 2006, 14, 3307 and J Med Chem. 2017, 60, 7703).
  • ATR attenuated total reflectance
  • NBS N-bromosuccinimide
  • Melting points were determined in open capillary tubes with a MFB 595010 M Gallenkamp melting point apparatus.
  • IR Infrared
  • IR spectra were run on a Perkin-Elmer Spectrum RX I spectrophotometer (using the attenuated total reflectance (ATR) technique). Absorption values are expressed as wavenumbers (cm -1 ); only significant absorption bands are given.
  • Preparative normal phase chromatography was performed on a CombiFlash Rf 150 (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges. Thin-layer chromatography was performed with aluminum-backed sheets with silica gel 60 F254 (Merck, ref 1 .05554 or Sigma-Aldrich, ref 60805), and spots were visualized with UV light, 1 % aqueous solution of KMnCL and/or ninhydrin.
  • HRMS High-resolution mass spectrometry
  • Example 1 Synthesis of 1-benzyl-N-(2-fluoro-4-(pentafluoro-A 6 - sulfanyl)benzyl)piperidine-4-carboxamide.
  • Example 11 Synthesis of 1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4- carboxamide.
  • Example 16 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- iodobenzyl)piperidine-4-carboxamide.
  • Example 17 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2- ylmethyl)piperidine-4-carboxamide.
  • Example 20 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1- phenethylpiperidine-4-carboxamide.
  • Example 41 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2- ylmethyl)piperidine-4-carboxamide.
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 450 mg, 1.39 mmol
  • N-(2,4-dichlorobenzyl)-1-(2- fluorobenzyl)piperidine-4-carboxamide 397 mg, 72% yield
  • IR (ATR) 679, 755, 802, 830, 993, 1099, 1137, 1220, 1292, 1324, 1380, 1422, 1469, 1551 , 1588, 1640, 2789, 2937, 3076, 3256 cm’ 1 .
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide (350 mg, 1.08 mmol) hydrochloride in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCI 2 tube. To that, NaBH 3 CN (95%, 136 mg, 2.16 mmol), acetic acid (0.4 mL) and 4- fluorobenzaldehyde (201 mg, 1.62 mmol) were added. The mixture was stirred at RT for 2 h.
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 450 mg, 1.39 mmol
  • N-(2,4-dichlorobenzyl)-1-(3,4- difluorobenzyl)piperidine-4-carboxamide 329 mg, 57% yield
  • Example 48 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- methylbenzyl)piperidine-4-carboxamide.
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 450 mg, 1.39 mmol
  • N-(2,4-dichlorobenzyl)-1-(4- methylbenzyl)piperidine-4-carboxamide 459 mg, 84% yield
  • IR (ATR) 651 , 804, 865, 993, 1024, 1100, 1136, 1202, 1231 , 1272, 1325, 1363, 1469, 1514, 1552, 1590, 1639, 2754, 2792, 2936, 3070, 3251 cm’ 1 .
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 450 mg, 1.39 mmol
  • N-(2,4-dichlorobenzyl)-1-(4- chlorobenzyl)piperidine-4-carboxamide 315 mg, 55% yield
  • Example 54 Synthesis of N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine- 4-carboxamide.
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 450 mg, 1.39 mmol
  • N-(2,4-dichlorobenzyl)-1-(3,4- dichlorobenzyl)piperidine-4-carboxamide 379 mg, 61% yield
  • IR (ATR) 687, 802, 829, 864, 911 , 928, 994, 1026, 1098, 1137, 1230, 1281 , 1325, 1379,1422, 1444, 1469, 1550, 1590, 1640, 2789, 2938, 3077, 3267 cm’ 1 .
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 450 mg, 1.40 mmol
  • N-(2,4-dichlorobenzyl)-1-(thiophen- 3-ylmethyl)piperidine-4-carboxamide (223 mg, 42% yield) was obtained as a white solid, mp 119-120 °C.
  • Example 57 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4- ylmethyl)piperidine-4-carboxamide.
  • Example 58 Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- (trifluoromethyl)benzyl)piperidine-4-carboxamide.
  • N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride 300 mg, 0.93 mmol
  • N-(2,4-dichlorobenzyl)-1-(4- (trifluoromethyl)benzyl)piperidine-4-carboxamide 234 mg, 57% yield
  • Example 60 Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
  • N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 400 mg, 1.00 mmol
  • N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide 130 mg, 27% yield
  • IR (ATR) 670, 812, 824, 889, 991 , 1054, 1114, 1164, 1278, 1302, 1408, 1432, 1513, 1547, 1645, 2754, 2794, 2937, 3074, 3291cm’ 1 .
  • N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (420 mg, 1.05 mmol) and following the procedure of Example 47, N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (353 mg, 58% yield) was obtained as a white solid, mp 163-164 °C.
  • Example 62 Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
  • N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (380 mg, 0.95 mmol) and following the procedure of Example 19, N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (184 mg, 40% yield) was obtained as a white solid, mp 111-112 °C.
  • Example 63 Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 300 mg, 0.75 mmol
  • N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 273 mg, 79% yield
  • IR (ATR) 670, 825, 909, 990, 1054, 1113, 1163, 1279, 1305, 1344, 1446, 1515, 1544, 1646, 2792, 2939, 3075, 3289 cm’ 1 .
  • Example 64 Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1- phenethylpiperidine-4-carboxamide.
  • N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.79 mmol
  • N-(2-chloro-4-cyanobenzyl)-1- phenethylpiperidine-4-carboxamide was obtained as a white crystalline solid (152 mg, 50% yield), mp: 191-192 °C.
  • Example 66 Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1- phenethylpiperidine-4-carboxamide.
  • N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.67 mmol
  • N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide 26 mg, 9% yield
  • N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.60 mmol
  • N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide was obtained as a beige crystalline solid (58 mg, 20% yield), mp 157-158 °C.
  • N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 200 mg, 0.55 mmol
  • N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide was obtained as a beige crystalline solid (115 mg, 48% yield), mp 161-162 °C.
  • N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.60 mmol
  • N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (93 mg, 13% yield), mp 127-128 °C.
  • Example 70 Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
  • N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.73 mmol
  • N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide 50 mg, 17% yield
  • N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (215 mg, 0.60 mmol) and following the procedure of Example 44, N-(4-chloro-2- (trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (101 mg, 39% yield) was obtained as an off-white crystalline solid, mp 121-122 °C.
  • N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.79 mmol
  • N-(2-chloro-4-cyanobenzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide 63 mg, 21% yield
  • IR (ATR) 688, 767, 785, 827, 871 , 989, 1051 , 1119, 1220, 1265, 1333, 1391 , 1411 , 1482, 1508, 1556, 1641 , 2236, 2751 , 2939, 3067, 3251 cm’ 1 .
  • N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.67 mmol
  • N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide 59 mg, 20% yield
  • N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.60 mmol
  • N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (139 mg, 47% yield), mp 112-113 °C.
  • Example 75 Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
  • N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 200 mg, 0.55 mmol
  • N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (57 mg, 24% yield), mp 121-122 °C.
  • Example 76 Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
  • N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.73 mmol
  • N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide 150 mg, 48%) was obtained as an off-white crystalline solid, mp 112-113 °C.
  • Example 77 Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
  • N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.70 mmol
  • N-(4- chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide 289 mg, 94% yield
  • N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.79 mmol
  • N-(2-chloro-4-cyanobenzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (34 mg, 11 % yield), mp 129-130 °C.
  • Example 79 Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
  • N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.67 mmol
  • N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide 65 mg, 21 % yield
  • Example 80 Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
  • N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.60 mmol
  • N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (104 mg, 35% yield), mp 115-116 °C.
  • Example 81 Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.73 mmol
  • N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 87 mg, 30% yield
  • Example 82 Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.70 mmol
  • N-(4-chloro-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 290 mg, 99% yield
  • Example 83 Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.80 mmol
  • N-(2-chloro-4-cyanobenzyl)-1- (thiophen-3-ylmethyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (106 mg, 35% yield), mp 152-153 °C.
  • Example 84 Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.67 mmol
  • N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 106 mg, 37% yield
  • IR (ATR) 769, 788, 849, 945, 1073, 1122, 1158, 1208, 1250, 1431 , 1483, 1547, 1640, 2462, 2750, 2780, 2933, 3296 cm’ 1 .
  • Example 85 Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.60 mmol
  • N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 177 mg, 62% yield
  • Example 86 Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
  • N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 200 mg, 0.55 mmol
  • N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 137 mg, 59% yield
  • N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 200 mg, 0.55 mmol
  • N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (68 mg, 29% yield), mp 138-139 °C.
  • N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.73 mmol
  • N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide 163 mg, 43% yield
  • N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.68 mmol
  • N-(4-methoxy-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide 97 mg, 32 % yield
  • N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride 250 mg, 0.68 mmol
  • N-(4-methoxy-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide 157 mg, 54% yield
  • binding properties of the test compounds to human S1 R were studied in transfected HEK-293 membranes using [ 3 H]-(+)-pentazocine (PerkinElmer, NET-1056) as the radioligand.
  • the assay was carried out with 7 pg of membrane suspension, [ 3 H]-(+)- pentazocine (5 nM) in either absence or presence of either buffer or 10 pM haloperidol for total and nonspecific binding, respectively.
  • Binding buffer contained Tris-HCI (50 mM, at pH 8). Plates were incubated at 37 °C for 120 min.
  • reaction mix was transferred to MultiScreen HTS, FC plates (Millipore) were presoaked in 0.1 % polyethylenimine and filtered. Then, plates were washed (3 times) with ice-cold Tris-HCI (10 mM, pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (PerkinElmer) using EcoScint liquid scintillation cocktail.
  • the sEH inhibition activity can be determined by the following fluorescent assay with a purified recombinant human sEH protein using cyano(6-methoxynaphthalen-2- yl)methyl 2-(3-phenyloxiran-2-yl)methylcarbonate as the substrate (cf. Morisseau, C.; Hammock, B. D. Measurement of soluble epoxide hydrolase (sEH) activity. Curr Protoc Toxicol. 2007, Chapter 4, Unit 4.23.).
  • Results are obtained by regression analysis from a linear region of the curve.
  • sEH it is considered that the compound has negligible inhibitory effect when the IC50 value is higher than 1000 nM.
  • IC50 values between 100-1000 nM indicate that the compound has a low/very low potency for the inhibitory effect.
  • a significant inhibitory effect is considered when the IC50 is below 100 nM; it is considered especially good when the IC50 value is below 50 nM and excellent when IC50 is below 10 nM.
  • all the compounds of the invention have IC50 values below 100 nM, providing, at least, a significant inhibitory effect of sEH. It is well-established that a compound has a negligible affinity for S1 R when the Ki value is higher than 1000 nM. When the K value is between 400 and 1000 nM means that the compound has a low affinity. A K value between 150-400 nM means that the compound has a significant affinity for S1 R. K values between 50-150 nM mean that the compounds have high affinity for the receptor and a K below 50 nM means that the compound has a very high affinity.
  • the comparative compounds provided at the end of the table are sEHIs with no significant binding to S1 R (EC5026, AR9281 , compound 8-42, compound 6-26, compound 6-29, and the compounds disclosed in W02007098352) and S1 R ligands (S1 RA, BMY-14802, dextromethorphan, NE-100, BD-1063, PRE-084) inactive in sEH.
  • S1 R EC5026, AR9281 , compound 8-42, compound 6-26, compound 6-29, and the compounds disclosed in W02007098352
  • S1 R ligands S1 RA, BMY-14802, dextromethorphan, NE-100, BD-1063, PRE-084
  • Rat livers Male Sprague Dawley rats, Envigo RMS S.r.l. were homogenized in ice- cold phosphate buffer (10 mM, pH 7.4) containing 0.32 M sucrose with a Potter- Elvehjem glass homogenizer. The suspension was centrifuged at 3,000 x g for 10 min at 4 °C. The supernatant was separated and centrifuged at 21 ,100 x g for 60 min at 4 °C. The pellet was resuspended with ice-cold buffer and incubated at RT for 20 min. Then, the suspension was centrifuged at 21 ,100 x g for 30 min at 4 °C. The protein concentration was determined by the method of Bradford.
  • Binding experiments were carried out incubating 200 pL of membrane preparation with 50 pL of 20 nM [ 3 H](+)-pentazocine (26.9 Ci/mmol, PerkinElmer), 50 pL of cold ligand or its solvent, and 20 pL of 25 mM DPH (Merck Life Science S.r.l.) or its solvent (0.3 M NaOH) for 120 min at 37 °C. The final volume was 0.5 mL.
  • the test compound solutions were prepared by dissolving approximately 10 pmol of test compound in DMSO so that a 10 mM stock solution was obtained.
  • the required test concentrations for the assay (from 10" 5 to 10" 1 ° M) have been prepared by diluting the DMSO stock solution with the respective assay buffer. Unlabeled (+)-pentazocine (10 pM) was used to measure nonspecific binding. Bound and free radioligand were separated by fast filtration under reduced pressure using a Millipore filter apparatus through Whatman GF/6 glass fiber filters, which were presoaked in a 0.5% poly(ethyleneimine) water solution for 120 min. Each filter paper was rinsed three times with 3 mL ice-cold Tris buffer (50 mM, pH 8), dried at rt, and incubated overnight with 3 mL scintillation cocktail into pony vials. The bound radioactivity has been determined using a liquid scintillation counter (Beckman LS 6500).
  • the K-values were calculated with the program GraphPad Prism® 7.0 (GraphPad Software, San Diego, CA, USA). The K-values are given as mean value ⁇ SD from at least two independent experiments performed in duplicate.
  • mice Female CD1 mice (Charles River) were used in the experiments. Mice weighing 24-30 g were tested randomly throughout the estrous cycle. They were housed in colony cages with free access to food and water prior to the experiments, and were maintained in temperature- and light-controlled rooms (22 ⁇ 2 °C, lights on at 08:00 h and off at 20:00 h). The experiments were performed during the light phase (from 9:00 h to 16:00 h). Animal care was provided in accordance with institutional (Research Ethics Committee of the University of Granada, Granada, Spain), regional (Junta de Andalucia, Spain) and international standards (European Communities Council directive 2010/63).
  • Example 2 The compound of Example 2 above was used as a prototypic dual S1 R antagonist/ sEHI.
  • the S1 R agonist PRE-084 (2-[4- morpholinethyl]-1 -phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China) was used. This compound is considered to be a selective S1 R agonist (cf. Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66.; Ruiz-Cantero et al., Pharmacol Res. 2021 , 163:105339).
  • PRE-084 was dissolved in sterile physiological saline, and Compound of Example 2 was dissolved in 1 % Tween-80 in physiological saline.
  • MS-PPOH was dissolved in 5% DMSO in 40% (2-hydroxypropyl)-p-cyclodextrin in ultrapure water. All drugs were prepared just before administration, and injected subcutaneously (s.c.) in the interscapular area in an injection volume of 5 mL/kg.
  • Compound of example 2 was administered 45 min before the behavioral evaluation.
  • PRE-084 or MS-PPOH were administered 5 min before the administration of compound of example 2 (50 min before the behavioral evaluation).
  • COMPOUND OF EXAMPLE 2 were tested on capsaicin-induced secondary tactile hypersensitivity, which is developed in the area surrounding capsaicin injection and it is known to result from central sensitization, a feature of pathological pain (Baron R, Lancet, 2000, 356:785-7).
  • the procedure for assessing tactile allodynia was performed as previously described (Entrena et al., Pain, 2009, 143(3):252-261). Briefly, animals were placed into individual test compartments for 2 h to habituate them to the test conditions. The test compartments had black walls and were situated on an elevated mesh-bottomed platform with a 0.5 cm 2 grid to provide access to the ventral surface of the hind paws. Then, animals were carefully removed from the compartment to be s.c. injected with the drugs to be tested (see section above), and returned to the compartment.
  • mice 30 min after drug injection, mice were removed from the compartment again to be injected intraplantarly (i.pl.) with 20 pL of a solution containing 1 pg capsaicin (Sigma-Aldrich Quimica S.A., Madrid, Spain) or its solvent (1% DMSO in physiological saline). Injection was performed into the right hind paw, proximate to the heel, using a 1710 TLL Hamilton microsyringe (Teknokroma, Barcelona, Spain) with a 30 1/2 -gauge needle. Immediately after the i.pl. administration, mice were returned to the compartment.
  • a solution containing 1 pg capsaicin S.A., Madrid, Spain
  • DMSO 1% DMSO in physiological saline
  • Punctate mechanical stimulation was applied with a Dynamic Plantar Aesthesiometer (Ugo Basile, Varese, Italy) at 15 min after the administration of capsaicin or its solvent.
  • a nonflexible filament (0.5 mm diameter) was electronically driven into the ventral side of the right hind paw, at least 5 mm away from the site of the injection towards the fingers.
  • the intensity of the stimulation was fixed at 0.5 g force.
  • the filament was applied three times, separated by intervals of 0.5 min, and the mean value of the three trials was considered the withdrawal latency time of the animal. A cut-off time of 50 s was used.
  • capsaicin administration induced a marked decrease in the paw withdrawal latency in comparison to control nonsensitized mice (dashed lines), denoting the presence of tactile allodynia (compare the point at the 0 mg/kg dose with the dashed lines from nonsensitized control mice value).
  • the administration of COMPOUND OF EXAMPLE 2 (0.625-10 mg/kg, s.c.) dose-dependently increased the paw withdrawal latency in mice up to the value of control nonsensitized mice, indicating that this compound is able to induce marked antiallodynic effects.
  • Test 2 evaluation of postoperative pain in mice
  • mice Female CD1 mice (Charles River) were used in the experiments. Mice weighing 24-30 g were tested randomly throughout the estrous cycle. They were housed in colony cages with free access to food and water prior to the experiments, and were maintained in temperature- and light-controlled rooms (22 ⁇ 2 °C, lights on at 08:00 h and off at 20:00 h). The experiments were performed during the light phase (from 9:00 h to 16:00 h). Animal care was provided in accordance with institutional (Research Ethics Committee of the University of Granada, Granada, Spain), regional (Junta de Andalucia, Spain) and international standards (European Communities Council directive 2010/63).
  • COMPOUND OF EXAMPLE 2 was used as a prototypic dual S1 R antagonist/ sEHI.
  • the S1 R agonist PRE-084 (2-[4- morpholinethyl]-1 -phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China) was used. This compound is considered to be a selective S1 R agonist (Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66.; Ruiz-Cantero et al., Pharmacol Res. 2021 , 163:105339).
  • PRE-084 was dissolved in sterile physiological saline, and COMPOUND OF EXAMPLE 2 was dissolved in 1 % Tween-80 in physiological saline.
  • MS-PPOH was dissolved in 5% DMSO in 40% (2-hydroxypropyl)-p-cyclodextrin in ultrapure water. All drugs were prepared just before administration, and injected subcutaneously (s.c.) in the interscapular area in an injection volume of 5 mL/kg.
  • PRE-084 or MS-PPOH were administered 5 min before the administration of COMPOUND OF EXAMPLE 2. Mice were evaluated before and at several time-points (60, 120 and 180 min) after drug administration.
  • R 5 is CRxR’x, being R x and R’ x the same or different and are independently selected from -H, (C 1 -C 5 )alkyl or (C 1 -C 5 )haloalkyl; or, alternatively, R x and R’ x together with the C atom to which they are attached, form a ring having from 3 to 6 members;
  • R 6 is an aromatic known ring system, which is selected from the group consisting of: an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CR y , and N; R y being selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )alkyl; (C 2- C 10 )alkenyl; (C 2- C 10 )alkynyl; (C 1 -C 10 )alkyl substituted with one or more Sus; (C 2- C 10 )alkenyl substituted with one or more Su?;
  • RvR’v is CRvR’v, being R v and R’ v the same or different and are independently selected from H, (C 1 -C 5 )alkyl, or (C 1 -C 5 )haloalkyl; or, alternatively, R v and R’ v together with the C atom to which they are attached, form a ring having from 3 to 6 members;
  • Rs and R’s are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C 8 )cycloalkyl; aryl; and heteroaryl;
  • R9, R13, R17 and Rtw are selected from the group consisting of: (C 1 -C 10 )alkyl; (C 3- C 8 )cycloalkyl; aryl; and heteroaryl;
  • R10 and R11 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C 8 )cycloalkyl;
  • R12 and R’12 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; and (C 3- C 8 )cycloalkyl;
  • R14 and R15 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C 8 )cycloalkyl; and -S(O)2R2i;
  • R16 and R’16 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; and (C 3- C 8 )cycloalkyl;
  • R 1 s and R19 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 1 -C 10 )haloalkyl; (C 3- C 8 )cycloalkyl; and -S(O)2R22;
  • R’18 and R’19 are the same or different and are selected from the group consisting of: -H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; (C 1 -C 10 )haloalkyl; and -S(O)2R23;
  • Rtw and R’tw are the same or different and are selected from the group consisting of: - H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; (C 1 -C 10 )haloalkyl; and -S(O)2Rti3;
  • R21 to R23 and Rti3 are selected from the group consisting of (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; or (C 1 -C 10 )haloalkyl;
  • R24, R25, and R’n2 are selected from the group consisting of -H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; and (C 1 -C 10 )haloalkyl; m is an integer value selected from 0, 1 or 2; n is an integer value selected from 1 or 2;
  • aryl means an aromatic ring system comprising 6 CR c members, being R c selected from H, halogen, cyano, nitro, (C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, -O-(C 1 -C 5 )alkyl, or -O-(C 1- Cs)haloalkyl;
  • heteroaryl means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, cyano, nitro, (C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, -O-(C 1 -C 5 )alkyl, -O-(C 1 -C 5 )haloalkyl;
  • Sui to Su 8 are independently selected from the group consisting of: halogen, cyano, nitro, (C 1- C 6 )haloalkyl, (C 1- C 6 )alkyl, (C 1- C 6 )hydroxyalkyl, (C 1- C 6 )alkoxy, (C 1- C 6 )alkylsulfinyl, (C 1- C 6 )alkylsulfonyl, (C 1- C 6 )alkylcarbonyl, (C 1- C 6 )alkoxycarbonyl, carbamoyl, N-(C 1- C 4 )alkylcarbamoyl, N,N-di-(C 1- C 4 )alkylcarbamoyl, (C 1- C 6 )alkylcarbonyloxy, (C 3- C 6 )cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto,
  • R y is selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )alkyl; (C2- C 10 )alkenyl; (C 2- C 10 )alkynyl; (C 1 -C 10 )alkyl substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C 1- C 6 )alkyl, (C 1- C 6 )hydroxyalkyl, (C 1- C 6 )alkoxy, (C 1- Ce)alkylsulfinyl, (C 1- C 6 )alkylsulfonyl, (C 1- C 6 )alkylcarbonyl, (C 1- C 6 )alkoxycarbonyl, carbamoyl, N-(C 1- C 4 )alkylcarbamoyl, N,N-di-(C 1- C 4 )alkylcarbamoyl, (C 1- C 6 )alkylcarbonyloxy
  • R’P is selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )haloalkyl; -O- (C 1 -C 10 )alkyl; -0-(C 1 -C 10 )haloalkyl; SF5; S(O)2R’I?; NR’isR’ig; and COOR25;
  • R z is selected from the group consisting of: H; OH; CN; halogen; (C 1 -C 10 )haloalkyl; -O- (C 1 -C 10 )alkyl; -0-(C 1 -C 10 )haloalkyl; SFs; S(O)2RI?; NR18R19; and COOR24;
  • R9, R13, and R17 represent (C 1 -C 10 )alkyl; and (C 3- C8)cycloalkyl;
  • R 1 s and R19 are the same or different and are selected from the group consisting of: H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; and (C 1 -C 10 )haloalkyl;
  • R’18 and R’19 are the same or different and are selected from the group consisting of: H, (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; and (C 1 -C 10 )haloalkyl; and
  • R23 and R24 are selected from the group consisting of H, and (C 1 -C 10 )alkyl; and (C 3- C8)cycloalkyl.
  • R2 is selected from the group consisting of: H, CN; halogen; -0-(C 1 -C 10 )alkyl; -O-(C 1- C 10 )haloalkyl; and (C 1 -C 10 )haloalkyl.
  • R3 is selected from the group consisting of: H; CN; halogen; -0-(C 1 -C 10 )alkyl; -O-(C 1- C 10 )haloalkyl; SFs; S(O)2Rg, wherein R9 is as defined above; particularly R9 is selected from (C 1 -C 10 )alkyl or aryl; particularly R9 is selected from (C 1 -C 10 )alkyl.
  • R 6 is an aromatic 6-membered ring system selected from the group consisting of a system of formula (II) and of formula (III): wherein
  • Ry a to Ry e are the same or different and are selected from the group consisting of: H; OH; CN; halogen; nitro; (C 1 -C 10 )alkyl; (C 2- C 10 )alkenyl; (C 2- C 10 )alkynyl; (C 1 -C 10 )alkyl substituted with one or more Sus; (C 2- C 10 )alkenyl substituted with one or more Sug; (C2- C 10 )alkynyl substituted with one or more SuTM; -0-(C 1 -C 10 )alkyl; -0-(C 1 -C 10 )haloalkyl; - SF5; and -S(O)2R26; particularly Ry a to Ry e are the same or different and are selected from the group consisting of: H, halogen, (C 1 -C 10 )alkyl,-0-(C 1 -C 10 )alkyl, and COOR24;
  • R26 is selected from the group consisting of: (C 1 -C 10 )alkyl; (C 3- C8)cycloalkyl; (C2- C 10 )alkenyl; (C 2- C 10 )alkynyl; aryl; and heteroaryl; and
  • Su 8 to Suw are independently selected from the group consisting of: halogen, cyano, nitro, (C 1- C 6 )haloalkyl, (C 1- C 6 )alkyl, (C 1- C 6 )hydroxyalkyl, (C 1- C 6 )alkoxy, (C 1- Ce)alkylsulfinyl, (C 1- C 6 )alkylsulfonyl, (C 1- C 6 )alkylcarbonyl, (C 1- C 6 )alkoxycarbonyl, carbamoyl, N-(C 1- C 4 )alkylcarbamoyl, N,N-di-(C 1- C 4 )alkylcarbamoyl, (C 1- Ce)alkylcarbonyloxy, (C 3- C 6 )cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenyl
  • R1 is selected from the group consisting of: halogen; -O-(C 1 -C 10 )haloalkyl; and (C 1- C 10 )haloalkyl.
  • R2 is selected from the group consisting of: H; halogen; and (C 1 -C 10 )haloalkyl.
  • R2 represents H.
  • R1 is selected from the group consisting of halogen, CN, -0-(C 1 -C 10 )alkyl, (C 1- C 10 )haloalkyl, and -O-(C 1 -C 10 )haloalkyl;
  • R3 is selected from the group consisting of -CN, halogen, -0-(C 1 -C 10 )alkyl, -O-(C 1- C 10 )haloalkyl, -SF5, and -S(O)2Rg; and R 6 is selected from the group consisting of:
  • each R y is independently selected from the group consisting of: H; halogen; nitro; CN; (C 1 -C 5 )alkyl; (C 1 -C 5 )alkyl substituted with one or more halogens; -O-(C 1 -C 5 )alkyl; -O-(C 1 -C 5 )haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each R y is independently selected from the group consisting of: H; halogen; (C 1 -C 5 )alkyl; -O-(C 1 -C 5 )alkyl; and -COOH;
  • R1 is selected from the group consisting of halogen; -0-(C 1 -C 10 )alkyl; (C 1 -C 10 )alkyl substituted with one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl; and
  • R3 is selected from the group consisting of CN, -0-(C 1 -C 10 )alkyl, -O-(C 1 -C 10 )haloalkyl, and halogen.
  • R 1 is selected from the group consisting of halogen; (C 1 -C 10 )alkyl substituted with one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl;
  • R2 is H
  • R3 is selected from the group consisting of CN, -0-(C 1 -C 10 )alkyl, -O-(C 1 -C 10 )haloalkyl, and halogen.
  • R1 is selected from the group consisting of halogen, (C 1 -C 10 )haloalkyl, and -O-(C 1- C 10 )haloalkyl;
  • R2 represents H
  • R3 is selected from the group consisting of -CN, halogen, -O-(C 1 -C 10 )haloalkyl, and -O- (C 1 -C 10 )alkyl; and R 6 is selected from the group consisting of:
  • each R y is independently selected from the group consisting of: H; halogen; nitro; CN; (C 1 -C 5 )alkyl; (C 1 -C 5 )alkyl substituted with one or more halogens; -O-(C 1 -C 5 )alkyl; -O-(C 1 -C 5 )haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each R y is independently selected from the group consisting of: H; halogen; (C 1 -C 5 )alkyl; -O-(C 1 -C 5 )alkyl; and -COOH;
  • R1 is selected from the group consisting of halogen, (C 1 -C 10 )haloalkyl; and -O-(C 1- C 10 )haloalkyl;
  • R2 is selected from the group consisting of halogen and (C 1 -C 10 )haloalkyl; R3 represents -H; and R 6 is a 6-membered aromatic ring system is a ring of formula (II) as defined in clause 7; particularly R 6 represents phenyl.
  • R1 is selected from the group consisting of halogen; (C 1 -C 10 )alkyl substituted by one or more halogen atoms; and -O-(C 1 -C 10 )haloalkyl;
  • R2 represents H
  • R2 represents H
  • R3 is selected from the group consisting of -CN, halogen, -O-(C 1 -C 10 )haloalkyl, and -O- (C 1 -C 10 )alkyl; and R 6 is a ring of formula (IV) as defined above.
  • Clause 21 The compound for use according to any one of the preceding clauses, wherein the pain is post-operative pain; a pain induced by tissue damage; pain associated to inflammation, cancer pain; articular pain; chronic pain or any other pain condition involving allodynia and/or hyperalgesia.
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof, as defined in any of the clauses 22-23, together with one or more pharmaceutically acceptable salts.
  • Clause 25 A compound as defined in any one of the clauses 23-24 for use in therapy.
  • Clause 26 The compound for use according to any one of the preceding clauses 1-21 or 25, the compound according to any one of the clauses 22-23 or the pharmaceutical composition according to clause 24, wherein the compound is selected from the group consisting of:
  • a process for preparing a compound of formula (I) as defined in any of the preceding clauses which comprises the step of subjecting a compound of formula (X): (X) to a reductive alkylation with a benzaldehyde of formula (XI), in the presence of a reductor agent; or, alternatively, to a nucleophilic substitution with an alkylaryl halide of formula (XII) in the presence of a base, wherein “Hal” represents halogen, and R 1 to R 7 , m and n are as defined in the preceding clauses, and w is 0 or 1.

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Abstract

The present invention provides compounds of formula (I) for use in the treatment or prevention of pain. The present invention further provides compounds of formula (I') or (Ibis), as well as pharmaceutical composition comprising thereof. Advantageously, the compounds of formula (I), (I') and (Ibis) show a dual effect, inhibiting the soluble epoxide hydrolase and binding to S1 receptor, two of the targets well-documented as involved in pain. (I)

Description

DUAL INHIBITORS OF SIGMA-1 RECEPTOR AND SOLUBLE EPOXIDE HYDROLASE AND THEIR USE IN THE TREATMENT OF PAIN
FIELD OF THE INVENTION
The present invention relates to the field of medicine, particularly to the field of analgesia. Concretely, the present invention provides compounds and pharmaceutical compositions, as well as their use in the treatment or prevention of pain.
BACKGROUND OF THE INVENTION
The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions is documented in the large number of scientific works that have appeared recently in the field of applied analgesics.
Pain is defined by the International Association for the Study of Pain (I ASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. (I ASP Pain Terminology, https://www.iasp-pain.org/resources/terminology/).
The IASP recommends using specific features to describe a patient's pain: (a) region of the body involved (e.g., abdomen, lower limbs), (b) system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal), (c) duration and pattern of occurrence, (d) intensity, and (e) cause.
Pain can be broadly divided into three classes: nociceptive, inflammatory, and neuropathic pain. Nociceptive pain corresponds to the sensation associated with the detection of noxious stimuli able to induce tissue damage, whereas inflammatory pain is associated with the milieu of factors released during tissue inflammation, and neuropathic pain triggers in response to the damage of the nervous system by either trauma or chemical insult (e.g., treatments with antineoplastics) (cf. Woolf, J Clin Invest., 2010, 120(11): 3742-3744).
Diseases such as rheumatoid arthritis have a clear predominant inflammatory component which contributes to the pain state. However, in other situations such us during the immediate postoperative period, there might also be an inflammatory component but there is also a powerful nociceptive pain component.
Neuropathic pain is a complex phenomenon with a marked contribution of central mechanisms. The intradermal injection of capsaicin decreases the mechanical pain threshold in the area surrounding the injection even when the area was not stimulated with capsaicin (the so-called area of secondary hypersensitivity). This decrease in the mechanical threshold can be attributed to central sensitization, which is a key feature of neuropathic pain, and in fact, this model is considered a surrogate model of neuropathic pain, since anti-neuropathic drugs show antiallodynic activity in this test in both humans and rodents (cf. Sanchez-Fernandez et al., Adv Exp Med Biol., 2017, 964:109-132).
Inadequate treatment of pain is widespread throughout surgical wards, intensive care units, and accident and emergency departments, in general practice, in the management of all forms of chronic pain including cancer pain, and in end-of-life care. This issue extends to all ages, from newborns to medically frail elderly.
Current analgesics (including opioids, nonsteroidal anti-inflammatory drugs [NSAIDs] and gabapentinoids) show limited efficacy in many pain conditions, or a number of side effects which limit their use. For instance, the analgesic effect of NSAIDs is limited and insufficient for the treatment of severe pain states, and they can induce gastrointestinal events or the impairment of renal function, among several other adverse effects (cf. Yaksh et al., FlOOOPrime Rep., 2015, 7, 56). Opioids can induce a much higher analgesic effect, but also constipation, respiratory depression, tolerance, emesis and physical dependence, among other adverse events (cf. Al-Hasani and Bruchas, Anesthesiology, 2011 , 115:1363-1381). Gabapentinoids are used in neuropathic pain patients, but induce dizziness, somnolence, peripheral edema, ataxia or gait disturbance and diarrhea (cf. Meng et al., Minerva Anestesiol., 2014, 80(5): 556-67).
In an attempt to overcome limitations of the already known analgesics, researchers have focused the attention on other targets.
The sigma-1 receptor (S1 R) is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system (cf. Ruiz-Cantero et al., Pharmacol Res., 2021 , 163:105339). S1 R antagonists modify the chaperoning activity of S1 R by increasing opioid signalling and decreasing N-methyl-D-aspartate receptor (NMDAR) responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions. Furthermore, S1 R antagonists (in the absence of opioids) have been shown to exert antinociceptive effects in preclinical models of neuropathic pain induced by nerve trauma or chemical injury (e.g., the antineoplastic paclitaxel), and more recently in inflammatory pain. Although most studies attributed the analgesic properties of S1 R antagonists to their central actions, it is now known that peripheral S1 R also participate in their effects (cf. Ruiz-Cantero et al., 2021 , supra). On the other hand, epoxyeicosatrienoic acids (EETs) are potent endogenous antiinflammatory and anti-nociceptive mediators, but they are rapidly degraded by the soluble epoxide hydrolase (sEH) to the less active or inactive dihydroxyeicosatrienoic acids. In vitro and in vivo studies have demonstrated that the modulation of chronic inflammation and neuronal pain by EETs is inversely dependent on the extent of their hydrolysis by sEH. Thus, the use of sEH inhibitors (sEHIs) to maintain high in vivo levels of EETs is a promising pharmacological approach to treat pain and inflammation. Consequently, sEHIs are in development for the treatment of neuropathic pain in human patients. In addition to their use in humans, sEHIs may become suitable analgesics for use in veterinary medicine (cf. Hammock et al., J Med Chem., 2021 , 64(4): 1856-1872).
In spite of the efforts made, there is still the need of further therapeutic approaches to the appropriate management of the pain.
SUMMARY OF THE INVENTION
The inventors of the present invention have designed, for the first time, molecules of formula (I) efficiently acting on S1 R as well as on sEH.
As it is shown below, in Table 1 , the compounds of formula (I) significantly inhibited sEH (requiring concentrations below 100 nM) and bound S1 R (requiring concentrations below 400 nM).
As it has been discussed above, S1 R and sEH have been widely reported to be involved in pain as well as recognized targets in the inhibition of pain. Therefore, the data provided in T able 1 below support the suitability of the compounds of formula (I) as candidates in the treatment and prevention of pain.
In order to assess the agonistic or antagonist character of the compounds of this invention on the S1 R, the well stablished phenytoin-based functional assay was carried out (cf. Cobos et al., Synapse, 2005, 55:192-195). Previous studies have shown that phenytoin, a low-potent allosteric modulator for the S1 R, differentially modulates affinities of S1 R ligands depending on their agonist versus antagonist functionality. Phenytoin potentiates the receptor binding affinity of S1 R agonists (ratios of K without phenytoin/with phenytoin >1); however, it produces no effects or slightly reduces receptor binding affinity for S1 R antagonists (ratios of K without phenytoin/with phenytoin <1).
It was found that both, the compound of the invention and BD-1063, a representative S1 R antagonist, exhibited a very small shift to lower receptor binding affinity with ratios of K\ without phenytoin/with phenytoin as 0.8 and 0.7, respectively. However, SKF- 10047, a representative S1 R agonist, showed a ratio of 6.0 in the presence of 1 mM phenytoin. These observations indicated that the compound of the invention acts as an antagonist for the S1 R.
The above was further confirmed in two in vivo models of pain, one of tactile allodynia and another of postoperative pain.
As it is shown below, the administration of the compound of the invention was able to induce a marked antiallodynic effect in capsaicin-induced mechanical hypersensitivity (FIG. 1 and 2) and during postoperative pain (FIG. 3 and 4) were determined. In addition, it was found that this effect was reversed when either PRE-084 (S1 R agonist) or MS- PPOH (a CYP450 epoxygenase inhibitor) were associated (FIG. 2 and 4), confirming that both S1 R antagonism and EET accumulation (due to the inhibition of sEH) participate in the antiallodynic effect of the compounds of the invention.
Altogether, the compounds of formula (I) mean a great advance in the efficient management of pain, simplifying the management of pain with molecules having a broader analgesic effect by acting on two targets.
Thus, in a first aspect the present invention provides compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treatment or prevention of pain, wherein: R1 is selected from the group consisting of: CN, halogen, (C1-C10)haloalkyl, -O-(C2-C10 )alkyl, and -0-(C1-C10)haloalkyl;
R2 to R4 are the same or different and are independently selected from the group consisting of: H; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more substituents Sui; (C2-C10)alkenyl substituted with one or more substituents SU2; (C2-C10)alkynyl substituted with one or more substituents Sus; -O-(C1-C10)alkyl; -O-(C1-C10)alkyl substituted with one or more substituents SU4; -O- (C1-C10)haloalkyl; -O-(C1-C10)haloalkyl substituted with one or more substituents Sus; - SFs, -S(O)2R9; -NR10R11; aryl; and heteroaryl. R5 is CRxR’x, being Rx and R’x the same or different and are independently selected from -H, (C1-C5)alkyl or (C1-C5)haloalkyl; or, alternatively, Rx and R’x together with the C atom to which they are attached, form a ring having from 3 to 6 members; R6 is an aromatic known ring system, which is selected from the group consisting of: an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRy, and N; Ry being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more substituents Sue; (C2-C10)alkenyl substituted with one or more substituents Su?; (C2-C10)alkynyl substituted with one or more substituents Sus; -0-(C1-C10)alkyl; -O-(C1- C10)haloalkyl; SFs; S(O)2R13; NR14R15; CONRsR’s; and COOR24; an aromatic 5-membered ring system, wherein the members are selected from the group consisting of: CRZ, S, N, NH, and O; Rz being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; SFs; S(O)2R17; NR18R19; CONR12R 12; and COOR24; an aromatic fused ring system consisting of two rings, each one of the aromatic rings having 6 members selected from CH or N; and an aromatic fused ring system of formula (XI) wherein Rn to Rt9 are selected from N, NRP, or CR’P; Rp being selected from the group consisting of H, (C1-C10)haloalkyl, S(O)2Rtw, CONRtuR’tn, and C00R’n2; and R’p being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; O-(C1- C10)alkyl; -0-(C1-C10)haloalkyl; SFs; S(O)2R’I?; NR’isR’ig; CONR-isR’is; and COOR25;
R? is CRvR’v, being Rv and R’v the same or different and are independently selected from H, (C1-C5)alkyl, or (C1-C5)haloalkyl; or, alternatively, Rv and R’v together with the C atom to which they are attached, form a ring having from 3 to 6 members;
Rs and R’s are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl; Rg, R13, R17 and Rtw are selected from the group consisting of: (C1-C10)alkyl; (C3- C8)cycloalkyl; aryl; and heteroaryl;
R10 and R11 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl;
R12 and R’12 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; and (C3-C8)cycloalkyl;
R14 and R15 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R2i;
R16 and R’16 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; and (C3-C8)cycloalkyl; R1s and R19 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R22;
R’18 and R’19 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C3-C8)cycloalkyl; (C1-C10)haloalkyl; and -S(O)2R23;
Rtw and R’tw are the same or different and are selected from the group consisting of: - H, (C1-C10)alkyl; (C3-C8)cycloalkyl; (C1-C10)haloalkyl; and -S(O)2Rti3;
R21 to R23 and Rti3 are selected from the group consisting of (C1-C10)alkyl; (C3- C8)cycloalkyl; or (C1-C10)haloalkyl;
R24, R25, and R’n2 are selected from the group consisting of -H, (C1-C10)alkyl; (C3- C8)cycloalkyl; and (C1-C10)haloalkyl; m is an integer value selected from 0, 1 or 2; n is an integer value selected from 1 or 2;
“aryl” means an aromatic ring system comprising 6 CRc members, being Rc selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, or -O-(C1- Cs)haloalkyl;
“heteroaryl” means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl;
Sui to Su8 are independently selected from the group consisting of: halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1- C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3- C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl. provided that at least one of R2 to R4 is other than H.
This aspect can alternatively be defined as the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, solvate or prodrug, in the manufacture of a medicament for the treatment or prevention of pain. This aspect can alternatively be defined as a method for the treatment or prevention of pain, the method comprising the step of administering a therapeutically effective amount of the compound of formula (I) as defined above, a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof.
In a second aspect the present invention provides a compound selected from the group consisting of: a compound of formula (I’): is) or a pharmaceutically salt thereof, solvate or prodrug thereof, wherein
R1, R2, R3, R4, R6, and R7, m and n are as defined in the first aspect of the invention, and R5’ represents CRfR’f, wherein Rf and R’f are the same or different and are selected from the group consisting of: H and (C1-C5)haloalkyl; or, alternatively, Rf and R’f, together with the C atom to which they are attached, form a ring having from 3 to 6 members provided that: at least one of R2 to R4 is other than hydrogen; R6 is other than a ring of formula (i): when R1 and R4 are the same and represent a -O-(C1-C10)alkyl or halogen; R2 and R3 are H; m= n=1 ; R5 is -CH2- and R?= -CH2- or CH(CH3)-; then R6 is other than: an aromatic 6-membered ring system, wherein all 6 members are CRy, as defined above (i.e., phenyl or phenyl substituted), and a furyl; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 or 2; and R5=R7= -CH2-; then R6 is other than phenyl; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 ; and R5=R7= -CH2-; then R6 is other than a ring of formula (ii): wherein Ri= Me or Et; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 ; and R5=R7= -CH2-; then R6 is other than phenyl substituted by a (C1-C10)alkyl or one or more halogens; when R1 and R3 are Cl; m=n= 1 ; R2=R4= H; and R5=R7= -CH2-; then R6 is other than a phenyl ring, a phenyl ring substituted with (C1-C10)alkyl, a meta-O-(C1-C10)alkyl, or one or more halogens, or a naphthalenyl ring; when R1 and R3 are the same or different and represent halogen; R2=R4= H; m=n=1 , and R5=R7= -CH2-; and R6 is one of formula (VI) or (VII) then Rzi to Rzs are H; and when R1 and R3 are the same or different and represent halogen; R2=R4= H; m=n=1 , and R5=R7= -CH2-; and R6 is one of formula (XI) as defined above, then RP is H; when R1 and R3 are F; R2=R4= H; m=1 ; n=2, and R5=R7= -CH2-; then R6 is other than a 1/7-pyrrolo[2,3-b]pyridin-3-yl ring; and when R1 is ethoxy; R2=Rs= H; R4 is methyl; m=0; n=1 ; and R5=R7= -CH2-; then R6 is other than a phenyl ring.
In a third aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof, as defined in the second aspect of the invention, together with one or more pharmaceutically acceptable salts.
In a fourth aspect the present invention provides the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof for use in therapy.
In final aspects, the present invention provides processes for preparing compounds of formula (I), (I’) and (Ibis).
In particular, the present invention provides a process for preparing a compound of formula (I), (I’) or (Ibis) as defined in any of the above aspects, wherein the process comprises the coupling reaction between:
- a compound of formula (VIII), either as a free base or in the form of a pharmaceutically acceptable salt in the presence of an amide coupling reagent and a base, wherein R1 to R7, n and m are as defined in any of the preceding clauses.
The invention provides a further process for preparing a compound of formula (I), (I’) and (Ibis) as defined in any of the preceding aspects, which comprises the step of subjecting a compound of formula (X): to a reductive alkylation with a benzaldehyde of formula (XI), in the presence of a reductor agent; or, alternatively, to a nucleophilic substitution with a compound of formula (XII) in the presence of a base,
(XI) (XII) wherein “Hal” represents halogen, and R1 to R7, m and n are as defined above, and w is 0 or 1. BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 represents a dose-response curve of the effects induced by the dual S1 R antagonist/sEH inhibitor (sEHI) COMPOUND OF EXAMPLE 2 (compound of the invention, Ex. 2) on capsaicin-induced mechanical allodynia. A: Paw withdrawal latency (s). Effects of the s.c. administration of Ex. 2 (0.625-10 mg/kg) or its solvent (“S”, white square, dose 0) on the latency to paw withdrawal in response to the application of a mechanical stimulus after the intraplantar (i. pl.) administration of capsaicin 1 pg in mice. N = 8-11. Statistically significant differences: *p < 0.05 between nonsensitized mice (dashed lines) and the other experimental groups; #p < 0.05 between capsaicin-treated mice injected with Ex. 2 or its solvent (one-way ANOVA followed by Bonferroni test).
FIG. 2 represents the antiallodynic effect of COMPOUND OF EXAMPLE 2 (compound of the invention, Ex. 2) in capsaicin-treated mice through both S1 R antagonism and sEH inhibition. B: % Antiallodynic effect. The data shown represent the effect of the subcutaneous (s.c.) administration of Ex. 2 (2.5 mg/kg), alone or associated with the S1 R agonist PRE-084 (32 mg/kg, s.c.) or the CYP450 epoxygenase inhibitor MS-PPOH (20 mg/kg, s.c.), on paw withdrawal latency in mice treated intraplantarly with capsaicin (1 pg). N = 8-11. Statistically significant differences: *p < 0.05 between capsaicin-treated mice injected with Ex. 2 or its solvent (first bar); #p < 0.05 Ex. 2-treated mice associated or not with PRE-084 or MS-PPOH (one-way ANOVA followed by Bonferroni test).
FIG. 3 represents the time course of the effect on postoperative pain of the association of the dual S1 R antagonist/sEH I COMPOUND OF EXAMPLE 2 (Ex. 2). F: von Frey threshold (g). T: Time after treatment (min). L: 2.5 h after laparotomy. The data shows that the subcutaneous (s.c.) administration of Ex. 2 (10-40 mg/kg) induces a prominent relief of sensory hypersensitivity in laparotomized mice, in particular at 120 min after drug administration. Statistically significant differences: *p < 0.05 between the baseline (BL) recording and the values after laparotomy; #p < 0.05 between the values obtained in mice treated with Ex. 2 or its solvent (“S”, white square) (two-way ANOVA repeated measures followed by Bonferroni test).
FIG. 4 represents the antiallodynic effects induced in mice with postoperative pain by COMPOUND OF EXAMPLE 2 (Ex. 2) through both S1 R antagonism and sEH inhibition. F: von Frey threshold (g). T: Time after treatment (min). L: 2.5 h after laparotomy. The data shown represent the effect of the subcutaneous (s.c.) administration of Ex. 2 (20 mg/kg), alone or associated with the S1 R agonist PRE-084 (32 mg/kg, s.c.) or the CYP450 epoxygenase inhibitor MS-PPOH (20 mg/kg, s.c.), on mice after laparotomy. N = 8-11. Statistically significant differences: *p < 0.05 between the baseline (BL) recording and the values after laparotomy; #p < 0.05 between the values obtained in mice treated with Ex. 2 or its solvent (“S”, white square); fp < 0.05 Ex. 2-treated mice associated or not with PRE-084 or MS-PPOH (one-way ANOVA followed by Bonferroni test).
FIG. 5 represents the displacement by increasing concentrations of BD-1063, SKF- 10047, and COMPOUND OF EXAMPLE 2 (Ex. 2) on [3H]-(+)-pentazocine binding in the presence of 1 mM phenytoin (DPH, continuous lines) or its solvent (dotted lines). The y- axis is the % Specific Binding (A), and the x-axis is the logarithm of the Ligand Concentration (B).
DETAILED DESCRIPTION OF THE INVENTION
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
Throughout the present specification and the accompanying clauses, the words "comprise" and variations such as "comprises", "comprising" are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. The word “comprise” also includes the term “consists of”.
For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range.
In a first aspect the present invention provides the use of compounds of formula (I) in the treatment or prevention of pain.
In the context of the invention, the term "alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. Typical alkyl groups have from 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e.g., methyl, ethyl, n-propyl, /-propyl, n-butyl, f-butyl, n- pentyl, etc. If substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropyl methyl. If substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl or phenethyl. If substituted by heterocyclyl, it corresponds to a "heterocyclylalkyl" radical.
In the context of the invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one 0=0 double bond, and which is attached to the rest of the molecule by a single bond. Typical alkenyl radicals have from 2 to about 10, 2 to about 8 or 2 to about 6 carbon atoms. In a particular embodiment, the alkenyl group is vinyl, 1-methyl-ethenyl, 1 -propenyl, 2- propenyl, or butenyl.
In the context of the invention, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical containing one or more C=C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
In the context of the invention, the term “hydroxyalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogens are replaced by -OH. Illustrative non-limitative examples of hydroxyalkyl are methanol, ethanol, isopropanol, isobutanol or f-butanol, among others.
In the context of the invention, the term “alkoxy” refers to a -O-alkyl, wherein “alkyl” is as defined above. Illustrative non-limitative examples of hydroxyalkyl are methoxy, ethoxy, or f-butoxy, among others.
In the context of the invention, the term “alkylsulfinyl” refers alkyl-SO-, being “alkyl” as defined above.
In the context of the invention, the term “alkylsulfonyl” refers to alkyl-SCh-, being “alkyl” as defined above.
In the context of the invention, the term “alkylcarbonyl” means a straight or branched hydrocarbon chain radical containing no unsaturation, where the alkyl chain is interrupted with a carbonyl (C=O) group (i.e., an alkyl-C(O)-alkylene-group). Representative alkylcarbonyl groups include methylcarbonymethyl, ethylcarbonylmethyl, methylcarbonylethyl, (2-methylpropyl)carbonylmethyl, and the like.
In the context of the invention, the term “alkoxycarbonyl” refers to an “alkoxy”, as defined above, where the alkyl chain is interrupted with a carbonyl (C=O) group.
In the context of the invention, the term “carbamoyl” refers to -C(O)NH2.
In the context of the invention, the term “alkylcarbonyloxy” refers to -C(O)-O-alkyl, being alkyl as defined above.
In the context of the invention, the term “sulfamoyl” refers to -S(O)2NH2.
In the context of the invention, the term "halogen" refers to bromo, chloro, iodo or fluoro. In the context of the invention, the term “haloalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogen atoms are replaced by halogen. Illustrative non-limitative examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like.
In the context of the invention, the expression “form a ring having from 3 to 6 members together with the C atom to which they are attached”, when referring to groups Rx-R’x, Rv-R’v, and Rf-R’f, refers to a known ring, either saturated or partially saturated, having from 3 to 6 members selected from H, (C1-C5)alkyl, or (C1-C5)haloalkyl. In one embodiment, optionally in combination with any of the embodiments provided above or below, the ring is saturated. In another embodiment, optionally in combination with any of the embodiments provided above or below, the ring is a cyclopropyl.
In the context of the invention R6 represents an aromatic ring system as defined in the first aspect of the invention. In one embodiment, optionally in combination with any of the embodiments provided above or below, R6 includes one or more heteroatoms. Illustrative non-limitative examples of R6 aromatic ring systems including one or more heteroatoms include: In the context of the present invention, the term "salt" must be understood as any form of a compound used in accordance with this invention in which said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly, complexes formed via ionic interactions. The definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts".
In the context of the present invention, the term "pharmaceutically acceptable salts" means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly, as a result of the counter-ion) when used in an appropriate manner for a treatment, applied or used, particularly, in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention -normally an acid (deprotonated)- such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used in humans and/or mammals. Salts with alkali and alkali earth metals are preferred particularly, as well as those formed with ammonium cations (NH4 +). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e., salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals. Examples of this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
In the context of the present invention, the term "solvate" should be understood as meaning any form a compound in accordance with the invention in which said compound is bonded by a non-covalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates, like for example, methanolate. A preferred solvate is the hydrate. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (I) that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Preferably, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods.
Any compound of formula (I) referred to herein is intended to represent such specific compound as well as certain variations or forms. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus, any given compound of formula (I) referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same as, or different to, the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
Furthermore, any compound of formula (I) referred to herein may exist as tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another.
In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below:
Ry is selected from the group consisting of: H; OH; CN; halogen; (C1-C10)alkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- Ce)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1- C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl; (C2-C10)alkenyl substituted with one or more halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1- Ce)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1- C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl; (C2-C10)alkynyl substituted with one or more halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1- Ce)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1- C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl; (C1-C10)haloalkyl; -0-(C1-C10)alkyl; -O- (C1-C10)haloalkyl; SF5; S(O)2R13; NR14R15; and COOR24;
R’P is selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -O- (C1-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2R’I?; NR’isR’ig; and COOR25;
Rz is selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -O- (C1-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2RI?; NR18R19; and COOR24;
R9, R13, and R17 represent (C1-C10)alkyl; and (C3-C8)cycloalkyl; R1s and R19 are the same or different and are selected from the group consisting of: H, (C1-C10)alkyl; (C3-C8)cycloalkyl; and (C1-C10)haloalkyl;
R’18 and R’19 are the same or different and are selected from the group consisting of: H, (C1-C10)alkyl; (C3-C8)cycloalkyl; and (C1-C10)haloalkyl; and
R23 and R24 are selected from the group consisting of H, and (C1-C10)alkyl; and (C3- C8)cycloalkyl.
In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compound is one of formula (Ibis): wherein R1 to R3 and R6 and n are as defined in the first aspect of the invention.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is selected from the group consisting of: halogen; -O-(C1-C10)haloalkyl; and (C1-C10)haloalkyl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R2 is selected from the group consisting of: H, CN; halogen; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; and (C1- C10)haloalkyl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R2 is selected from the group consisting of: H; halogen; and (C1-C10)haloalkyl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R3 is selected from the group consisting of: H; CN; halogen; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; SF5; S(O)2Rg, wherein R9 is as defined above; particularly R9 is selected from (C1-C10)alkyl or aryl; particularly R9 is selected from (C1-C10)alkyl.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R3 is selected from the group consisting of: CN; halogen; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; and SF5.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R6 is an aromatic 5- or 6-membered ring system, as defined in the first aspect of the invention.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R6 is an aromatic 6-membered ring system selected from the group consisting of a system of formula (II) and of formula (III): wherein
Rya to Ryeare the same or different and are selected from the group consisting of: H; OH; CN; halogen; nitro; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more Sus; (C2-C10)alkenyl substituted with one or more Sug; (C2- C10)alkynyl substituted with one or more Su™; -0-(C1-C10)alkyl; -0-(C1-C10)haloalkyl; - SF5; and -S(O)2R26; particularly Rya to Ryeare the same or different and are selected from the group consisting of: H, halogen, (C1-C10)alkyl,-0-(C1-C10)alkyl, and COOR24;
R26 is selected from the group consisting of: (C1-C10)alkyl; (C3-C8)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl; and heteroaryl; and
Su8 to Suw are independently selected from the group consisting of: halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- Ce)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1- Ce)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl.
Alternatively, in another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R6 is an aromantic 5-membered ring system of formula (IV):
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, wherein R2 represents -H.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, wherein R3 represents -H. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below: R1 is selected from the group consisting of halogen, CN, -0-(C1-C10)alkyl, (C1- C10)haloalkyl, and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -0-(C1-C10)alkyl, -O-(C1- C10)haloalkyl, -SF5, and -S(O)2Rg; and R6 is selected from the group consisting of:
(a) an aromatic 6-membered ring system, wherein the members are CRy, and each Ry is independently selected from the group consisting of: H; halogen; nitro; CN; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1-C5)alkyl; -O-(C1-C5)haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1-C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
(b) an aromatic 6-membered ring system, wherein one of the members is N and the remaining members are CRy, Ry being as defined in preceding clauses; particularly, it corresponds to the system of formula (III) as defined above; and
(c) an aromatic 5-membered ring system wherein the members are selected from CRZ, N, and S, provided that at least one of the members is S; particularly, it corresponds to the system of formula (IV) as defined above.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below:
R1 is selected from the group consisting of halogen; -0-(C1-C10)alkyl; (C1-C10)alkyl substituted with one or more halogen atoms; and -O-(C1-C10)haloalkyl; and
R3 is selected from the group consisting of CN, -0-(C1-C10)alkyl, -O-(C1-C10)haloalkyl, and halogen.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below:
R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted with one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 is H; and Rs is selected from the group consisting of CN, -0-(C1-C10)alkyl, -O-(C1-C10)haloalkyl, and halogen.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below: R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted by one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -O-(C1-C10)haloalkyl, and -O- (C1-C10)alkyl; and R6 is selected from the group consisting of:
(a) an aromatic 6-membered ring system, wherein the members are CRy, and each Ry is independently selected from the group consisting of: H; halogen; nitro; CN; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1-C5)alkyl; -O-(C1-C5)haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1-C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
(b) an aromatic 6-membered ring system, wherein one of the members is N and the remaining members are CRy, Ry being as defined in preceding clauses; particularly, it corresponds to the system of formula (III) as defined above; and
(c) an aromatic 5-membered ring system wherein the members are selected from CRZ, N, and S, provided that at least one of the members is S; particularly, it corresponds to the system of formula (IV) as defined above.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below:
R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted by one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -O-(C1-C10)haloalkyl, and -O- (C1-C10)alkyl; and R6 is a 6-membered aromatic ring system is a ring of formula (II) as defined above, wherein Ry is selected from the group consisting of: H; halogen; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1-C5)alkyl; -O-(C1-C5)haloalkyl; and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1-C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below:
R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted by one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -O-(C1-C10)haloalkyl, and -O- (C1-C10)alkyl; and R6 is a ring of formula (IV) as defined above.
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below:
R1 is selected from the group consisting of halogen, (C1-C10)haloalkyl; and -O-(C1- C10)haloalkyl;
R2 is selected from the group consisting of halogen and (C1-C10)haloalkyl;
R3 represents -H; and R6 is a 6-membered aromatic ring system is a ring of formula (II) as defined above, particularly R6 represents phenyl.
Throughout the present description, the term "treatment" includes, but is not limited to, alleviating, diminishing or eliminating one or more symptoms of the disorder (i.e. , pain), reducing the degree of the pain, stabilizing (i.e., not worsening) the condition, delaying or slowing the progression of the pain, alleviating or improving its condition, and remitting (whether total or partial).
As used in the present invention, the term "prevention" refers to preventing the onset of the pain from occurring in a patient who is predisposed, but who does not yet have symptoms of the disease, or when the intervention is done before pain-inducing procedure.
As used herein, the term “pain” shall refer to all types of pain. Illustrative non-limitative examples are acute and chronic pains, such as surgical pain, articular pain, neuropathic pain and post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, migraine, angina pain, and genitourinary tract-related pain including cystitis, the term shall also refer to nociceptive pain or nociception.
These embodiments can also be used within the context of the treatment of dysmenorrhea, tendinitis, and bursitis. They can also be used in the treatment of pain symptoms of myalgia, dental pain, and migraine, in the treatment of pain of cancerous origin, and also as additional treatments for infectious and febrile states.
Finally, these embodiments can find use in the treatment of neuropathic pain, and in particular of nervous pain, herpes zoster, desafferentation (phantom member) pain, diabetic neuropathies, and chemotherapy-induced neuropathic pain.
In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the pain is post-operative pain; a pain induced by tissue damage; pain associated to inflammation, cancer pain; articular pain; chronic pain or any other pain condition involving allodynia and/or hyperalgesia.
As used herein, the term “animal” shall refer to a vertebrate animal. Such animals include both domestic animals; for example, livestock, laboratory animals and household pets, and non-domestic animals such as wildlife. In one embodiment, the animal is a vertebrate. In a particular embodiment the animal is a domestic mammal or a human. For such purposes, a compound of this invention may be administered as a feed additive.
In a further embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compounds of formula (I) are administered in combination with a further analgesic compound. In a further embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compounds of formula (I) are administered sequentially, separately or simultaneously with a further analgesic compound.
In a second aspect the present invention provides a compound of formula (I’).
All the embodiments provided under the first aspect of the invention, regarding R1 to R?, m, and n, are also embodiments of the compound (I’) of the second aspect of the invention, applying the provisos pointed out under the second aspect of the invention.
Alternatively, the second aspect of the invention also provides a compound of formula (Ibis) as defined above. All the embodiments provided for the compound of formula (Ibis) in the context of the first aspect are also embodiments of the compound in the context of the second aspect of the invention, applying the corresponding provisos pointed out above.
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the invention (Ibis) or (I’) or a pharmaceutical salt thereof, as defined above.
By “therapeutically effective amount”, it is understood the amount of the compound(s) that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
The precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the invention, may depend on several variables. Some of these would be: route of administration, time of drug release (e.g., instant or extended), administration schedule, pain severity, condition of the patient, and the like.
The pharmaceutical compositions can be prepared as a liquid, semi-solid or solid dosage form, for example in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pills or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, or administered as such.
These compositions can be prepared with the aid of conventional means, devices, methods or processes known in the art.
Pharmaceutically acceptable adjuvants, vehicles or excipients which may be used in such compositions are adjuvants, vehicles or excipients known to those skilled in the art or commonly used in the preparation of therapeutic compositions, which may be selected, for example, from the group consisting of excipients, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, flavoring agents or binders.
The term "pharmaceutically acceptable" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio in animals and, particularly, in humans. The selection of physiologically compatible adjuvants or the number of adjuvants to be used depends on the form of administration of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, otic or intratympanic. Preparations in the form of tablets, dragees, capsules, granules, pills, drops, in particular otic drops, juices or syrups are preferably suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations or also sprays are preferably suitable for parenteral, topical or inhalation administration. The compounds in accordance with the invention used in the pharmaceutical composition in accordance with the invention in a depot, in a dissolved form or in a dressing, or if appropriate having added other agents favoring penetration into the skin, are preparations suitable for percutaneous administration. The preparation forms administrable orally or percutaneously can also release the respective compound according to the invention in a delayed form.
For instance, for oral administration in the form of a tablet or capsule, the active drug components can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.
The dosage administered of the pharmaceutical composition will, of course, vary depending on the use and known factors such as the age, health, and weight of the recipient; nature and extent of symptoms, concurrent treatments, if any, frequency of treatment, and the effect desired. The recipient may be any type of mammal, but is preferably a human.
According to another aspect of the present invention, the compounds of formula (I) may be prepared by reacting the amine of formula (VIII), either as free base or in the form of a salt such as the hydrochloride, with the carboxylic acid of formula (IX) (such as 1- benzylpiperidine-4-carboxylic acid and N-boc-piperidine-4-carboxylic acid) in the presence of a coupling agent such as EDCI or HOBt or using an acyl chloride in the presence of a base, such as triethylamine, in an organic solvent such as ethyl acetate.
According to another aspect of the present invention, the compounds of formula (I), may also be prepared following the three-step reaction scheme shown below:
T1
Scheme 1 : compound (I)
Compounds of formula (I) may be prepared by reacting the amine of formula (VIII), preferably in the form of a salt such as the hydrochloride, with a carboxylic acid of formula (XIII), wherein PG is a protecting group (e.g., a Boc group), in the presence of a coupling agent such as EDCI or HOBt or using an acyl chloride in the presence of a base, such as triethylamine, in an organic solvent such as ethyl acetate. The protected compound of formula (XIV) may be deprotected using a standard procedure (e.g., HCI/dioxane in an organic solvent) to synthesize an amide of formula (X), followed by conventional alkylation reactions, such as a reductive alkylation with benzaldehydes of general structure (XI) and a suitable reductor agent, such as NaBHsCN or a nucleophilic substitution reaction with the appropriate halide compound of formula (XII) in the presence of a base, such as Na2COa, in an organic solvent as acetonitrile, at 80 °C.
The amines of formula (VIII) are commercially available or may be obtained using a range of different reactions already disclosed in the literature (see for example WO 2009/049157 A1 ; WO 2007/098352; WO 2010/096722 A1 ; Bioorg Med Chem. 2006, 14, 3307 and J Med Chem. 2017, 60, 7703).
To those skilled in the art, other objects, advantages or features of the invention will be apparent in part from the description or in part from the practice of the invention. The following examples are provided by way of illustration or are not intended to be limiting of the present invention.
EXAMPLES
ABBREVIATIONS
The following abbreviations have been used along the present application: anh.: anhydrous
ATR: attenuated total reflectance
Calcd: calculated
DCM: dichloromethane
DMF: N,N-dimethylformamide
DMSO: dimethylsulfoxide
EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
ESI: electrospray ionization
Et2O: diethylether
EtsN: triethylamine
EtOAc: ethyl acetate
HOBt: hydroxybenzotriazole h: hours
HRMS: high resolution mass spectroscopy
IR: infrared
MeOH: methanol min: minutes mp: melting point
NBS: N-bromosuccinimide
RT: room temperature
THF: tetrahydrofuran ANALYTICAL METHODS
Melting points were determined in open capillary tubes with a MFB 595010 M Gallenkamp melting point apparatus.
Infrared (IR) spectra were run on a Perkin-Elmer Spectrum RX I spectrophotometer (using the attenuated total reflectance (ATR) technique). Absorption values are expressed as wavenumbers (cm-1); only significant absorption bands are given.
Elemental analyses were carried out at the Microanalysis Service of the IIQAB (CSIC, Barcelona, Spain) with a Carlo Erba model 1106 analyzer.
Preparative normal phase chromatography was performed on a CombiFlash Rf 150 (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges. Thin-layer chromatography was performed with aluminum-backed sheets with silica gel 60 F254 (Merck, ref 1 .05554 or Sigma-Aldrich, ref 60805), and spots were visualized with UV light, 1 % aqueous solution of KMnCL and/or ninhydrin.
High-resolution mass spectrometry (HRMS) analyses were performed with an LC/MSD TOF Agilent Technologies spectrometer.
- Analytical grade solvents were used for crystallization, while pure for synthesis solvents were used in the reactions, extractions and column chromatography.
Example 1 : Synthesis of 1-benzyl-N-(2-fluoro-4-(pentafluoro-A6- sulfanyl)benzyl)piperidine-4-carboxamide.
To a solution of 2-fluoro-4-pentafluorosulfanylbenzylamine (249 mg, 0.99 mmol) in EtOAc (15 mL), 1-benzylpiperidine-4-carboxylic acid (198 mg, 0.90 mmol), HOBt (182 mg, 1.35 mmol), EDCI HCI (259 mg, 1.35 mmol) and Et3N (0.25 mL, 1.80 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SC>4, filtered and evaporated to give 1-benzyl-N-(2-fluoro-4-(pentafluoro-A6-sulfanyl)benzyl)piperidine-4- carboxamide (365 mg, 90% yield) as a white solid. The analytical sample was obtained by crystallization from hot EtOAc, mp 123-124 °C. IR (ATR): 733, 804, 844, 922, 994, 1022, 1128, 1228, 1369, 1419, 1495, 1541 , 1641 , 2759, 2945, 3064, 3229 cm’1. HRMS- ESI+ m/z [M+H]+ calcd for [C2oH22F6N2OS+H]+: 453.1430, found: 453.1427. Anal. Calcd for C20H22F6N2OS: C 53.09, H 4.90, N 6.19, S 7.09. Found: C 52.94, H 5.06, N 6.20, S 6.96. Example 2: Synthesis of 1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl) piperidine-4-carboxamide.
To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (264 mg, 1.32 mmol, synthesized as in W02009049157A1) in EtOAc (15 mL), 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCI (345 mg, 1.80 mmol) and Et3N (0.34 mL, 2.40 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (10 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give a yellowish solid (490 mg). Crystallization from hot EtOAc afforded 1-benzyl-N-(4-cyano-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide (420 mg, 87% yield) as a white solid, mp 113-114 °C. IR (ATR): 725, 791 , 841 , 881 , 929, 994, 1056, 1106, 1142, 1172, 1206, 1231 , 1267, 1319, 1369, 1425, 1540, 1650, 2237, 2762, 2803, 2937, 3065, 3086, 3291 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H22F3N3O+H]+: 402.1788, found: 402.1794. Anal. Calcd for C22H22F3N3O: C 65.82, H 5.52, N 10.47. Found: C 65.57, H 5.63, N 10.30.
Example 3: Synthesis of 1-benzyl-N-(4-methoxy-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
To a solution of 4-methoxy-2-(trifluoromethyl)benzylamine (271 mg, 1.32 mmol) in EtOAc (15 mL), 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCI (345 mg, 1.80 mmol) and Et3N (0.34 mL, 2.40 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give 1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (420 mg, 86% yield) as a white solid. The analytical sample was obtained by crystallization from hot EtOAc, mp 101-102 °C. IR (ATR): 699, 731 , 748, 865, 989, 1036, 1107, 1159, 1245, 1289, 1316, 1336, 1432, 1449, 1538, 1640, 2760, 2770, 2799, 2819, 2935, 3278 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F3N2O2+H]+: 407.1941 , found: 407.1941. Anal. Calcd for C22H25F3N2O2: C 65.01 , H 6.20, N 6.89. Found: C 65.24, H 6.35, N 6.78. Example 4: Synthesis of 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4- carboxamide.
To a solution of 2,4-dichlorobenzylamine (232 mg, 1.32 mmol) in EtOAc (15 mL), 1- benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCI (345 mg, 1 .80 mmol) and Et3N (0.34 mL, 2.40 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give a white solid (452 mg). Crystallization from EtOAc afforded 1-benzyl-N-(2,4- dichlorobenzyl)piperidine-4-carboxamide (320 mg, 71% yield) as a white solid. The analytical sample was obtained by washing with Et20 and pentane, mp 122-123 °C. IR (ATR): 685, 697, 735, 810, 832, 865, 994, 1045, 1121 , 1231 , 1257, 1295, 1423, 1445, 1471 , 2755, 2806, 2915, 2942, 3289 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH22Cl2N20+H]+: 377.1182, found: 377.184. Anal. Calcd for C20H22CI2N2O: C 63.67, H 5.88, N 7.42. Found: C 63.51 , H 5.81 , N 7.28.
Example 5: Synthesis of 1-benzyl-N-(4-bromo-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
To a solution of 4-bromo-2-trifluoromethoxybenzylamine (146 mg, 0.54 mmol, synthesized as in W02007098352A2) in EtOAc (10 mL), 1-benzylpiperidine-4-carboxylic acid (129 mg, 0.59 mmol), HOBt (109 mg, 0.81 mmol), EDCI HCI (155 mg, 0.81 mmol) and Et3N (0.15 mL, 1.08 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (10 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 solution (3 x 5 mL) and brine (2 x 5 mL), dried over anh. Na2SO4, filtered and evaporated to give 1-benzyl-N-(4-bromo-2- (trifluoromethoxy)benzyl)piperidine-4-carboxamide (238 mg, 93% yield) as a beige solid. The analytical sample was obtained by crystallization from hot EtOAc, mp 112-113 °C. IR (ATR): 732, 792, 821 , 845, 879, 939, 994, 1023, 1069, 1130, 1167, 1206, 1251 , 1340, 1368, 1398, 1432, 1484, 1551 , 1601 , 1643, 2756, 2802, 2935, 2947, 3085, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH22BrF3N2O2+H]+: 471.089, found: 471.0893. Anal. Calcd for C2iH22BrF3N2O2: C 53.52, H 4.71 , N 5.94. Found: C 53.61 , H 4.75, N 5.84.
Example 6: Synthesis of 1-benzyl-N-(2-chloro-4-
(methylsulfonyl)benzyl)piperidine-4-carboxamide.
To a solution of 2-chloro-4-(methylsulfonyl)benzylamine hydrochloride (338 mg, 1.32 mmol, synthesized as in W02009098352A2) in EtOAc (15 mL), 1-benzylpiperidine-4- carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCI (345 mg, 1.80 mmol) and Et3N (0.84 mL, 6.0 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give 1-benzyl-N- (2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide (450 mg, 89% yield) as a white solid. The analytical sample was obtained by crystallization from hot EtOAc, mp 165-166 °C. IR (ATR): 737, 764, 789, 833, 891 , 976, 986, 1055, 1100, 1125, 1147, 1158, 1215, 1267, 1298, 1316, 1370, 1392, 1452, 1550, 1640, 2769, 2812, 2941 , 3065, 3283 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH25CIN2O3S+H]+: 421.1347; Found: 421.1347. Anal. Calcd for C21H25CIN2O3S: C 59.92, H 5.99, N 6.65, S 7.62. Found: C 60.12, H 6.01 , N 6.45, S 7.55.
Example 7: Synthesis of 1-benzyl-N-(2-methoxy-4-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
To a solution of 2-methoxy-4-(trifluoromethoxy)benzylamine (292 mg, 1.32 mmol) in EtOAc (15 mL), 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCI (345 mg, 1.8 mmol) and Et3N (0.34 mL, 2.40 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give a yellowish solid (509 mg). Crystallization from hot EtOAc afforded 1- benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (364 mg, 72% yield) as a white solid, mp 101-102 °C. IR (ATR): 775, 791 , 845, 877, 914, 975, 995, 1033, 1071 , 1124, 1159, 1222, 1253, 1273, 1367, 1430, 1448, 1503, 1549, 1609, 1641 , 2766, 2801 , 2919, 2945, 3310 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F3N2O3+H]+: 423.1890, found: 423.1893. Anal. Calcd for C22H25F3N2O3: C 62.55, H 5.97, N 6.63. Found: C 62.41 , H 5.89, N 6.45.
Example 8: Synthesis of 1-benzyl-N-(4-cyano-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
To a solution of the hydrochloride salt of 4-(aminomethyl)-3- (trifluoromethoxy)benzonitrile (104 mg, 0.41 mmol, synthesized as in W02010096722A1) in EtOAc (7 mL), 1-benzylpiperidine-4-carboxylic acid (81 mg, 0.37 mmol), HOBt (76 mg, 0.56 mmol), EDCI HCI (107 mg, 0.56 mmol) and Et3N (0.26 mL, 1.85 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (7 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (3 x 5 mL) and brine (3 x 3 mL), dried over anh. Na2SC>4, filtered and evaporated to give an orange oil that crystallized into a solid (167 mg). Column chromatography (SiC>2, DCM/MeOH mixtures) afforded 1 -benzyl-N-(4- cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (121 mg, 79% yield) as a beige solid, mp 117-118 °C. IR (ATR): 649, 697, 731 , 792, 832, 875, 921 , 972, 993, 1025, 1068, 1100, 1126, 1144, 1167, 1219, 1248, 1365, 1426, 1542, 1646, 2237, 2760, 2797, 2807, 2918, 2948, 3072, 3283 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H22F3N3O2+H]+: 418.1737, found: 418.1738. Anal. Calcd for C22H22F3N3O2: C 63.30, H 5.31 , N 10.07. Found: C 63.35, H 5.35, N 9.80.
Example 9: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3- fluorobenzyl)piperidine-4-carboxamide.
Synthesis of tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1- carboxylate
To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (264 mg, 1.32 mmol) in EtOAc (15 mL), N-boc-piperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCI (345 mg, 1.80 mmol) and EtsN (0.34 mL, 2.40 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give a beige solid (550 mg). Column chromatography (SiC>2, DCM/MeOH mixtures) gave tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1- carboxylate (430 mg, 87% yield) as an off-white foamy solid, mp 163 °C. IR (ATR): 639, 675, 771 , 818, 839, 880, 931 , 1017, 1055, 1104, 1143, 1168, 1225, 1277, 1319, 1365, 1416, 1557, 1651 , 1694, 2845, 2974, 3077, 3273 cm’1. HRMS-ESI’ m/z [M-H]’ calcd for [C20H24F3N3O3-H]-: 410.1697, found: 410.1708. Anal, calcd for C20H24F3N3O3: C 58.39, H 5.88, N 10.21. Found: C 58.47, H 5.88, N 10.00.
Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride
To a solution of tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1- carboxylate (430 mg, 1.05 mmol) in DCM (2.5 mL), 4N HCI in dioxane (2.5 mL) was added. The reaction mixture was stirred at RT for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (384 mg, quantitative yield) as a white solid. HRMS-ESI+ m/z [M+H]+ calcd for [Ci5Hi6F3N3O+H]+: 312.1318; Found: 312.1320. Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)- 1 -(3-fluorobenzyl)piperidine-4- carboxamide
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (200 mg, 0.58 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBHsCN (95%, 77 mg, 1.16 mmol), acetic acid (0.3 mL) and 3-fluorobenzaldehyde (108 mg, 0.87 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 40 mg, 0.61 mmol) and 3- fluorobenzaldehyde (60 mg, 0.48 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 1 N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give a yellowish oil (309 mg). Column chromatography (SiC>2, DCM/MeOH mixtures) afforded N-(4- cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide (82 mg, 34% yield) as a white solid, mp 115-116 °C. IR (ATR): 638, 685, 745, 774, 793, 839, 879, 924, 995, 1025, 1056, 1108, 1142, 1171 , 1263, 1317, 1426, 1447, 1485, 1543, 1587, 1615, 1649, 2236, 2762, 2805, 2942, 3081 , 3282 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2IF4N3O+H]+: 420.1694, found: 420.1698. Anal. Calcd for C22H21F4N3O: C 63.00, H 5.05, N 10.02. Found: C 62.78, H 5.07, N 10.00.
Example 10: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3- methylbenzyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBHsCN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL) and 3-methylbenzaldehyde (130 mg, 1.08 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 50 mg, 0.76 mmol) and 3- methylbenzaldehyde (72 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 2N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an orange oil (392 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N-(4- cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide (134 mg, 45% yield) as a beige solid, mp 110-111 °C. IR (ATR): 639, 671 , 692, 765, 793, 840, 881 , 927, 1056, 1105, 1142, 1171 , 1266, 1296, 1318, 1368, 1425, 1496, 1539, 1649, 2237, 2756, 2798, 2933, 3064, 3287 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H24F3N3O+H]+: 416.1944, found: 416.1943. Anal. Calcd for C23H24F3N3O: C 66.49, H 5.82, N 10.11. Found: C 62.27, H 5.85, N 10.10.
Example 11 : Synthesis of 1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4- carboxamide.
To a solution of 2,4-dichloro-5-fluorobenzylamine (321 mg, 1 .65 mmol) in EtOAc (20 mL), 1-benzylpiperidine-4-carboxylic acid (329 mg, 1.50 mmol), HOBt (306 mg, 2.26 mmol), EDCI HCI (433 mg, 2.26 mmol) and Et3N (0.4 mL, 2.71 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (15 mL), dried over anh. Na2SO4, filtered and evaporated to afford 1-benzyl-N-(2,4-dichloro- 5-fluorobenzyl)piperidine-4-carboxamide (403 mg, 68% yield) as a white solid. The analytical sample was obtained by crystallization from hot EtOAc, mp 114-115 °C. IR (ATR): 732, 876, 992, 1027, 1088, 1139, 1230, 1270, 1384, 1421 , 1474, 1549, 1641 , 1744, 2799, 2946, 3253, 3668 cm-1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2iCl2FN20+H]+: 395.10, found: 395.4083 Anal. Calcd for C20H21CI2FN2O O.25H2O: C 60.08, H 5.42, N 7.01. Found: C 60.02, H 5.56, N 6.72.
Example 12: Synthesis of 1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4- carboxamide.
To a solution of (2,3,5-trichlorophenyl)methanamine (589 mg, 2.80 mmol) in EtOAc (15 mL), 1-benzylpiperidine-4-carboxylic acid (557 mg, 2.54 mmol), HOBt (515 mg, 3.81 mmol), EDCI HCI (730 mg, 3.81 mmol) and Et3N (0.5 mL, 4.57 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (15 mL), dried over anh. Na2SO4, filtered and evaporated to provide a yellow oil. Column chromatography (4 g, SiO2, DCM/MeOH mixtures) afforded 1-benzyl- N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide (364 mg, 35% yield) as a white solid, mp 127-128 °C. IR (ATR): 737, 813, 994, 1048, 1108, 1230, 1384,1414, 1534, 1640, 1656, 2823, 2893, 3068, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2iCl3N20+H]+: 411.07, found: 411.0711. Anal. C20H21CI3N2O: C 58.34, H 5.14, N 6.80. Found: C 57.97, H 5.09, N 6.61.
Example 13: Synthesis of N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4- carboxamide.
Synthesis of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride To a solution of tert-butyl 4-((2,4-dichlorobenzyl)carbamoyl)piperidine-1 -carboxylate (750 mg, 1.94 mmol, synthesized as in W02009097476) in DCM (5 mL), 4N HCI in dioxane (5 mL) was added. The reaction mixture was stirred at RT for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give the hydrochloride salt of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide (640 mg, quantitative yield) as an off-white solid. The product was used in the next reaction without further purification. HRMS-ESI+ m/z [M+H]+ calcd for [C13H16CI2N2O+H]+: 287.0712, found: 287.0715.
Synthesis of N-(2, 4-dichlorobenzyl)- 1-(3-fluorobenzyl)piperidine-4-carboxamide
A solution of the hydrochloride salt of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide (350 mg, 1.08 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBHsCN (95%, 143 mg, 2.16 mmol), acetic acid (0.4 mL) and 3-fluorobenzaldehyde (201 mg, 1.62 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 75 mg, 1.14 mmol) and 3-fluorobenzaldehyde (112 mg, 0.90 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 2N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give an orange oil (636 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N-(2,4-dichlorobenzyl)-1-(3- fluorobenzyl)piperidine-4-carboxamide (175 mg, 41% yield) as a colorless gumish solid. The analytical sample (119 mg) was obtained by a second column chromatography purification (SiO2, DCM/MeOH mixtures), mp 116-117 °C. IR (ATR): 669, 685, 722, 780, 795, 867, 925, 996, 1045, 1104, 1120, 1146, 1231 , 1255, 1300, 1322, 1338, 1421 , 1444, 1472, 1487, 1555, 1567, 1594, 1650, 2756, 2799, 2919, 2925, 2944, 3092, 3289 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C20H2ICI2FN2O+H]+: 395.1088, found: 395.1086. Anal. Calcd for C20H2ICI2FN2O: C 60.77, H 5.35, N 7.09. Found: C 60.75, H 5.34, N 7.04.
Example 14: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3- chlorobenzyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBHsCN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL) and 3-chlorobenzaldehyde (152 mg, 1.08 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 50 mg, 0.76 mmol) and 3- chlorobenzaldehyde (84 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 2N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give a yellow oil (461 mg). Column chromatography (SiC>2, DCM/MeOH mixtures) afforded N-(4- cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide (128 mg, 41 % yield) as an off-white solid. The analytical sample (81 mg) was obtained by a second column chromatography purification (SiO2, DCM/MeOH mixtures), mp 143-145 °C. IR (ATR): 637, 674, 682, 694, 780, 794, 829, 850, 932, 998, 1055, 1091 , 1114, 1141 1170, 1264, 1304, 1323, 1367, 1424, 1475, 1547, 1646, 2234, 2762, 2805, 2935, 3075, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2ICIF3N3O+H]+: 436.1398, found: 436.1393. Anal. Calcd for C22H21CIF3N3O: C 60.62, H 4.86, N 9.64. Found: C 60.47, H 4.69, N 9.40.
Example 15: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL) and 4-fluorobenzaldehyde (134 mg, 1.08 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 50 mg, 0.76 mmol) and 4- fluorobenzaldehyde (75 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 2N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an orange oil (475 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N-(4- cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (108 mg, 36% yield) as an off-white crystalline solid, mp 169-170 °C. IR (ATR): 589, 638, 667, 681 , 768, 824, 836, 859, 925, 989, 1056, 1091 , 1121 , 1146, 1164, 1220, 1225, 1294, 1320, 1423, 1507, 1554, 1645, 2239, 2916, 2945, 3079, 3311 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2IF4N3O+H]+: 420.1694; Found: 420.1686. Anal. Calcd for C22H21F4N3O O.35CH3OH: C 62.34, H 5.24, N 9.76. Found: C 62.13, H 4.99, N 9.67.
Example 16: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- iodobenzyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (300 mg, 0.86 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 114 mg, 1.72 mmol), acetic acid (0.4 mL) and 4-iodobenzaldehyde (299 mg, 1.29 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 60 mg, 0.91 mmol) and 4- iodobenzaldehyde (167 mg, 0.72 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 1 N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an orange oil (746 mg). Column chromatography (SiC>2, DCM/MeOH mixtures) afforded N-(4- cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (180 mg, 40% yield) as an off-white crystalline solid, mp 144-146 °C. IR (ATR): 638, 670, 786, 800, 928, 990, 1006, 1057, 1117, 1138, 1174, 1267, 1298, 1319, 1386, 1421 , 1446, 1481 , 1541 , 1649, 2236, 2755, 2787, 2938, 3282 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2IF3IN3O+H]+: 528.0754, found: 528.0750. Anal. Calcd for C22H21F3IN3O: C 50.11 , H 4.01 , N 7.97. Found: C 50.16, H 3.74, N 7.74.
Example 17: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2- ylmethyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (350 mg, 1 .01 mmol) in MeOH (6 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 134 mg, 2.02 mmol), acetic acid (0.4 mL) and thiophene-2-carbaldehyde (169 mg, 1.51 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 70 mg, 1.06 mmol) and thiophene- 2-carbaldehyde (94 mg, 0.84 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 1 N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an orange oil (506 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide (167 mg, 41 % yield) as an off-white crystalline solid, mp 136-137 °C. IR (ATR): 639, 696, 840, 881 , 927, 992, 1023, 1054, 1105, 1140, 1171 , 1263, 1317, 1369, 1423, 1538, 1649, 2236, 2762, 2803, 2937, 3065, 3081 , 3291 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2OH2OF3N3OS+H]+: 408.1352, found: 408.1352. Anal. Calcd for C2oH2oF3N3OS: C 58.96, H 4.95, N 10.31 , S 7.87. Found: C 58.89, H 4.99, N 10.27, S 7.59. Example 18: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (300 mg, 0.86 mmol) in MeOH (6 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBH3CN (95%, 114 mg, 1.72 mmol), acetic acid (0.4 mL) and thiophene-3-carbaldehyde (145 mg, 1.29 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 60 mg, 0.91 mmol) and thiophene- 3-carbaldehyde (81 mg, 0.72 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 1 N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an orange oil (433 mg). Column chromatography (SiO3, DCM/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (147 mg, 42% yield) as an off-white solid, mp 122-124 °C. IR (ATR): 638, 673, 766, 794, 839, 882, 929, 994, 1056, 1106, 1141 , 1172, 1267, 1296, 1319, 1372, 1424, 1449, 1540, 1650, 2237, 2751 , 2786, 2935, 3080, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2oF3N3OS+H]+: 408.1352, found: 408.1351.
Example 19: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL) and 4-methoxybenzaldehyde (147 mg, 1.08 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 50 mg, 0.76 mmol) and 4- methoxybenzaldehyde (82 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 1 N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give a colorless oil (443 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N-(4- cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (111 mg, 36% yield) as a white solid. The analytical sample (79 mg) was obtained by a second column chromatography purification (SiO2, DCM/MeOH mixtures), mp 119-120 °C. IR (ATR): 591 , 638, 671 , 706, 785, 806, 840, 928, 993, 1024, 1036, 1056, 1105, 1142, 1170, 1259, 1318, 1366, 1425, 1515, 1538, 1617, 1649, 2237, 2756, 2799, 2934, 3063, 3290 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H24F3N3O2+H]+: 432.1893, found: 432.1893.
Example 20: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1- phenethylpiperidine-4-carboxamide.
A solution of the hydrochloride salt of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide (300 mg, 0.86 mmol) in MeOH (5 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBHsCN (95%, 114 mg, 1.72 mmol), acetic acid (0.4 mL) and 2-phenylacetaldehyde (155 mg, 1.29 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 60 mg, 0.91 mmol) and 2- phenylacetaldehyde (87 mg, 0.72 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 1 N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an off- white solid (640 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N- (4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide (134 mg, 38% yield) as a white solid, mp 189-191 °C. IR (ATR): 638, 671 , 698, 742, 841 , 881 , 927, 994, 1024, 1057, 1105, 1141 , 1171 , 1230, 1267, 1291 , 1318, 1371 , 1425, 1449, 1496, 1540, 1649, 2237, 2768, 2810, 2940, 3067, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H24F3N3O+H]+: 416.1944, found: 416.1944.
Example 21 : Synthesis of N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4- carboxamide.
A solution of the hydrochloride salt of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide (234 mg, 0.72 mmol) in MeOH (4 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBHsCN (95%, 91 mg, 1.44 mmol), acetic acid (0.3 mL) and 4-methoxybenzaldehyde (148 mg, 1.09 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 50.3 mg, 0.76 mmol) and 4- methoxybenzaldehyde (83.1 mg, 0.61 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to the obtained crude was added water (20 mL). Then, 2N NaOH solution was added until basic pH was reached and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an orange oil (546 mg). Column chromatography (SiO2, DCM/MeOH mixtures) afforded N-(2,4- dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (138 mg, 47% yield) as an off-white solid, mp 133 °C. IR (ATR): 570, 640, 691 , 742, 793, 809, 817, 831 , 866, 982, 995, 1030, 1099, 1121 , 1144, 1167, 1223, 1244, 1297, 1330, 1384, 1422, 1469, 1509, 1546, 1643, 2754, 2793, 2938, 2955, 3072, 3281 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH24Cl2N2O2+H]+: 407.1288, found: 407.1293. Anal, calcd for C21H24CI2N2O2: C 61.92, H 5.94, N 6.88. Found: C 61.71 , H 5.90, N 6.69.
Example 22: Synthesis of 1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4- carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (239 mg, 1.09 mmol) and Et3N (0.41 mL, 2.97 mmol) in EtOAc (6 mL), 4-(aminomethyl)-3-chlorobenzonitrile (165 mg, 0.99 0.88 mmol, synthesized as in W02009049157A1), HOBt (200 mg, 1.48 mmol) and EDCI HCI (284 mg, 1.48 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with saturated Na2SO2 (2 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, Hexane/EtOAc mixtures) to afford 1-benzyl-N-(2-chloro-4- cyanobenzyl)piperidine-4-carboxamide (70 mg, 19% yield) as a beige solid, mp 158-159 °C. IR (ATR): 589, 696, 732, 791 , 871 , 992, 1051 , 1128, 1196, 1228, 1295, 1321 , 1340, 1411 , 1446, 1540, 1647, 2234, 2756, 2798, 2927, 2948, 3069, 3266 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22CIN3O+H]+: 368.1524; Found: 368.1520. Anal. Calcd for C21H22CIN3O: C 68.56, H 6.03, N 11.42. Found: C 68.51 , H 5.89, N 11.23.
Example 23: Synthesis of 1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4- carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (30 mg, 0.14 mmol) and Et3N (60 pL, 0.41 mmol) in EtOAc (1 mL), 4-bromo-2-chlorobenzylamine (31 mg, 0.14 mmol), HOBt (27 mg, 0.20 mmol) and EDCI HCI (39 mg, 0.20 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (30 mL) was added and the mixture was washed with water (3 x 30 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(4-bromo-2- chlorobenzyl)piperidine-4-carboxamide (30 mg, 51 % yield) as a white solid, mp 117-118 °C. IR (ATR): 605, 697, 735, 813, 863, 988, 1046, 1268, 1295, 1380, 1469, 1538, 1584, 1645, 2757, 2801 , 2921 , 3063, 3278 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22BrCIN2O+H]+: 421.0677; Found: 421.0682. Anal. Calcd for C21H22BrCIN2O: C 56.96, H 5.26, N 6.64. Found: C 56.87, H 5.24, N 6.37. Example 24: Synthesis of 1-benzyl-N-(4-bromo-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (136 mg, 0.62 mmol) and Et3N (0.23 mL, 1.68 mmol) in EtOAc (4 mL), 4-bromo-2-(trifluoromethyl)benzylamine (142 mg, 0.56 mmol), HOBt (114 mg, 0.84 mmol) and EDCI HCI (161 mg, 0.84 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with water (3 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(4-bromo-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide (34 mg, 13% yield) as a white solid, mp 88-89 °C. IR (ATR): 669, 698, 732, 827, 889, 1048, 1125, 1165, 1304, 1411 , 1556, 1646, 2802, 2942, 3073, 3273 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH22BrF3N2O+H]+: 455.0940; Found: 455.0941.
Example 25: Synthesis of 1-benzyl-N-(4-chloro-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (105 mg, 0.48 mmol) and Et3N (0.18 mL, 1.32 mmol) in EtOAc (3 mL), (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (99 mg, 0.44 mmol), HOBt (84 mg, 0.62 mmol) and EDCI HCI (119 mg, 0.62 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with water (3 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, Hexane/EtOAc mixtures) to afford 1-benzyl-N-(4- chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (70 mg, 37% yield) as a white solid, mp 97-98 °C. IR (ATR): 585, 638, 697, 735, 792, 854, 947, 989, 1067, 1164, 1207, 1252, 1450, 1488, 1552, 1642, 2765, 2945, 3085, 3287 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH22CIF3N2O2+H]+: 427.1395; Found: 427.1397. Anal. Calcd for C21H22CIF3N2O2: C 59.09, H 5.19, N 6.56. Found: C 58.83, H 5.25, N 6.25.
Example 26: Synthesis of 1-benzyl-N-(4-methoxy-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (167 mg, 0.76 mmol) and Et3N (0.29 mL, 2.07 mmol) in EtOAc (5 mL), (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine (153 mg, 0.69 mmol), HOBt (141 mg, 1.04 mmol) and EDCI HCI (199 mg, 1.04 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with water (3 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, Hexane/EtOAc mixtures) to afford 1-benzyl- N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (104 mg, 36% yield) as a white solid, mp 90-91 °C. IR (ATR): 643, 698, 727, 844, 878, 971 , 994, 1032, 1145, 1206, 1288, 1435, 1508, 1548, 1642, 2801 , 2942, 3294 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F3N2O3+H]+: 423.1890; Found: 423.1894.
Example 27: Synthesis of 1-benzyl-N-(2-chloro-3-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (92 mg, 0.42 mmol) and EtsN (0.16 mL, 1.14 mmol) in EtOAc (1.5 mL), (2-chloro-3-(trifluoromethyl)benzylamine (80 mg, 0.38 mmol), HOBt (77 mg, 0.57 mmol) and EDCI HCI (109 mg, 0.57 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with water (2 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(2-chloro-3- (trifluoromethyl)benzyl)piperidine-4-carboxamide (50 mg, 32% yield) as a white solid, mp 120-121 °C. IR (ATR): 598, 696, 735, 769, 788, 990, 1091 , 1119, 1163, 1228, 1295, 1327, 1433, 1554, 1645, 2767, 2809, 2945, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH22CIF3N2O+H]+: 411.1446; Found: 411.1445. Anal. Calcd for C21H22CIF3N2O: C 61.39, H 5.40, N 6.82. Found: C 61.53, H 5.57, N 6.55.
Example 28: Synthesis of 1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4- carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (138 mg, 0.63 mmol) and Et3N (0.24 mL, 1.71 mmol) in EtOAc (3 mL), 2,3-dichlorobenzylamine (100 mg, 0.57 mmol), HOBt (115 mg, 0.85 mmol) and EDCI HCI (163 mg, 0.85 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with water (2 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(2,3- dichlorobenzyl)piperidine-4-carboxamide (101 mg, 47% yield) as a white solid, mp 124- 125 °C. IR (ATR): 694, 731 , 786, 992, 1120, 1221 , 1297, 1329, 1414, 1448, 1543, 1636, 2753, 2941 , 3068, 3278 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH22Cl2N20+H]+: 377.1182, found: 377.1180. Anal. Calcd for C20H22CI2N2O: C 63.67, H 5.88, N 7.42. Found: C 63.72, H 5.96, N 7.40. Example 29: Synthesis of 1-benzyl-N-(4-fluoro-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (125 mg, 0.57 mmol) and Et3N (0.22 mL, 1.56 mmol) in EtOAc (3 mL), 4-fluoro-2-(trifluoromethyl)benzylamine (100 mg, 0.52 mmol), HOBt (105 mg, 0.78 mmol) and EDCI HCI (150 mg, 0.78 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with water (2 x 20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(4-fluoro-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide (108 mg, 53% yield) as a white solid, mp 112-113 °C. IR (ATR): 668, 698, 714, 735, 884, 903, 991 , 1046, 1122, 1163, 1212, 1316, 1427, 1494, 1567, 1641 , 2803, 2947, 3086, 3251 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH22F4N2O+H]+: 395.1741 , found: 395.1739. Anal, calcd for C21H22F4N2O: C 63.95, H 5.62, N 7.10. Found: C 63.98, H 5.63, N 6.87.
Example 30: Synthesis of 1-benzyl-N-(4-chloro-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
To a solution of 1-benzylpiperidine-4-carboxylic acid (116 mg, 0.53 mmol) and EtsN (0.20 mL, 1.44 mmol) in EtOAc (3 mL), 4-chloro-2-(trifluoromethyl)benzylamine (100 mg, 0.48 mmol), HOBt (97 mg, 0.72 mmol) and EDCI HCI (138 mg, 0.72 mmol) were added. The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added and the mixture was washed with saturated Na2CO3 (2 x 20 mL) and brine (20 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (155 mg, 79% yield) as a white solid, mp 97-98 °C. IR (ATR): 678, 697, 737, 839, 891 , 991 , 1047, 1137, 1157, 1261 , 1300, 1416, 1556, 1650, 2807, 2947, 3086, 3273 cm’1. Anal, calcd for C21H22CIF3N2O: C 61.39, H 5.40, N 6.82. Found: C 61.64, H 5.45, N 6.61.
Example 31 : Synthesis of 1-benzyl-N-(4-(methylsulfonyl)-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
A mixture of 1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (215 mg, 0.46 mmol, see Example 5), sodium methanesulfinate (70.4 mg, 0.69 mmol), N,N'-dimethylethylenediamine (0.06 mL, 0.55 mmol), water (0.3 mL, 16.6 mmol) and Cui (104.7 mg, 0.55 mmol) in DMF (3 mL) was heated in a microwave reactor at 120 °C for 2 h. After cooling to ambient temperature, the mixture was filtered through a pad of Celite® using EtOAc as eluting agent. EtOAc (20 mL) was then added to the filtrate, and it was washed with water acidified to pH = 3 with HCI 2N solution (3 x 40 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM/MeOH mixtures) to afford 1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine- 4-carboxamide (23 mg, 11% yield) as a white solid. The analytical sample was obtained by washing with Et2O (2 x 5 mL), mp 170-171 °C. IR (ATR): 592, 637, 699, 738, 765, 793, 820, 857, 947, 973, 1031 , 1087, 1128, 1150, 1171 , 1208, 1258, 1314, 1357, 1404,
1416, 1462, 1494, 1635, 2421 , 2766, 2812, 2946, 3028, 3083, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F3N2O4S+H]+: 471.1560; Found: 471.1562.
Example 32: Synthesis of 1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4- carboxamide.
To a solution of (2-chloro-3-fluorophenyl)methanamine (276 mg, 1.73 mmol) in EtOAc (20 mL), 1-benzylpiperidine-4-carboxylic acid (344 mg, 1.57 mmol), HOBt (319 mg, 2.36 mmol), EDCI HCI (452 mg, 2.36 mmol) and Et3N (0.4 mL, 2.83 mmol) were added. The reaction mixture was stirred at RT for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 solution (15 mL), dried over anh. Na2SO4, filtered and evaporated to provide a transparent oil. Column chromatography (4 g, SiO2, DCM/MeOH mixtures) afforded 1- benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide (394 mg, 69% yield) as a white solid, mp 140-141 °C. IR (ATR): 732, 991 , 1067, 1171 , 1266, 1362,1422, 1446, 1488, 1542, 1639, 1744, 2798, 2935, 3048, 3265 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C20H22CIFN2O+H]+: 361.14, found: 361.1467 Anal. Calcd for C20H22CIFN2O: C 66.57, H 6.15, N 7.76. Found: C 66.55, H 6.23, N 7.66.
Example 33: Synthesis of 1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4- carboxamide.
From (3-bromo-2-chlorophenyl)methanamine (225 mg, 1.02 mmol) and following the procedure of Example 32, 1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4- carboxamide (336 mg, 86% yield) was obtained as an orange solid, mp 122-123 °C. IR (ATR): 697, 724, 770, 831 , 905, 991 , 1025, 1096, 1118, 1145, 1230, 1265, 1335, 1365,
1417, 1447, 1493, 1560, 1638, 2762, 2804, 2939, 3245 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C20H22BrCIN2O+H]+: 423.06, found: 423.0644. Anal. Calcd for C20H22BrCIN2O: C 56.96, H 5.26, N 6.51. Found: C 56.70, H 5.14, N 6.51. Example 34: Synthesis of 1-benzyl-N-(3-fluoro-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
From (3-fluoro-2-(trifluoromethyl)phenyl)methanamine (270 mg, 1.40 mmol) and following the procedure of Example 32, 1-benzyl-N-(3-fluoro-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide (395 mg, 79% yield) was obtained as an orange solid, mp 109-110 °C. IR (ATR): 697, 735, 785, 988, 1035, 1056, 1119, 1188, 1266, 1288, 1337, 1365,1423, 1439, 1475, 1556, 1585 1644, 2760, 2797, 2936, 3087, 3296 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH22F4N2O+H]+: 395.17, found: 395.1729. Anal. Calcd for C21H22F4N2O: C 63.95, H 5.62, N 7.10. Found: C 64.04, H 5.81 , N 7.05.
Example 35: Synthesis of 1-benzyl-N-(3-chloro-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
From (3-chloro-2-(trifluoromethyl)phenyl)methanamine (300 mg, 1.43 mmol) and following the procedure of Example 32, 1-benzyl-N-(3-chloro-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide (346 mg, 59% yield) was obtained as a beige solid, mp 95-96 °C. IR (ATR): 696, 732, 780, 844, 991 , 1035, 1121 , 1169, 1228, 1282, 1338, 1366, 1448, 1494, 1543, 1642, 2758, 2803, 2936, 3266 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22CIF3N2O+H]+: 411.14, found: 411.1440. Anal. Calcd for C21H22CIF3N2O 0.25H2O: C 60.72, H 5.46, N 6.74. Found: C 60.93, H 5.73, N 6.42.
Example 36: Synthesis of 1-benzyl-N-(3-methoxy-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
From (3-methoxy-2-(trifluoromethyl)phenyl)methanamine (197 mg, 0.96 mmol) and following the procedure of Example 32, 1-benzyl-N-(3-methoxy-2- (trifluoromethyl)benzyl)piperidine-4-carboxamide (248 mg, 70% yield) was obtained as a white solid, mp 120-121 °C. IR (ATR): 697, 735, 785, 988, 1035, 1056, 1119, 1188, 1266, 1288, 1337, 1365,1423, 1439, 1475, 1556, 1585 1644, 2760, 2797, 2936, 3087, 3296 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F3N2O2+H]+: 407.19, found: 407.1945. Anal. Calcd for C22H25F3N2O2: C 65.01 , H 6.20, N 6.89. Found: C 64.99, H 6.34, N 6.87.
Example 37: Synthesis of 1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4- carboxamide.
From (4-bromo-2-fluorophenyl)methanamine (280 mg, 1.37 mmol) and following the procedure of Example 32, 1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4- carboxamide (355 mg, 70% yield) was obtained as a salmon solid, mp 102-103 °C. IR (ATR): 696, 729, 746, 818, 865, 985, 1176, 1211 , 1265, 1361 , 1448, 1481 , 1547, 1638, 2748, 2794, 2933, 3070, 3286 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C20H22BrFN2O+H]+: 405.09, found: 405.0973. Anal. Calcd for C20H22BrFN2O: C 59.27, H 5.47, N 6.91. Found: C 59.24, H 5.59, N 6.84.
Example 38: Synthesis of 1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4- carboxamide.
From (2-chloro-4-methoxyphenyl) methanamine (315 mg, 1.84 mmol) and following the procedure of Example 32, 1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4- carboxamide (456 mg, 73% yield) was obtained as a beige solid, mp 92-93 °C. IR (ATR): 693, 735, 816, 853, 885, 984, 1052, 1117, 1213, 1239, 1283, 1451 , 1494, 1547 , 1638, 2768, 2818, 2939, 3283 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H25CIN2O2+H]+: 373.16, found: 373.1679. Anal. Calcd for C21H25CIN2O2: C 67.64, H 6.76, N 7.51. Found: C 67.64, H 6.71 , N 7.49.
Example 39: Synthesis of 1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4- carboxamide.
From (2-bromo-4-chlorophenyl)methanamine hydrochloride (108 mg, 0.49 mmol) and following the procedure of Example 32, 1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine- 4-carboxamide (157 mg, 84% yield) was obtained as a beige solid, mp 116-117 °C. IR (ATR): 696, 734, 807, 860, 993, 1031 , 1122, 1228, 1256, 1293, 1421 , 1445, 1484, 1554, 1647, 2755, 2923, 2943 3086, 3288 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C20H22BrCIN2O+H]+: 423.06, found: 423.0657. Anal. Calcd for C20H22BrCIN2O: C 56.96, H 5.26, N 6.64. Found: C 56.84, H 5.35, N 6.73.
Example 40: Synthesis of N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4- carboxamide.
A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. NaBHsCN (95%, 176 mg, 2.80 mmol), acetic acid (0.4 mL) and 2- phenylacetaldehyde (253 mg, 2.10 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 92 mg, 1.47 mmol) and 2-phenylacetaldehyde (140 mg, 1.16 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and water (5 mL) and saturated aqueous NaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give a white solid. Column chromatography (10 g, AI2C>3, DCM/MeOH mixtures) followed by a second column chromatography (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide (208 mg, 38% yield) as a white solid, mp 158-159 °C. IR (ATR): 670, 767, 833, 856, 913, 993, 1054, 1084, 1117, 1164, 1197, 1228, 1277, 1345,1424, 1446, 1543, 1647, 2784, 2940, 3290 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH24Cl2N2O+H]+: 391.13, found: 391.1336. Anal. Calcd for C21H24CI2N2O: C 64.45, H 6.18, N 7.16. Found: C 64.39, H 6.13, N 6.85.
Example 41 : Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2- ylmethyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (430 mg, 1.33 mmol) in MeOH (15 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. NaBHsCN (95%, 174 mg, 2.76 mmol), acetic acid (0.4 mL) and 2-naphthaldehyde (323 mg, 2.07 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 91 mg, 1.45 mmol) and 2-naphthaldehyde (143 mg, 1.15 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and water (5 mL) and saturated aqueous NaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures) followed by a column chromatography (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4-carboxamide (257 mg, 38% yield) as a white solid , mp 166-167 °C. IR (ATR): 672, 751 , 830, 865, 888, 948, 995, 1072, 1106, 1151 , 1223, 1281 , 1323, 1439, 1546, 1591 , 1630, 2868, 2943, 3073, 3289 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C26H24F3N3O+H]+: 452.19, found: 452.1939. Anal. Calcd for C26H24F3N3O O.5H2O: C 67.81 , H 5.47, N 9.12. Found: C 67.87, H 5.42, N 8.94.
Example 42: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2- fluorobenzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (480 mg, 1.38 mmol) in MeOH (15 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 174 mg, 2.76 mmol), acetic acid (0.4 mL) and 2-fluorobenzaldehyde (323 mg, 2.6 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 68 mg, 1.08 mmol) and 2- fluorobenzaldehyde (143 mg, 1.15 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and water (5 mL) and saturated aqueous NaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A further purification (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide (216 mg, 37% yield) as a white solid, mp 120-121 °C. IR (ATR): 670, 750, 839, 881 , 926, 995, 1025, 1055, 1105, 1141 , 1170, 1225, 1267, 1317, 1369, 1425, 1453, 1487, 1541 , 1648, 2236, 2818, 2924, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2IF4N3O+H]+: 420.16, found: 420.1690. Anal. Calcd for C22H21F4N3O O.25H2O: C 62.33, H 5.11 , N 9.91. Found: C 62.54, H 5.27, N 9.71.
Example 43: Synthesis of N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4- carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) and following the procedure of Example 42, N-(2,4-dichlorobenzyl)-1-(2- fluorobenzyl)piperidine-4-carboxamide (397 mg, 72% yield) was obtained as a white solid, mp 97-98 °C. IR (ATR): 679, 755, 802, 830, 993, 1099, 1137, 1220, 1292, 1324, 1380, 1422, 1469, 1551 , 1588, 1640, 2789, 2937, 3076, 3256 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2iCl2FN20+H]+: 395.10, found: 395.1090. Anal. Calcd for C20H2ICI2FN2O: C 60.77, H 5.35, N 7.09. Found: C 60.39, H 5.33, N 7.17.
Example 44: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4- carboxamide.
A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide (350 mg, 1.08 mmol) hydrochloride in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 136 mg, 2.16 mmol), acetic acid (0.4 mL) and 4- fluorobenzaldehyde (201 mg, 1.62 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 66 mg, 1.13 mmol) and 4-fluorobenzaldehyde (134 mg, 1.08 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and water (5 mL) and saturated aqueous NaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give a white solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second column chromatography (10 g, SiO2, Hex/AcOEt/MeOH) afforded N-(2,4-dichlorobenzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide (354 mg, 83% yield) as a white solid, mp 121- 122°C. IR (ATR): 650, 823, 992, 1100, 1134, 1226, 1270, 1293, 1361 ,1420, 1444, 1467, 1507, 1546, 1639, 2791 , 2936, 3078, 3269 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C20H2ICI2FN2O+H]+: 395.10, found: 395.1088. Anal. Calcd for C20H2ICI2FN2O: C 60.77, H 5.35, N 7.09. Found: C 60.76, H 5.31 , N 6.98.
Example 45: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4- difluorobenzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (348 mg, 1.00 mmol) in MeOH (15 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 142 mg, 2.25 mmol), acetic acid (0.4 mL) and 3,4-difluorobenzaldehyde (240 mg, 1.68 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 74 mg, 1.18 mmol) and 3,4-difluorobenzaldehyde (132 mg, 0.93 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO3 solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide (166 mg, 38% yield) as a white solid, mp 147-148 °C IR (ATR): 676, 779, 836, 876, 927, 993, 1023, 1055, 1121 , 1142, 1162, 1205, 1226, 1287, 1319, 1422, 1433, 1517, 1552, 1612, 1645, 2239, 2761 , 2800, 2945, 3084, 3314 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H20F5N3O+H]+: 438.15, found: 438.1606. Anal. Calcd for C22H20F5N3O 0.5H2O: C 59.19, H 4.74, N 9.41. Found: C 58.91 , H 5.08, N 9.39.
Example 46: Synthesis of N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine- 4-carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) and following the procedure of Example 45, N-(2,4-dichlorobenzyl)-1-(3,4- difluorobenzyl)piperidine-4-carboxamide (329 mg, 57% yield) was obtained as a white solid, mp 109-110 °C. IR (ATR): 777, 806, 882, 938 955, 1109, 1150, 1200, 1222, 1270, 1368, 1388, 1426, 1511 , 1644, 2753, 2798, 2933, 3283 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2oCI2F2N20+H]+: 413.09, found: 413.0995. Anal. Calcd for C20H20CI2F2N2O 0.25H2O: C 57.25, H 4.97, N 6.68. Found: C 57.00, H 4.73, N 6.48. Example 47: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4- carboxamide.
A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBHsCN (95%, 176 mg, 2.80 mmol), acetic acid (0.4 mL) and 4- iodobenzaldehyde (488 mg, 2.10 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 92 mg, 1.47 mmol) and 4-iodobenzaldehyde (270 mg, 1.16 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give an white solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiC>2, Hex/AcOEt/MeOH mixtures) afforded N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine- 4-carboxamide (444 mg, 63% yield) as a white solid, mp 161-162 °C. IR (ATR): 686, 802, 830, 864, 978, 1025, 1039, 1099, 1136, 1230, 1324, 1380,1422, 1470, 1551 , 1590, 1639, 2750, 2789, 2937, 3076, 3258 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2iCl2lN20+H]+: 503.01 , found: 503.0147. Anal. Calcd for C20H21CI2IN2O: C 47.74, H 4.21 , N 5.57. Found: C 47.74, H 4.23, N 5.42.
Example 48: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- methylbenzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (350 mg, 1.00 mmol) in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBHsCN (95%, 142 mg, 2.26 mmol), acetic acid (0.4 mL) and 4-methylbenzaldehyde (236 mg, 2.10 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 75 mg, 1.18 mmol) and 4- methylbenzaldehyde (112 mg, 0.93 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCOs solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide (292 mg, 70% yield) as a white solid, mp 158-159 °C. IR (ATR): 638, 709, 781 , 846, 880, 990, 1022, 1055, 1121 , 1168, 1207, 1223, 1264, 1314, 1367, 1418, 1450, 1545, 1611 , 1655, 2238, 2873, 2966, 3299 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H24F3N3O+H]+: 416.19, found: 416.1950. Anal. Calcd for C23H24F3N3O O.5H2O: C 65.08, H 5.94, N 9.9. Found: C 65.31 , H 5.99, N 9.52.
Example 49: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4- carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) and following the procedure of Example 48, N-(2,4-dichlorobenzyl)-1-(4- methylbenzyl)piperidine-4-carboxamide (459 mg, 84% yield) was obtained as a white solid, mp 160-161 °C. IR (ATR): 651 , 804, 865, 993, 1024, 1100, 1136, 1202, 1231 , 1272, 1325, 1363, 1469, 1514, 1552, 1590, 1639, 2754, 2792, 2936, 3070, 3251 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2iH24Cl2N2O+H]+: 391.13, found: 391.1342. Anal. Calcd for C21H24CI2N2O O.25H2O: C 63.72, H 6.24, N 7.08. Found: C 63.75, H 6.07, N 7.01.
Example 50: Synthesis of 1-(4-chlorobenzyl)-N-(4-cyano-2-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (348 mg, 1.00 mmol) in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCh tube. To that, NaBH3CN (95%, 142 mg, 2.26 mmol), acetic acid (0.4 mL) and 4-chlorobenzaldehyde (240 mg, 1.70 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 75 mg, 1.19 mmol) and 4- chlorobenzaldehyde (132 mg, 0.94 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO3 solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded 1-(4-chlorobenzyl)- N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (287 mg, 66% yield) as a yellow solid, mp 147-148 °C. IR (ATR): 745, 784, 824, 844, 883, 929, 973, 988, 1014, 1057, 1084, 1117, 1175, 1207, 1255, 1290, 1317, 1366,1389, 1449, 1490, 1531 , 1574, 1614, 1651 , 2233, 2866, 2978, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2ICIF3N3O+H]+: 436.13, found: 436.1405. Anal. Calcd for C22H2ICIF3N3O- 1 H2O: C 58.22, H 5.11 , N 9.26. Found: C 58.54, H 5.09, N 9.09. Example 51 : Synthesis of 1-(4-chlorobenzyl)-N-(2,4-dichlorobenzyl)piperidine-4- carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) and following the procedure of Example 50, N-(2,4-dichlorobenzyl)-1-(4- chlorobenzyl)piperidine-4-carboxamide (315 mg, 55% yield) was obtained as a white solid, mp 148-149 °C. IR (ATR): 690, 809, 831 , 864, 995, 1014, 1087, 1135, 1230, 1282, 1326, 1382, 1422, 1487, 1549, 1647, 2749, 2783, 2939, 3078, 3277 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2iCl3N20+H]+: 411.07, found: 411.0793. Anal. Calcd for C20H2ICI3N2O: C 58.34, H 5.14, N 6.80. Found: C 58.07, H 5.10, N 6.70.
Example 52: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4- dichlorobenzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (430 mg, 1.24 mmol) in MeOH (15 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 174 mg, 2.76 mmol), acetic acid (0.4 mL) and 2,4-dichlorobenzaldehyde (363 mg, 2.07 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBH3CN (95%, 91 mg, 1.15 mmol) and 2,4-dichlorobenzaldehyde (201 mg, 1.15 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure and to obtain the crude. Then, water (5 mL) and saturated aqueous NaHCO3 solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiO2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4- carboxamide (168 mg, 29% yield) as a white solid, mp 190-191 °C. IR (ATR): 671 , 790, 818, 864, 926, 995, 1056, 1103, 1140, 1170, 1232, 1268, 1317, 1369, 1425, 1448, 1544, 1649, 2236, 2808, 2924, 3073, 3274 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H20CI2F3N3O+H]+: 470.09, found: 470.1001. Anal. Calcd for C23H20CI2F3N3O: C 56.18, H 4.29, N 8.93. Found: C 55.96, H 4.41 , N 8.72.
Example 53: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4- dichlorobenzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (348 mg, 1.00 mmol) in MeOH (10 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 142 mg, 2.26 mmol), acetic acid (0.4 mL) and 3,4-dichlorobenzaldehyde (296 mg, 1.70 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 75 mg, 1.18 mmol) and 3,4-dichlorobenzaldehyde (164 mg, 0.94 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueousNaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give a yellow solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiC>2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide (360 mg, 76% yield) as a white solid, mp 122-123 °C. IR (ATR): 673, 811 , 928, 993, 1055, 1120, 1105, 1171 , 1263, 1316, 1420, 1543, 1650, 2748, 2933, 3073, 3288 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H2oCl2F3N30+H]+: 470.09, found: 470.1012. Anal. Calcd for C22H20CI2F3N3O: C 56.18, H 4.29, N 8.93. Found: C 55.85, H 4.25, N 8.91.
Example 54: Synthesis of N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine- 4-carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) and following the procedure of Example 53, N-(2,4-dichlorobenzyl)-1-(3,4- dichlorobenzyl)piperidine-4-carboxamide (379 mg, 61% yield) was obtained as a white solid, mp 148-149 °C. IR (ATR): 687, 802, 829, 864, 911 , 928, 994, 1026, 1098, 1137, 1230, 1281 , 1325, 1379,1422, 1444, 1469, 1550, 1590, 1640, 2789, 2938, 3077, 3267 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2oCl4N20+H]+: 447.03, found: 447.0385. Anal. Calcd for C20H20CI4N2O: C 53.84, H 4.52, N 6.28. Found: C 53.59, H 4.64, N 6.46.
Example 55: Synthesis of N-(2,4-dichlorobenzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.40 mmol) and following the procedure of Example 18, N-(2,4-dichlorobenzyl)-1-(thiophen- 3-ylmethyl)piperidine-4-carboxamide (223 mg, 42% yield) was obtained as a white solid, mp 119-120 °C. IR (ATR): 670, 767, 833, 856, 913, 992, 1053, 1118, 1164, 1277, 1345,1423, 1543, 1644, 2793, 2941 , 3284 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C18H20C12N2OS+H]+: 383.07, found: 383.0742. Anal. Calcd forC18H20C12N2OS 0.25H2O: C 55.74, H 5.33, N 7.22. Found: C 55.89, H 5.23, N 6.91. Example 56: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2- ylmethyl)piperidine-4-carboxamide.
To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (200 mg, 1.00 mmol) in EtOAc (15 mL), 1-(furan-2-ylmethyl)piperidine-4-carboxylic acid (209 mg, 1.00 mmol), HOBt (203 mg, 1.50 mmol), EDCI.HCI (288 mg, 1.50 mmol) and Et3N (0.25 mL, 1.80 mmol) were added. The reaction mixture was stirred at RT for 24 h. After 24 h, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 solution (15 mL), dried over anh. Na2SO4, filtered and evaporated to provide an oil. Column chromatography (4 g, SiC>2, DCM/MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4- carboxamide (336 mg, 86% yield) as a white solid, mp 127-128 °C. IR (ATR): 684, 744, 813, 881 , 995, 1053, 1116, 1171 , 1261 , 1316, 1424, 1490, 1540, 1645, 2237, 2749, 2787, 2937, 3072, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH2oF3N302+H]+: 392.15, found: 392.1576. Anal. Calcd for C2oH2oF3N30: C 61.38, H 5.15, N 10.74. Found: C 61.24, H 5.20, N 10.45.
Example 57: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4- ylmethyl)piperidine-4-carboxamide.
To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (200 mg, 1.0 mmol) in EtOAc (15 mL), 1-(pyridin-4-ylmethyl)piperidine-4-carboxylic acid (221 mg, 1.0 mmol), HOBt (203 mg, 1.50 mmol), EDCI HCI (288 mg, 1.50 mmol) and Et3N (0.25 mL, 1.80 mmol) were added. The reaction mixture was stirred at RT for 24 h. After 24 h, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 solution (15 mL), dried over anh. Na2SO4, filtered and evaporated to provide an oil. Column chromatography (4 g, SiO2, DCM/MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4- carboxamide (229 mg, 57% yield) as a beige solid, mp 139-140 °C. IR (ATR): 670, 803, 834, 928, 993, 1054, 1106, 1170, 1229, 1267, 1315, 1418, 1543, 1648, 2803, 2941 , 3284 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H2IF3N4O+H]+: 403.17, found: 403.1733. Anal. Calcd for C21H2IF3N4O 0.25H2O: C 61.98, H 5.33, N 13.77. Found: C 62.05, H 5.42, N 13.54.
Example 58: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4- (trifluoromethyl)benzyl)piperidine-4-carboxamide.
A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (490 mg, 1.41 mmol) in MeOH (15 mL) was prepared in a round bottom flask equipped with a CaCI2 tube. To that, NaBH3CN (95%, 197 mg, 3.14 mmol), acetic acid (0.4 mL) and 4-(trifluoromethyl)benzaldehyde (411 mg, 2.36 mmol) were added. The mixture was stirred at RT for 2 h. Then, more NaBHsCN (95%, 104 mg, 1.08 mmol) and 4-(trifluoromethyl)benzaldehyde (226 mg, 1.30 mmol) were added, and the reaction mixture was stirred at RT for another 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCCh solution was added until basic pH. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SC>4, filtered and concentrated under vacuum to give an beige solid. The crude was purified several times using column chromatography (10 g, AI2O3, DCM/MeOH mixtures). A second purification (10 g, SiC>2, Hex/AcOEt/MeOH mixtures) afforded N-(4-cyano-2- (trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide (201 mg, 30% yield) as a white solid, mp 136-137 °C IR (ATR): 670, 789, 823, 881 , 912, 927, 994, 1018, 1067, 1104, 1161 , 1232, 1267, 1317, 1336, 1370, 1424, 1449, 1541 , 1619, 1650, 2237, 2798, 2925, 3289 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H2IF6N3O+H]+: 470.16, found: 469.1659. Anal. Calcd for C23H21F6N3O: C 58.85, H 4.51 , N 8.95. Found: C 58.88, H 4.60, N 8.81.
Example 59: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-
(trifluoromethyl)benzyl)piperidine-4-carboxamide.
From N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.93 mmol) and following the procedure of Example 58, N-(2,4-dichlorobenzyl)-1-(4- (trifluoromethyl)benzyl)piperidine-4-carboxamide (234 mg, 57% yield) was obtained as a white solid, mp 142-133 °C. IR (ATR): 812, 826, 909, 995, 1054, 1066, 1115, 1160, 1232, 1280, 1306, 1324, 1365, 1422, 1469, 1515, 1545, 1647, 2754, 2791 , 2941 , 3075, 3279 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H21Cl2F3N2O+H]+: 445.10, found: 445.1065. Anal. Calcd for C21H2ICI2F3N2O: C 56.64, H 4.75, N 6.89. Found: C 57.54, H 4.82, N 6.17.
Example 60: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (400 mg, 1.00 mmol) and following the procedure of Example 44, N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (130 mg, 27% yield) was obtained as a white solid, mp 99-100 °C. IR (ATR): 670, 812, 824, 889, 991 , 1054, 1114, 1164, 1278, 1302, 1408, 1432, 1513, 1547, 1645, 2754, 2794, 2937, 3074, 3291cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H21BrF4N2O+H]+: 473.08, found: 473.0848. Anal. Calcd for C21H21BrF4N2O: C 53.29, H 4.47, N 5.92. Found: C 53.34, H 4.64, N 5.62. Example 61 : Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4- iodobenzyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (420 mg, 1.05 mmol) and following the procedure of Example 47, N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (353 mg, 58% yield) was obtained as a white solid, mp 163-164 °C. IR (ATR): 670, 825, 909, 988, 1054, 1113, 1163, 1198, 1230, 1278, 1305, 1344, 1515, 1545, 1644, 2752, 2792, 2940, 3075, 3290 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H21BrF3lN2O+H]+: 580.98, found: 580.9896. Anal. Calcd for C21H21BrF3IN2O: C 43.40, H 3.64, N 4.82. Found: C 43.46, H 3.92, N 4.61.
Example 62: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (380 mg, 0.95 mmol) and following the procedure of Example 19, N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (184 mg, 40% yield) was obtained as a white solid, mp 111-112 °C. IR (ATR): 670, 812, 824, 991 , 1053, 1114, 1164, 1279, 1302, 1432, 1446, 1513, 1547, 1646, 2754, 2794, 2936, 3073, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H24BrF3N2O2+H]+: 485.10, found: 485.1046. Anal. Calcd for C22H24BrF3N2O2 0.5H2O: C 53.45, H 5.10, N 5.67. Found: C 53.79, H 5.22, N 5.52.
Example 63: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.75 mmol) and following the procedure of Example 18, N-(4-bromo-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (273 mg, 79% yield) was obtained as a yellow oil. IR (ATR): 670, 825, 909, 990, 1054, 1113, 1163, 1279, 1305, 1344, 1446, 1515, 1544, 1646, 2792, 2939, 3075, 3289 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [ C19H20BrF3N2OS+H]+: 461.04, found: 461.0486. Anal. Calcd for C19H20BrF3N2OS: C 59.56, H 5.35, N 6.04. Found: C 49.02, H 3.42, N 5.46.
Example 64: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1- phenethylpiperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethyl)benzyl)-4-carboxamide hydrochloride (250 mg, 0.70 mmol) and following the procedure of Example 40, N-(4-chloro-2-
(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide (44 mg, 13% yield) was obtained as a white crystalline solid, mp 161-162 °C. IR (ATR): 720, 823, 840, 888, 1033, 1051 , 1121 , 1142, 1157, 1257, 1305, 1416, 1454, 1487, 1555, 1635, 2462, 2914, 2949, 3309 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25CIF3N2O]+: 425.1602, found: 425.1602. Anal. Calcd for C22H24CIF3N2O: C 62.19, H 5.69, N 6.59. Found: C 61.96, H 5.68, N 6.38.
Example 65: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4- carboxamide.
From N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.79 mmol) and following the procedure of Example 40, N-(2-chloro-4-cyanobenzyl)-1- phenethylpiperidine-4-carboxamide was obtained as a white crystalline solid (152 mg, 50% yield), mp: 191-192 °C. IR (ATR): 694, 740, 823, 871 , 904, 995, 1023, 1117, 1129, 1230, 1310, 1340, 1392, 1481 , 1536, 1646, 2232, 2765, 2805, 2948, 3066, 3275 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25CIN3O]+: 382.1681 , found: 382.1671.
Example 66: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1- phenethylpiperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) and following the procedure of Example 40, N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide (26 mg, 9% yield) was obtained as a beige crystalline solid, mp 143-144 °C. IR (ATR): 697, 745, 820, 854, 945, 1161 , 1209, 1257, 1430, 1488, 1546, 1642, 1738, 2760, 2806, 2942, 3280 cm’1. HRMS- ESI+ m/z [M+H]+ calcd for [C22H25CIF3N2O2]+: 441.1551 , found: 441.1550. Anal. Calcd for C22H24CIF3N2O2: C 59.93, H 5.49, N 6.35. Found: C 59.91 , H 5.84, N 5.95.
Example 67: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1- phenethylpiperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) and following the procedure of Example 40, N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide was obtained as a beige crystalline solid (58 mg, 20% yield), mp 157-158 °C. IR (ATR): 637, 695, 742, 817, 846, 881 , 936, 995, 1022, 1079, 1122, 1148, 1206, 1252, 1362, 1432, 1485, 1548, 1602, 1645, 2765, 2939, 3027, 3275 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25BrF3N2O2]+: 485.1046, found: 485.1036. Anal. Calcd for C19H20BrF3N2O2S: C 54.44, H 4.98, N 5.77. Found: C 54.49, H 4.88, N 5.43. Example 68: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1- phenethylpiperidine-4-carboxamide.
From N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) and following the procedure of Example 40, N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide was obtained as a beige crystalline solid (115 mg, 48% yield), mp 161-162 °C. IR (ATR): 698, 750, 850, 977, 1030, 1119, 1161 , 1210, 1262, 1413, 1446, 1508, 1544, 1637, 2234, 2445, 2757, 2800, 2923, 3064, 3282 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H25F3N3O2]+: 432.1893, found: 432.1889.
Example 69: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) and following the procedure of Example 13, N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (93 mg, 13% yield), mp 127-128 °C. IR (ATR): 684, 780, 860, 924, 976, 1027, 1122, 1164, 1206, 1263, 1445, 1508, 1546, 1638, 2235, 2765, 2800, 2921 , 3281 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H21BrF4N2O2]+: 489.0795, found: 489.0800. Anal. Calcd for C21H21BrF4N2O2: C 51 .55, H 4.33, N 5.73. Found: C 51 .74, H 4.53, N 5.52.
Example 70: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) and following the procedure of Example 44, N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (50 mg, 17% yield) was obtained as an off-white crystalline solid, mp 127-128 °C. IR (ATR): 667, 760, 821 , 829, 882, 901 , 979, 1015, 1046, 1125, 1161 , 1209, 1281 , 1315, 1363, 1464, 1505, 1635, 2389, 2757, 2793, 2947, 3089, 3258 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21 H22F5N2O]+: 413.1647, found: 413.1651. Anal. Calcd for C21H21F5N2O: C 61.16, H 5.13, N 6.79. Found: C 60.96, H 5.39, N 6.49.
Example 71 : Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (215 mg, 0.60 mmol) and following the procedure of Example 44, N-(4-chloro-2- (trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (101 mg, 39% yield) was obtained as an off-white crystalline solid, mp 121-122 °C. IR (ATR): 683, 767, 782, 824, 841 , 856, 883, 913, 991 , 1053, 1123, 1220, 1276, 1302, 1341 , 1417, 1454, 1508, 1551 , 1636, 2464, 2758, 2798, 2917, 2948, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22CIF4N2O]+: 429.1351 , found: 429.1346. Anal. Calcd for C21H2ICIF4N2O 0.25H2O: C 58.81 , H 4.94, N 6.53. Found: C 58.44, H 5.24, N 6.48.
Example 72: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.79 mmol) and following the procedure of Example 44, N-(2-chloro-4-cyanobenzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide (63 mg, 21% yield) was obtained as a beige crystalline solid, mp 153-154 °C. IR (ATR): 688, 767, 785, 827, 871 , 989, 1051 , 1119, 1220, 1265, 1333, 1391 , 1411 , 1482, 1508, 1556, 1641 , 2236, 2751 , 2939, 3067, 3251 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22CIFN3O]+: 386.1430, found: 386.1426. Anal. Calcd for C21H21CIFN3O 0.25H2O: C 64.61 , H 5.55, N 10.76. Found: C 64.71 , H 5.41 , N 10.54.
Example 73: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) and following the procedure of Example 44, N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (59 mg, 20% yield) was obtained as a beige crystalline solid, mp 103-104 °C. IR (ATR): 786, 822, 946, 993, 1069, 1083, 1125, 1162, 1210, 1250, 1366, 1453, 1487, 1508, 1543, 1644, 2466, 2755, 2793, 2939, 3293 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22CIF4N2O2]+: 445.1300, found: 445.1301. Anal. Calcd for C21H21CIF4N2O2: C 56.70, H 4.76, N 6.30. Found: C 56.76, H 5.02, N 6.13.
Example 74: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) and following the procedure of Example 44, N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (139 mg, 47% yield), mp 112-113 °C. IR (ATR): 712, 761 , 788, 815, 827, 845, 937, 974, 1162, 1202, 1265, 1464, 1484, 1505, 1545, 1601 , 1629, 2401 , 2758, 2793, 2929, 3258 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22BrF4N2O2]+: 489.0795, found: 489.0799. Anal. Calcd for C21H21BrF4N2O2: C 51.55, H 4.33, N 5.73.
Found: C 51.51 , H 4.28, N 5.56.
Example 75: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4- fluorobenzyl)piperidine-4-carboxamide.
From N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) and following the procedure of Example 44, N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (57 mg, 24% yield), mp 121-122 °C. IR (ATR): 648, 712, 807, 827, 874, 972, 1125, 1167, 1212, 1250, 1363, 1424, 1456, 1508, 1637, 1737, 2235, 2447, 2795, 2951 , 3287 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H22F4N3O2 ]+: 436.1643, found: 436.1642. Anal. Calcd for C22H2iF4N3O2 0.25H2O: C 60.69, H 4.86, N 9.65. Found: C 60.38, H 4.71 , N 9.23.
Example 76: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) and following the procedure of Example 19, N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (150 mg, 48%) was obtained as an off-white crystalline solid, mp 112-113 °C. IR (ATR): 666, 696, 821 , 878, 902, 983, 1046, 1125, 1162, 1210, 1316, 1363, 1430, 1505, 1556, 1637, 2390, 2793, 2941 , 3267 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F4N2C>2]+: 425.1847, found: 425.1846. Anal. Calcd for C22H24F4N2O2 0.5H2O: C 60.96, H 5.81 , N 6.46. Found: C 61.08, H 6.18, N 6.20.
Example 77: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.70 mmol) and following the procedure of Example 19, N-(4- chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (289 mg, 94% yield) was obtained as an off-white crystalline solid, mp 129-130 °C. IR (ATR): 783, 819, 881 , 1032, 1054, 1117, 1138, 1165, 1247, 1305, 1423, 1452, 1512, 1551 , 1636, 2468, 2763, 2804, 2818, 2944, 3327 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25CIF3N2O2 ]+: 441.1551 , found: 441.1553. Anal. Calcd for
C22H24CIF3N2O2 0.25H2O: C 59.33, H 5.54, N 6.29. Found: C 59.16, H 5.44, N 6.17. Example 78: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.79 mmol) and following the procedure of Example 19, N-(2-chloro-4-cyanobenzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (34 mg, 11 % yield), mp 129-130 °C. IR (ATR): 682, 813, 830, 912, 991 , 1024, 1185, 1243, 1257, 1302, 1418, 1513, 1541 , 1613, 1645, 2238, 2520, 2755, 2932, 3064, 3328 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25CIN3O2]+: 398.1630, found: 398.1619. Anal. Calcd for C22H24CIN3O2 O.35H2O: C 65.37, H 6.16, N 10.40. Found: C 65.71 , H 6.02, N 10.00.
Example 79: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) and following the procedure of Example 19, N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (65 mg, 21 % yield) was obtained as a beige crystalline solid, mp 116-117 °C. IR (ATR): 735, 812, 822, 948, 993, 1032, 1160, 1212, 1243, 1490, 1512, 1550, 1612, 1644, 2759, 2841 , 2935, 3319 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25CIF3N2O3 ]+: 457.1500, found: 457.1494. Anal. Calcd for C22H24CIF3N2Ch 0.25H2O: C 57.27, H 5.35, N 6.07. Found: C 57.14, H 5.50, N 6.08.
Example 80: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) and following the procedure of Example 19, N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (104 mg, 35% yield), mp 115-116 °C. IR (ATR): 636, 715, 753, 811 , 940, 993, 1033, 1126, 1164, 1213, 1247, 1431 , 1452, 1512, 1551 , 1613, 1640, 2471 , 2759, 2795, 2936, 3322 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25BrF3N2O3]+: 501.0995, found: 501.0998. Anal. Calcd for C22H24BrF3N2O3: C 52.71 , H 4.83, N 5.59. Found: C 52.74, H 4.77, N 4.46.
Example 81 : Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) and following the procedure of Example 18, N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (87 mg, 30% yield) was obtained as an off-white crystalline solid, mp 115-116 °C. IR (ATR): 666, 696, 764, 823, 878, 904, 984, 1016, 1046, 1126, 1164, 1210, 1316, 1364, 1430, 1504, 1554, 1640, 2763, 2803, 2941 , 3271 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [ C19H20F4N2OS]+: 401.1305, found: 401.1316. Anal. Calcd for C19H20F4N2OS: C 56.99%, H 5.03%, N 7.00. Found: C 56.96%, H 5.23%, N 6.65.
Example 82: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.70 mmol) and following the procedure of Example 18, N-(4-chloro-2- (trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (290 mg, 99% yield) was obtained as an beige crystalline solid, mp 131-132 °C. IR (ATR): 682, 765, 820, 841 , 1035, 1052, 1111 , 1138, 1165, 1247, 1305, 1413, 1452, 1635, 2464, 2755, 2815, 2919, 2959, 3298 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C19H2ICIF3N2OS]+: 417.1010, found: 417.1014. Anal. Calcd for C19H20CIF3N2OS- 0.25 H2O: C 54.74, H 4.84, N 6.72. Found: C 54.27, H 5.07, N 6.56.
Example 83: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.80 mmol) and following the procedure of Example 18, N-(2-chloro-4-cyanobenzyl)-1- (thiophen-3-ylmethyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (106 mg, 35% yield), mp 152-153 °C. IR (ATR): 685, 766, 790, 829, 871 , 993, 1022, 1051 , 1119, 1228, 1297, 1322, 1444, 1542, 1643, 2233, 2743, 2779, 2944, 3069, 3258 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C19H21CIN3OS]+: 374.1088, found: 374.1084. Anal. Calcd for C19H20CIN3OS 0.2H2O: C 61.03, H 5.39, N 11.24. Found: C 60.64, H 5.36, N 10.91.
Example 84: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) and following the procedure of Example 18, N-(4-chloro-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (106 mg, 37% yield) was obtained as a beige crystalline solid, mp 126-127 °C. IR (ATR): 769, 788, 849, 945, 1073, 1122, 1158, 1208, 1250, 1431 , 1483, 1547, 1640, 2462, 2750, 2780, 2933, 3296 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [ C19H20CIF3N2O2S]+: 433.0959, found: 433.0953. Anal. Calcd for C19H20CIF3N2O2S 0.25H2O: C 52.72, H 4.66, N 6.47.
Found: C 52.25, H 4.83, N 6.15.
Example 85: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) and following the procedure of Example 18, N-(4-bromo-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (177 mg, 62% yield) was obtained as a beige crystalline solid, mp 113-114 °C. IR (ATR): 711 , 765, 841 , 937, 991 , 1023, 1072, 1156, 1208, 1250, 1362, 1481 , 1556, 1643, 2754, 2780, 2941 , 3080, 3258 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [Ci9H2iBrF3N2O2S]+: 477.0454, found: 477.0452. Anal. Calcd for Ci9H2oBrF3N202S: C 47.81 , H 4.22, N 5.87. Found: C 47.75, H 4.12, N 5.76.
Example 86: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3- ylmethyl)piperidine-4-carboxamide.
From N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) and following the procedure of Example 18, N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (137 mg, 59% yield) was obtained as a beige crystalline solid, mp 127-128 °C. IR (ATR): 674, 775, 789, 859, 974, 1026, 1122, 1158, 1209, 1261 , 1330, 1445, 1508, 1543, 1643, 2234, 2755, 2789, 2921 , 3064, 3283 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2OH2IF3N302S]+: 424.1301 , found: 424.1303. Anal. Calcd for C20H20F3N3O2S: C 56.73, H 4.76, N 9.92. Found: C 56.48, H 4.99, N 9.57.
Example 87: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) and following the procedure of Example 19, N-(4-cyano-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide was obtained as a beige crystalline solid (68 mg, 29% yield), mp 138-139 °C. IR (ATR): 749, 810, 819, 859, 987, 1028, 1120, 1165, 1209, 1242, 1264, 1415, 1508, 1544, 1612, 1640, 2235, 2755, 2790, 2922, 2955, 3062, 3280 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H25F3N3O3 ]+: 448.1843, found: 448.1845. Anal. Calcd for C23H24F3N3O3 0.25H2O: C 61.12, H 5.46, N 9.30. Found: C 60.94, H 5.24, N 9.00. Example 88: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4- iodobenzyl)piperidine-4-carboxamide.
From N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) and following the procedure of Example 47, N-(4-fluoro-2- (trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (163 mg, 43% yield) was obtained as an off-white crystalline solid, mp 161-162 °C. IR (ATR): 693, 744, 798, 828, 883, 906, 988, 1006, 1160, 1112, 1050, 1216, 1281 , 1295, 1318, 1363, 1432, 1480, 1499, 1551 , 1639, 2755, 2781 , 2949, 3285 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C21H22F4IN2O]+: 521.0707, found: 521.0713. Anal. Calcd for C21H2IF4IN2O: C 48.48, H 4.07, N 5.38. Found: C 48.67, H 4.21 , N 5.16.
Example 89: Synthesis of 1-(4-iodobenzyl)-N-(4-methoxy-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
From N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) and following the procedure of Example 47, 1-(4-iodobenzyl)-N-(4- methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (141 mg, 38% yield) was obtained as an off-white crystalline solid, mp 142-143 °C. IR (ATR): 673, 793, 858, 960, 992, 1034, 1106, 1158, 1212, 1245, 1430, 1508, 1547, 1643, 2754, 2811 , 2909, 2932, 3295 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F3IN2O3]+: 549.0856, found: 549.0872. Anal. Calcd for C22H24F3IN2O3: C 48.19, H 4.41 , N 5.11. Found: C 48.19, H 4.67, N 4.89.
Example 90: Synthesis of 1-(4-fluorobenzyl)-N-(4-methoxy-2-
(trifluoromethoxy)benzyl)piperidine-4-carboxamide.
From N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) and following the procedure of Example 44, 1-(4-fluorobenzyl)-N- (4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (91 mg, 30% yield) was obtained as an off-white crystalline solid, mp 109-110 °C. IR (ATR): 663, 789, 826, 862, 959, 993, 1031 , 1106, 1157, 1214, 1243, 1429, 1453, 1509, 1541 , 1623, 1641 , 2758, 2795, 2940, 3298 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C22H25F4N2O3]+: 441.1796, found: 441.1798. Anal. Calcd for C22H24F4N2O3: C 60.00, H 5.49, N 6.36. Found: C 60.01 , H 5.59, N 6.14.
Example 91 : Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4- methoxybenzyl)piperidine-4-carboxamide.
From N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) and following the procedure of Example 19, N-(4-methoxy-2- (trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (97 mg, 32 % yield) was obtained as an off-white crystalline solid, mp 113-114 °C. IR (ATR): 639, 675, 747, 812, 863, 961 , 991 , 1033, 1162, 1213, 1240, 1433, 1453, 1513, 1547, 1640, 2761 , 2799, 2838, 2934, 3290 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C23H28F3N2O4I+: 453.1996, found: 453.1996.
Example 92: Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen- 3-ylmethyl)piperidine-4-carboxamide.
From N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) and following the procedure of Example 18, N-(4-methoxy-2- (trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (157 mg, 54% yield) was obtained as an beige crystalline solid, mp 98-99 °C. IR (ATR): 681 , 765, 786, 815, 962, 988, 1035, 1113, 1155, 1210, 1252, 1439, 1511 , 1548, 1618, 1644, 2781 , 2936, 3076, 3292 cm’1. HRMS-ESI+ m/z [M+H]+ calcd for [C2oH24F3N203S]+: 429.1454, found: 429.1467. Anal. Calcd for C20H23F3N2O3S: C 56.06, H 5.41 , N 6.54. Found: C 55.72, H 5.74, N 6.23.
Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of tert-butyl 4-((4-chloro-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1- carboxylate. To a solution of (4-chloro-2-(trifluoromethyl)phenyl)methanamine (2 g, 9.54 mmol) in EtOAc (115 mL), N-boc-piperidine-4-carboxylic acid (1.98 g, 8.67 mmol), HOBt (1.75 g, 13.01 mmol), EDCI HCI (2.49 g, 13.01 mmol) and triethylamine (2.63 g, 13.01 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Then, water was added (80 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 20 mL) and brine (3 x 20 mL), dried over anh. Na2SO4, filtered and evaporated to give a white solid (4.12 g). Column chromatography (SiC>2, DCM/MeOH mixtures) gave the desired product as a yellowish solid (3.66 g, quantitative yield). b) Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-chloro-2- (trifluoromethyl)benzyl)carbamoyl)piperidine-1 -carboxylate (3.66 g, 8.69 mmol) in DCM (21 mL), 4N HCI in dioxane (21 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide hydrochloride (1 .36 g, 44% yield) as a white solid. IR (ATR): 665, 811 , 826, 842, 894, 913, 1014, 1048, 1107, 1164, 1188, 1227, 1261 , 1302, 1366, 1418, 1429, 1486, 1551 , 1652 cm’1.
Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of tert-butyl 4-((4-chloro-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine- 1 -carboxyl ate. To a solution of (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (1.40 g, 6.20 mmol) in EtOAc (80 mL), N-boc-piperidine-4-carboxylic acid (1.29 g, 5.63 mmol), HOBt (1.14 g, 8.46 mmol), EDCI HCI (1 .62 g, 8.46 mmol) and triethylamine (1 .71 g, 16.92 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 10 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give a white solid (3.0 g). Column chromatography (SiC>2, DCM/MeOH mixtures) gave the desired product as a yellowish solid (2.42 g, 98% yield). b) Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-chloro-2- (trifluoromethoxy)benzyl)carbamoyl)piperidine-1 -carboxylate (2.42 g, 5.54 mmol) in DCM (14 mL), 4N HCI in dioxane (14 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide hydrochloride (1 .85 g, 93% yield) as a white solid. IR (ATR): 638, 666, 708, 821 , 854, 949, 1003, 1071 , 1162, 1211 , 1256, 1429, 1489, 1567, 1654, 2503, 2739, 2808, 2850, 2956, 3299, 3535 cm’1.
Synthesis of N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of 4-(bromomethyl)-3-chlorobenzonitrile. A mixture of 4-methyl-3- chlorobenzonitrile (2.5 g, 16.49 mmol) and 2,2'-azobis(2-methylpropionitrile) (406 mg, 2.47 mmol) in acetic acid (20 mL) was stirred at 40 °C under an argon atmosphere. Then N-bromosuccinimide (2.93 g, 16.49 mol) was added in five batches to the reaction mixture. The resulting mixture was stirred at 75 °C for 3 h. After the completion of the reaction, the mixture was evaporated and extracted with EtOAc (3* 20 mL). Then organic layer was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to yield 4-(bromomethyl)-3-chlorobenzonitrile (3.57 g, 94% yield) as a yellow solid. b) Synthesis of 4-(aminomethyl)-3-chlorobenzonitrile. 4-(Bromomethyl)-3- chlorobenzonitrile (3.57 g, 15.48 mmol) was dissolved in a 7M solution of ammonia in MeOH (62 mL) and stirred at room temperature for 24 h. The solvent was removed under vacuum and EtOAc (15 mL) was added to the resulting crude followed by water. The mixture was basified with NaHCCh solution (15 mL, pH = 10) and the layers were separated. The aqueous layer was further extracted with EtOAc (15 mL). The organic layers were joined, dried over anh. Na2SO4, filtered and evaporated under vacuum to afford 4-(aminomethyl)-3-chlorobenzonitrile (2.48 g, 96% yield) that was used as such without further purification or characterization. c) Synthesis of tert-butyl 4-((2-chloro-4-cyanobenzyl)carbamoyl)piperidine-1- carboxylate. To a solution of 4-(aminomethyl)-3-chlorobenzonitrile (2.48 g, 14.91 mmol) in EtOAc (141 mL), N-boc-piperidine-4-carboxylic acid (3.10 g, 13.55 mmol), HOBt (2.74 g, 20.33 mmol), EDCI HCI (3.89 g, 20.33 mmol) and triethylamine (4.11 g, 40.67 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Then, water was added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCOs solution (3 x 10 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered and evaporated to give a yellow oil (4.69 g). Column chromatography (SiC>2, Hexane/EtOAc mixtures) gave the desired product as a yellowish solid (2.69 g, 53% yield). d) Synthesis of N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((2-chloro-4-cyanobenzyl)carbamoyl)piperidine-1 -carboxylate (2.69 g, 7.12 mmol) in DCM (15 mL), 4N HCI in dioxane (15 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(2-chloro-4- cyanobenzyl)piperidine-4-carboxamide (2.0 g, 89% yield) hydrochloride as a yellowish solid. IR (ATR): 684, 711 , 829, 888, 960, 1008, 1045, 1235, 1305, 1389, 1453, 1561 , 1639, 1737, 2234, 2503, 2725,
Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of (4-bromo-2-(trifluoromethoxy)benzylamine. 4-Bromo-2- (trifluoromethoxy)benzaldehyde (10.0 g, 37.17 mmol) was dissolved in 7M ammonia in MeOH (183 mL) under argon and stirred at room temperature overnight. Afterwards, the reaction was carefully treated with NaBH4 (3.09 mg, 81.77 mmol) and stirred at room temperature for 3 h. The solvents were evaporated and the residue was taken up slowly in 5% HCI solution and washed with Et20 three times. The phases were separated and the aqueous phase was basified with 2N NaOH solution and extracted with DCM (3 x 20 mL). The combined organic phases were dried over anh. Na2SC>4, filtered and concentrated under reduced pressure to give (4-bromo-2-(trifluoromethoxy)benzylamine (3.84 g, 38% yield) as a colorless oil. The product was used in the next step without any further purification or characterization. b) Synthesis of tert-butyl 4-((4-bromo-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine- 1 -carboxyl ate. To a solution of (4-bromo-2-(trifluoromethoxy)phenyl)methanamine (3.84 g, 14.21 mmol) in EtOAc (216 mL), N-boc-piperidine-4-carboxylic acid (2.96 g, 12.92 mmol), HOBt (2.61 g, 19.38 mmol), EDCI HCI (3.72 g, 19.4 mmol) and triethylamine (3.92 mg, 38.8 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Then, water was added (80 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 20 mL) and brine (3 x 20 mL), dried over anh. Na2SO4, filtered and evaporated to give a beige solid (7.15 g). Column chromatography (SiC>2, Hexane/AcOEt mixtures) gave the desired product as a white crystalline solid (5.21 g, 84% yield). c) Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-bromo-2- (trifluoromethoxy)benzyl)carbamoyl)piperidine-1 -carboxylate (2.00 g, 4.15 mmol) in DCM (11 mL), 4N HCI in dioxane (11 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4- carboxamide hydrochloride (1.73 g, quantitative yield) as a white solid. IR (ATR): 635, 694, 761 , 806, 846, 941 , 960, 1008, 1072, 1155, 1199, 1248, 1282, 1452, 1487, 1565, 1597, 1652, 2510, 2735, 2802, 2946, 3092, 3290, 3396, 3511 cm’1.
Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of tert-butyl 4-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1- carboxylate. A mixture of tert-butyl 4-((4-bromo-2- (trifluoromethoxy)benzyl)carbamoyl)piperidine-1 -carboxylate (3.20 g, 6.65 mmol), Zn(CN)2 (780 mg, 6.65 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol) in DMF (43 mL) was degassed for 10 minutes and, then, heated to 90 °C overnight. The reaction mixture was filtered and the resulting filtrate was washed three times with water and extracted with EtOAc. The resulting organic layers were joined, dried over anh. Na2SO4, filtered and concentrated under reduced pressure to give a yellow gummy oil (4.11 g). Column chromatography (SiO2, Hexane/EtOAc mixtures) gave tert-butyl 4-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1- carboxylate (1.51 mg, 53% yield) as a white solid. b) Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-cyano-2- (trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (1.51 g, 3.53 mmol) in DCM (8.25 mL), 4N HCI in dioxane (8.25 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(4-cyano-2- (trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (1.01 g, 79% yield) as a white solid. IR (ATR): 644, 686, 708, 829, 868, 976, 1008, 1071 , 1160, 1202, 1252, 1269, 1295, 1418, 1450, 1565, 1655, 2236, 2511 , 1730, 2802, 2957, 3266, 3471 cm’1.
Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of tert-butyl 4-((4-fluoro-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1- carboxylate. To a solution of (4-fluoro-2-(trifluoromethyl)phenyl)methanamine (2.5 g, 12.94 mmol) in EtOAc (140 mL), N-boc-piperidine-4-carboxylic acid (2.69 g, 11.73 mmol), HOBt (2.38 g, 17.65 mmol), EDCI HCI (3.38 g, 17.65 mmol) and triethylamine (3.57 g, 35.30 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Then, water was added (40 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 20 mL) and brine (3 x 20 mL), dried over anh. Na2SO4, filtered and evaporated to give a beige solid (5.0 g). Column chromatography (SiC>2, Hexane/AcOEt mixtures) gave the desired product as a white crystalline solid (4.74 g, quantitative yield). b) Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-fluoro-2- (trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (4.74 g, 11.73 mmol) in DCM (33 mL), 4N HCI in dioxane (33 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4- carboxamide hydrochloride (3.42 g, 85% yield) as a white solid. IR (ATR): 668, 696, 825, 867, 907, 960, 1008, 1043, 1072, 1120, 1162, 1216, 1259, 1319, 1394, 1432, 1451 , 1493, 1576, 1650, 2510, 2733, 2802, 2838, 2947, 3097, 3261 , 3487 cm’1. Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. a) Synthesis of (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine. To a solution of 4- methoxy-2-(trifluoromethoxy)benzonitrile (2 g, 9.21 mmol) in anh. THF (13 mL) at 0 °C, a solution of UAIH4 in THF (1.04 g, 1 M, 27.63 mmol) was added dropwise. Then, the suspension was stirred at RT for 4 h. The reaction suspension was quenched adding water dropwise under ice-bath until no more bubbling was observed. Then, Na2SC>4 anh. was added and the mixture was filtered through a pad with Celite® using a mixture of EtOAc/MeOH 1/1 (3 x 15 mL) as eluting agent. The solvent was concentrated in vacuo and the resulting crude (1.54 g, 75% yield) was used as such without further purification. b) Synthesis of tert-butyl 4-((4-methoxy-2-
(trifluoromethoxy)benzyl)carbamoyl)piperidine-1 -carboxylate. To a solution of (4- methoxy-2-(trifluoromethoxy)phenyl)methanamine (1.54 g, 6.96 mmol) in EtOAc (86 mL), N-boc-piperidine-4-carboxylic acid (1.45 g, 6.33 mmol), HOBt (1.28 g, 9.49 mmol), EDCI HCI (1.82 g, 9.49 mmol) and triethylamine (1.92 g, 18.98 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Then, water was added (40 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCCh solution (3 x 20 mL) and brine (3 x 20 mL), dried over anh. Na2SO4, filtered and evaporated to give a beige solid. Column chromatography (SiC>2, Hexane/AcOEt mixtures) gave the desired product as a brown crystalline solid (2.06 g, 75% yield). c) Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-methoxy-2- (trifluoromethoxy)benzyl)carbamoyl)piperidine-1 -carboxylate (2.06 g, 4.76 mmol) in DCM (11 mL), 4N HCI in dioxane (11 mL) was added. The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude was triturated in DCM and dried to give N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine- 4-carboxamide hydrochloride (1.40 g, 80% yield) as a white solid. IR (ATR): 648, 709, 744, 849, 877, 926, 970, 991 , 1030, 1075, 1102, 1132, 1152, 1165, 1207, 1245, 1269, 1405, 1443, 1463, 1505, 1522, 1644, 2499, 2705, 2811 , 2926, 3381 cm’1. IN VITRO TESTS OF THE COMPOUNDS OF THE INVENTION
Determination of Kt value of S1 R antagonists
The binding properties of the test compounds to human S1 R were studied in transfected HEK-293 membranes using [3H]-(+)-pentazocine (PerkinElmer, NET-1056) as the radioligand. The assay was carried out with 7 pg of membrane suspension, [3H]-(+)- pentazocine (5 nM) in either absence or presence of either buffer or 10 pM haloperidol for total and nonspecific binding, respectively. Binding buffer contained Tris-HCI (50 mM, at pH 8). Plates were incubated at 37 °C for 120 min. After the incubation period, the reaction mix was transferred to MultiScreen HTS, FC plates (Millipore) were presoaked in 0.1 % polyethylenimine and filtered. Then, plates were washed (3 times) with ice-cold Tris-HCI (10 mM, pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (PerkinElmer) using EcoScint liquid scintillation cocktail.
Determination of IC50 value of sEHIs
The sEH inhibition activity (IC50) can be determined by the following fluorescent assay with a purified recombinant human sEH protein using cyano(6-methoxynaphthalen-2- yl)methyl 2-(3-phenyloxiran-2-yl)methylcarbonate as the substrate (cf. Morisseau, C.; Hammock, B. D. Measurement of soluble epoxide hydrolase (sEH) activity. Curr Protoc Toxicol. 2007, Chapter 4, Unit 4.23.).
The enzyme is incubated at 30 °C with the inhibitor ([l]final = 0.4 - 100,000 nM) for 5 min in 100 mM sodium phosphate buffer (200 pL, pH 7.4) containing 0.1 mg/mL of BSA and 1 % of DMSO. The substrate (CMNPC) is then added ([S]final = 5 pM). Activity is assessed by measuring the appearance of the fluorescent 6-methoxynaphthaldehyde product (Aex = 330 nm, Aem = 465 nm) every 30 seconds for 10 min at 30 °C on a SpectraMax M2 (Molecular Devices).
Results are obtained by regression analysis from a linear region of the curve.
Table 1 below summarizes the obtained results for the tested compounds:
TABLE 1
Results regarding sEH:
The following scale has been adopted for representing the inhibition of human sEH expressed as IC50:
A IC50 (sEH) < 10 nM;
B 10 < IC50 (sEH) < 50 nM;
C 50 < IC50 (sEH) < 100 nM;
D 100 < IC50 (sEH) < 1000 nM;
E IC50 (sEH) > 1000 nM;
Results regarding S1 R:
The following scale has been adopted for representing the binding to S1 R expressed as K\.
A Ki (S1 R) < 50 nM;
B 50 < K (S1 R) < 150 nM;
C 150 < K (S1 R) < 400 nM;
D 400 < Kj (S1R) < 1000 nM;
E K (S1 R) > 1000 nM.
In the case of sEH, it is considered that the compound has negligible inhibitory effect when the IC50 value is higher than 1000 nM. IC50 values between 100-1000 nM indicate that the compound has a low/very low potency for the inhibitory effect. A significant inhibitory effect is considered when the IC50 is below 100 nM; it is considered especially good when the IC50 value is below 50 nM and excellent when IC50 is below 10 nM.
As it can be derived from Table 1 , all the compounds of the invention have IC50 values below 100 nM, providing, at least, a significant inhibitory effect of sEH. It is well-established that a compound has a negligible affinity for S1 R when the Ki value is higher than 1000 nM. When the K value is between 400 and 1000 nM means that the compound has a low affinity. A K value between 150-400 nM means that the compound has a significant affinity for S1 R. K values between 50-150 nM mean that the compounds have high affinity for the receptor and a K below 50 nM means that the compound has a very high affinity.
As it can be derived from Table 1 , all the compounds of the invention have K values below 400 nM, providing, at least, a significant binding effect of the S1 R.
The comparative compounds provided at the end of the table are sEHIs with no significant binding to S1 R (EC5026, AR9281 , compound 8-42, compound 6-26, compound 6-29, and the compounds disclosed in W02007098352) and S1 R ligands (S1 RA, BMY-14802, dextromethorphan, NE-100, BD-1063, PRE-084) inactive in sEH.
Assessment of the antagonist character of the compounds in the S1 R
In order to confirm that the effect of the compounds on S1 R was an antagonistic effect, the following assay was performed.
Rat livers (male Sprague Dawley rats, Envigo RMS S.r.l.) were homogenized in ice- cold phosphate buffer (10 mM, pH 7.4) containing 0.32 M sucrose with a Potter- Elvehjem glass homogenizer. The suspension was centrifuged at 3,000 x g for 10 min at 4 °C. The supernatant was separated and centrifuged at 21 ,100 x g for 60 min at 4 °C. The pellet was resuspended with ice-cold buffer and incubated at RT for 20 min. Then, the suspension was centrifuged at 21 ,100 x g for 30 min at 4 °C. The protein concentration was determined by the method of Bradford.
Binding experiments were carried out incubating 200 pL of membrane preparation with 50 pL of 20 nM [3H](+)-pentazocine (26.9 Ci/mmol, PerkinElmer), 50 pL of cold ligand or its solvent, and 20 pL of 25 mM DPH (Merck Life Science S.r.l.) or its solvent (0.3 M NaOH) for 120 min at 37 °C. The final volume was 0.5 mL. The test compound solutions were prepared by dissolving approximately 10 pmol of test compound in DMSO so that a 10 mM stock solution was obtained. The required test concentrations for the assay (from 10"5 to 10"1° M) have been prepared by diluting the DMSO stock solution with the respective assay buffer. Unlabeled (+)-pentazocine (10 pM) was used to measure nonspecific binding. Bound and free radioligand were separated by fast filtration under reduced pressure using a Millipore filter apparatus through Whatman GF/6 glass fiber filters, which were presoaked in a 0.5% poly(ethyleneimine) water solution for 120 min. Each filter paper was rinsed three times with 3 mL ice-cold Tris buffer (50 mM, pH 8), dried at rt, and incubated overnight with 3 mL scintillation cocktail into pony vials. The bound radioactivity has been determined using a liquid scintillation counter (Beckman LS 6500).
The K-values were calculated with the program GraphPad Prism® 7.0 (GraphPad Software, San Diego, CA, USA). The K-values are given as mean value ± SD from at least two independent experiments performed in duplicate.
The results are provided in FIG. 5. and show that the compounds of the invention present antagonism towards S1 R.
IN VIVO TESTS OF THE COMPOUNDS OF THE INVENTION
In the following section, the different experimental set-ups for carrying out the assays will be described, including the drugs used as well as the experimental models used to assess the analgesic effects in mice.
Test 1 : evaluation of tactile allodynia in an experimental pain model in mice
Animals
Female CD1 mice (Charles River) were used in the experiments. Mice weighing 24-30 g were tested randomly throughout the estrous cycle. They were housed in colony cages with free access to food and water prior to the experiments, and were maintained in temperature- and light-controlled rooms (22 ± 2 °C, lights on at 08:00 h and off at 20:00 h). The experiments were performed during the light phase (from 9:00 h to 16:00 h). Animal care was provided in accordance with institutional (Research Ethics Committee of the University of Granada, Granada, Spain), regional (Junta de Andalucia, Spain) and international standards (European Communities Council directive 2010/63).
Drugs and drug administration
The compound of Example 2 above was used as a prototypic dual S1 R antagonist/ sEHI.
To reverse the effect of S1 R antagonism, the S1 R agonist PRE-084 (2-[4- morpholinethyl]-1 -phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China) was used. This compound is considered to be a selective S1 R agonist (cf. Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66.; Ruiz-Cantero et al., Pharmacol Res. 2021 , 163:105339).
MS-PPOH (N-(methylsulfonyl)-2-(2-propynyloxy)benzenehexanamide) (Cayman Chemicals, Ann Arbor, Michigan, USA), a selective inhibitor of CYP450 epoxygenase which leads to the production of epoxyeicosatrienoic acids (EETs) (cf. Wang et al., J Pharmacol Exp Ther., 1998, 284:966-973) was used to reverse the effect of sEH inhibition.
PRE-084 was dissolved in sterile physiological saline, and Compound of Example 2 was dissolved in 1 % Tween-80 in physiological saline. MS-PPOH was dissolved in 5% DMSO in 40% (2-hydroxypropyl)-p-cyclodextrin in ultrapure water. All drugs were prepared just before administration, and injected subcutaneously (s.c.) in the interscapular area in an injection volume of 5 mL/kg. Compound of example 2 was administered 45 min before the behavioral evaluation. PRE-084 or MS-PPOH were administered 5 min before the administration of compound of example 2 (50 min before the behavioral evaluation).
Experimental model of tactile allodynia in mice and results
The effects of COMPOUND OF EXAMPLE 2 were tested on capsaicin-induced secondary tactile hypersensitivity, which is developed in the area surrounding capsaicin injection and it is known to result from central sensitization, a feature of pathological pain (Baron R, Lancet, 2000, 356:785-7).
The procedure for assessing tactile allodynia was performed as previously described (Entrena et al., Pain, 2009, 143(3):252-261). Briefly, animals were placed into individual test compartments for 2 h to habituate them to the test conditions. The test compartments had black walls and were situated on an elevated mesh-bottomed platform with a 0.5 cm2 grid to provide access to the ventral surface of the hind paws. Then, animals were carefully removed from the compartment to be s.c. injected with the drugs to be tested (see section above), and returned to the compartment. 30 min after drug injection, mice were removed from the compartment again to be injected intraplantarly (i.pl.) with 20 pL of a solution containing 1 pg capsaicin (Sigma-Aldrich Quimica S.A., Madrid, Spain) or its solvent (1% DMSO in physiological saline). Injection was performed into the right hind paw, proximate to the heel, using a 1710 TLL Hamilton microsyringe (Teknokroma, Barcelona, Spain) with a 301/2-gauge needle. Immediately after the i.pl. administration, mice were returned to the compartment. Punctate mechanical stimulation was applied with a Dynamic Plantar Aesthesiometer (Ugo Basile, Varese, Italy) at 15 min after the administration of capsaicin or its solvent. A nonflexible filament (0.5 mm diameter) was electronically driven into the ventral side of the right hind paw, at least 5 mm away from the site of the injection towards the fingers. The intensity of the stimulation was fixed at 0.5 g force. When a paw withdrawal response occurred, the stimulus was automatically terminated, and the response latency was automatically recorded. The filament was applied three times, separated by intervals of 0.5 min, and the mean value of the three trials was considered the withdrawal latency time of the animal. A cut-off time of 50 s was used.
As shown in Fig. 1 , capsaicin administration induced a marked decrease in the paw withdrawal latency in comparison to control nonsensitized mice (dashed lines), denoting the presence of tactile allodynia (compare the point at the 0 mg/kg dose with the dashed lines from nonsensitized control mice value). The administration of COMPOUND OF EXAMPLE 2 (0.625-10 mg/kg, s.c.) dose-dependently increased the paw withdrawal latency in mice up to the value of control nonsensitized mice, indicating that this compound is able to induce marked antiallodynic effects. The s.c. treatment with a dose of 2.5 mg/kg of COMPOUND OF EXAMPLE 2 was enough to induce a prominent increase in paw withdrawal latency in capsaicin-treated mice (75.49% antiallodynic effect) (Fig. 2). The administration of either PRE-084 (32 mg/kg, s.c.) or MS-PPOH (20 mg/kg, s.c.) was able to fully reverse this antiallodynic effect induced by COMPOUND OF EXAMPLE 2 (Fig. 2). These data indicate that both S1 R antagonism and EET accumulation (due to the inhibition of sEH) participate on the antiallodynic effect observed, and therefore COMPOUND OF EXAMPLE 2 induces its in vivo effect on capsaicin-induced tactile allodynia through the interaction of both intended pharmacological targets.
Test 2: evaluation of postoperative pain in mice
Animals
Female CD1 mice (Charles River) were used in the experiments. Mice weighing 24-30 g were tested randomly throughout the estrous cycle. They were housed in colony cages with free access to food and water prior to the experiments, and were maintained in temperature- and light-controlled rooms (22 ± 2 °C, lights on at 08:00 h and off at 20:00 h). The experiments were performed during the light phase (from 9:00 h to 16:00 h). Animal care was provided in accordance with institutional (Research Ethics Committee of the University of Granada, Granada, Spain), regional (Junta de Andalucia, Spain) and international standards (European Communities Council directive 2010/63).
Drugs and drug administration
COMPOUND OF EXAMPLE 2 was used as a prototypic dual S1 R antagonist/ sEHI.
To reverse the effect of sigma-1 antagonism, the S1 R agonist PRE-084 (2-[4- morpholinethyl]-1 -phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China) was used. This compound is considered to be a selective S1 R agonist (Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66.; Ruiz-Cantero et al., Pharmacol Res. 2021 , 163:105339).
MS-PPOH (N-(methylsulfonyl)-2-(2-propynyloxy)benzenehexanamide) (Cayman Chemicals, Ann Arbor, Michigan, USA), a selective inhibitor of CYP450 epoxygenase which leads to the production of epoxyeicosatrienoic acids (EETs) (Wang et al., J Pharmacol Exp Then, 1998, 284:966-973) was used to reverse the effect of sEH inhibition.
PRE-084 was dissolved in sterile physiological saline, and COMPOUND OF EXAMPLE 2 was dissolved in 1 % Tween-80 in physiological saline. MS-PPOH was dissolved in 5% DMSO in 40% (2-hydroxypropyl)-p-cyclodextrin in ultrapure water. All drugs were prepared just before administration, and injected subcutaneously (s.c.) in the interscapular area in an injection volume of 5 mL/kg. PRE-084 or MS-PPOH were administered 5 min before the administration of COMPOUND OF EXAMPLE 2. Mice were evaluated before and at several time-points (60, 120 and 180 min) after drug administration.
Postoperative pain model in mice and results
A baseline mechanical threshold was recorded in the abdomen of mice using a procedure described previously (Gonzalez-Cano et al., Anesthesiology, 2013, 118(3):691— 700). Briefly, forces ranging from 0.02 to 2 g were applied to the abdomen with a series of calibrated von Frey filaments (Touch-Test Sensory Evaluators; North Coast Medical Inc., Gilroy, CA) using the up-down paradigm. Interapplication intervals of 5 s were used. Testing was initiated with the 0.4-g von Frey filament. In each consecutive test, if there was no response to the filament, a stronger stimulus was then selected; if there was a positive response, a weaker one was then used. The response to the filament was considered positive if immediate licking/scratching of the application site, sharp retraction of the abdomen, or jumping was observed. The typical mechanical threshold of naive mice in the abdomen is about 1.7 g (see Baseline -BL- in Fig. 3).
After the determination of the baseline mechanical threshold, a laparotomy was performed according to the previously described protocol in mice (Roughan et al., Eur J Pain, 2016, 20(2):231-40). Mice were anesthetized with isoflurane 3%. An eye ointment was applied during the procedure to prevent irritation of the eyeballs. The abdomen was shaved and aseptically prepared for surgery. A 1.5 cm midline incision of the skin along the linea alba was made, followed by an incision through the peritoneum. The peritoneum was closed with simple interrupted sutures, and muscle layers and skin edges were closed with horizontal mattress sutures. A new threshold determination was performed 2.5 h after the surgical procedure. Mice showed a marked drop of their von Frey threshold (Fig. 3, time 0). Then, COMPOUND OF EXAMPLE 2 (10-40 mg/kg) or their solvent (1 % Tween-80 in physiological saline) were s.c. administered and the mechanical threshold was assessed at 60, 120 and 180 min after drug injection. COMPOUND OF EXAMPLE 2 dose-dependently increased the sensory threshold, in particular at 120 min after drug administration, indicating that this compound is able to induce marked antiallodynic effect on mice after laparotomy (Fig. 3).
The dose of 20 mg/kg of COMPOUND OF EXAMPLE 2 was selected to test for the S1 R and sEHI components in vivo. As shown in Fig. 4, a BL determination was taken. The mice were tested again 2.5 h after laparotomy (time 0). Then, COMPOUND OF EXAMPLE 2 was administered alone or associated with PRE-084 (32 mg/kg, s.c.) or MS-PPOH (20 mg/kg, s.c.). The administration of either PRE-084 or MS-PPOH was able to fully reverse the antiallodynic effect induced by COMPOUND OF EXAMPLE 2. These data indicate that both S1 R antagonism and EET accumulation (due to the inhibition of sEH) participate on the antiallodynic effect observed, and therefore COMPOUND OF EXAMPLE 2 induces its in vivo effect on postoperative pain through the interaction of both intended pharmacological targets.
Clauses:
For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:
Clause 1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treatment or prevention of pain, wherein: R1 is selected from the group consisting of: CN, halogen, (C1-C10)haloalkyl, -O-(C1- C10)alkyl, and -O-(C1-C10)haloalkyl;
R2 to R4 are the same or different and are independently selected from the group consisting of: H; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1- C10)alkyl substituted with one or more Sui; (C2-C10)alkenyl substituted with one or more SU2; (C2-C10)alkynyl substituted with one or more SU3; -0-(C1-C10)alkyl; -O-(C1-C10)alkyl substituted with one or more SU4; -O-(C1-C10)haloalkyl; -O-(C1-C10)haloalkyl substituted with one or more Sus; -SFs, -S(O)2Rg; -NR10R11; aryl; and heteroaryl. R5 is CRxR’x, being Rx and R’x the same or different and are independently selected from -H, (C1-C5)alkyl or (C1-C5)haloalkyl; or, alternatively, Rx and R’x together with the C atom to which they are attached, form a ring having from 3 to 6 members; R6 is an aromatic known ring system, which is selected from the group consisting of: an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRy, and N; Ry being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more Sus; (C2-C10)alkenyl substituted with one or more Su?; (C2-C10)alkynyl substituted with one or more Sus; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; SFs; S(O)2R1a; NR14R15; CONRsR’s; and COOR24; an aromatic 5-membered ring system, wherein the members are selected from the group consisting of: CRZ, S, N, NH, and O; Rz being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; SFs; S(O)2R17; NR1sR1g; CONR12R 12; and COOR24; an aromatic fused ring system consisting of two rings, each one of the aromatic rings having 6 members selected from CH or N; and an aromatic fused ring system of formula (XI) wherein Rn to Rtg are selected from N, NRP, or CR’P; Rp being selected from the group consisting of H, (C1-C10)haloalkyl, S(O)2Rtw, CONRtuR’tn, and C00R’n2; and R’p being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; O-(C1- C10)alkyl; -0-(C1-C10)haloalkyl; SFs; S(O)2R’I?; NR’isR’ig; CONR-isR’is; and COOR25; R? is CRvR’v, being Rv and R’v the same or different and are independently selected from H, (C1-C5)alkyl, or (C1-C5)haloalkyl; or, alternatively, Rv and R’v together with the C atom to which they are attached, form a ring having from 3 to 6 members;
Rs and R’s are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;
R9, R13, R17 and Rtw are selected from the group consisting of: (C1-C10)alkyl; (C3- C8)cycloalkyl; aryl; and heteroaryl;
R10 and R11 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl;
R12 and R’12 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; and (C3-C8)cycloalkyl;
R14 and R15 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R2i;
R16 and R’16 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; and (C3-C8)cycloalkyl; R1s and R19 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R22;
R’18 and R’19 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C3-C8)cycloalkyl; (C1-C10)haloalkyl; and -S(O)2R23;
Rtw and R’tw are the same or different and are selected from the group consisting of: - H, (C1-C10)alkyl; (C3-C8)cycloalkyl; (C1-C10)haloalkyl; and -S(O)2Rti3;
R21 to R23 and Rti3 are selected from the group consisting of (C1-C10)alkyl; (C3- C8)cycloalkyl; or (C1-C10)haloalkyl;
R24, R25, and R’n2 are selected from the group consisting of -H, (C1-C10)alkyl; (C3- C8)cycloalkyl; and (C1-C10)haloalkyl; m is an integer value selected from 0, 1 or 2; n is an integer value selected from 1 or 2;
“aryl” means an aromatic ring system comprising 6 CRc members, being Rc selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, or -O-(C1- Cs)haloalkyl; “heteroaryl” means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl;
Sui to Su8 are independently selected from the group consisting of: halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1- C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3- C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl. provided that at least one of R2 to R4 is other than H.
Clause 2. The compound for use according to clause 1 , wherein
Ry is selected from the group consisting of: H; OH; CN; halogen; (C1-C10)alkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- Ce)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1- C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl; (C2-C10)alkenyl substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1- Ce)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1- C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl; (C2-C10)alkynyl substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1- Ce)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1- C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl; (C1-C10)haloalkyl; -0-(C1-C10)alkyl; -O- (C1-C10)haloalkyl; SF5; S(O)2R13; NR14R15; and COOR24;
R’P is selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -O- (C1-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2R’I?; NR’isR’ig; and COOR25; Rz is selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -O- (C1-C10)alkyl; -0-(C1-C10)haloalkyl; SFs; S(O)2RI?; NR18R19; and COOR24;
R9, R13, and R17 represent (C1-C10)alkyl; and (C3-C8)cycloalkyl; R1s and R19 are the same or different and are selected from the group consisting of: H, (C1-C10)alkyl; (C3-C8)cycloalkyl; and (C1-C10)haloalkyl;
R’18 and R’19 are the same or different and are selected from the group consisting of: H, (C1-C10)alkyl; (C3-C8)cycloalkyl; and (C1-C10)haloalkyl; and
R23 and R24 are selected from the group consisting of H, and (C1-C10)alkyl; and (C3- C8)cycloalkyl.
Clause 3. The compound for use according to any one of the clauses 1-2, which is one of formula (Ibis): wherein R1 to R3 and R6 and n are as defined in clause 1.
Clause 4. The compound for use according to any one of the preceding clauses, wherein R2 is selected from the group consisting of: H, CN; halogen; -0-(C1-C10)alkyl; -O-(C1- C10)haloalkyl; and (C1-C10)haloalkyl.
Clause 5. The compound for use according to any one of the preceding clauses, wherein R3 is selected from the group consisting of: H; CN; halogen; -0-(C1-C10)alkyl; -O-(C1- C10)haloalkyl; SFs; S(O)2Rg, wherein R9 is as defined above; particularly R9 is selected from (C1-C10)alkyl or aryl; particularly R9 is selected from (C1-C10)alkyl.
Clause 6. The compound for use according to any one of the preceding clauses, wherein R6 is an aromatic 5- or 6-membered ring system, as defined in clause 1 .
Clause 7. The compound for use according to any one of the preceding clauses, wherein R6 is an aromatic 6-membered ring system selected from the group consisting of a system of formula (II) and of formula (III): wherein
Rya to Ryeare the same or different and are selected from the group consisting of: H; OH; CN; halogen; nitro; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more Sus; (C2-C10)alkenyl substituted with one or more Sug; (C2- C10)alkynyl substituted with one or more Su™; -0-(C1-C10)alkyl; -0-(C1-C10)haloalkyl; - SF5; and -S(O)2R26; particularly Rya to Ryeare the same or different and are selected from the group consisting of: H, halogen, (C1-C10)alkyl,-0-(C1-C10)alkyl, and COOR24;
R26 is selected from the group consisting of: (C1-C10)alkyl; (C3-C8)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl; and heteroaryl; and
Su8 to Suw are independently selected from the group consisting of: halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1- Ce)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1- Ce)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1- C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl.
Clause 8. The compound for use according to any one of the preceding clauses 1 to 6, wherein R6 is an aromantic 5-membered ring system of formula (IV):
Clause 9. The compound for use according to any one of the preceding clauses, wherein R1 is selected from the group consisting of: halogen; -O-(C1-C10)haloalkyl; and (C1- C10)haloalkyl.
Clause 10. The compound for use according to any one of the preceding clauses, wherein R2 is selected from the group consisting of: H; halogen; and (C1-C10)haloalkyl. Clause 11. The compound for use according to preceding clause, wherein R2 represents H.
Clause 12. The compound for use according to any one of the preceding clauses, wherein R3 is selected from the group consisting of: H, CN; halogen; -0-(C1-C10)alkyl; - O-(C1-C10)haloalkyl; and SF5.
Clause 13. The compound for use according to the preceding clause, wherein R3 represents H.
Clause 14. The compound for use according to any one of the preceding clauses 1-12, wherein:
R1 is selected from the group consisting of halogen, CN, -0-(C1-C10)alkyl, (C1- C10)haloalkyl, and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -0-(C1-C10)alkyl, -O-(C1- C10)haloalkyl, -SF5, and -S(O)2Rg; and R6 is selected from the group consisting of:
(a) an aromatic 6-membered ring system, wherein the members are CRy, and each Ry is independently selected from the group consisting of: H; halogen; nitro; CN; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1-C5)alkyl; -O-(C1-C5)haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1-C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
(b) an aromatic 6-membered ring system, wherein one of the members is N and the remaining members are CRy, Ry being as defined in preceding clauses; particularly, it corresponds to the system of formula (III) as defined in clause 7; and
(c) an aromatic 5-membered ring system wherein the members are selected from CRZ, N, and S, provided that at least one of the members is S; particularly, it corresponds to the system of formula (IV) as defined in clause 8.
Clause 15. The compound for use according to any of the preceding clauses, wherein:
R1 is selected from the group consisting of halogen; -0-(C1-C10)alkyl; (C1-C10)alkyl substituted with one or more halogen atoms; and -O-(C1-C10)haloalkyl; and
R3 is selected from the group consisting of CN, -0-(C1-C10)alkyl, -O-(C1-C10)haloalkyl, and halogen. Clause 16. The compound for use according to any of the preceding clauses, wherein:
In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below: R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted with one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 is H; and
R3 is selected from the group consisting of CN, -0-(C1-C10)alkyl, -O-(C1-C10)haloalkyl, and halogen.
Clause 17. The compound for use according to any of the preceding clauses, wherein:
R1 is selected from the group consisting of halogen, (C1-C10)haloalkyl, and -O-(C1- C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -O-(C1-C10)haloalkyl, and -O- (C1-C10)alkyl; and R6 is selected from the group consisting of:
(a) an aromatic 6-membered ring system, wherein the members are CRy, and each Ry is independently selected from the group consisting of: H; halogen; nitro; CN; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1-C5)alkyl; -O-(C1-C5)haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1-C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
(b) an aromatic 6-membered ring system, wherein one of the members is N and the remaining members are CRy, Ry being as defined in preceding clauses; particularly, it corresponds to the system of formula (III) as defined above; and
(c) an aromatic 5-membered ring system wherein the members are selected from CRZ, N, and S, provided that at least one of the members is S; particularly, it corresponds to the system of formula (IV) as defined above.
Clause 18. The compound for use according to any of the preceding clauses, wherein:
R1 is selected from the group consisting of halogen, (C1-C10)haloalkyl; and -O-(C1- C10)haloalkyl;
R2 is selected from the group consisting of halogen and (C1-C10)haloalkyl; R3 represents -H; and R6 is a 6-membered aromatic ring system is a ring of formula (II) as defined in clause 7; particularly R6 represents phenyl.
Clause 19. The compound for use according to any of the preceding clauses, wherein:
R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted by one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -O-(C1-C10)haloalkyl, and -O- (C1-C10)alkyl; and R6 is a 6-membered aromatic ring system is a ring of formula (II) as defined above, wherein Ry is selected from the group consisting of: H; halogen; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1-C5)alkyl; -O-(C1-C5)haloalkyl; and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1-C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
Clause 20. The compound for use according to any of the preceding clauses, wherein:
R1 is selected from the group consisting of halogen; (C1-C10)alkyl substituted by one or more halogen atoms; and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -O-(C1-C10)haloalkyl, and -O- (C1-C10)alkyl; and R6 is a ring of formula (IV) as defined above.
Clause 21. The compound for use according to any one of the preceding clauses, wherein the pain is post-operative pain; a pain induced by tissue damage; pain associated to inflammation, cancer pain; articular pain; chronic pain or any other pain condition involving allodynia and/or hyperalgesia.
Clause 22. A compound selected from the group consisting of: a compound of formula (I’): a compound of formula (Ibis) as defined in clause 3, or a pharmaceutically salt thereof, solvate or prodrug thereof, wherein R1, R2, R3, R4, R6, and R7, m and n are as defined in any of the preceding clauses, and R5’ represents CRfR’f, wherein Rf and R’f are the same or different and are selected from the group consisting of: H and (C1-C5)haloalkyl; or, alternatively, Rf and R’f, together with the C atom to which they are attached, form a ring having from 3 to 6 members provided that: at least one of R2 to R4 is other than hydrogen; R6 is other than a ring of formula (i): when R1 and R4 are the same and represent a -O-(C1-C10)alkyl or halogen; R2 and R3 are H; m= n=1 ; R5 is -CH2- and R7= -CH2- or CH(CH3)-; then R6 is other than: an aromatic 6-membered ring system, wherein all 6 members are CRy, as defined in claim 9, and a furyl; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 or 2; and R5=R7= -CH2-; then R6 is other than phenyl; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 ; and R5=R7= -CH2-; then R6 is other than a ring of formula (ii): wherein Ri= Me or Et; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m=1 ; n=1 ; and R5= R7= -CH2-; then R6 is other than phenyl substituted by a (C1-C10)alkyl or one or more halogens; when R1 and R3 are Cl; m=n= 1 ; R2=R4= H; and R5=R7= -CH2-; then R6 is other than a phenyl ring, a phenyl ring substituted with (C1-C10)alkyl, a meta-O-(C1-C10)alkyl, or one or more halogens, or a naphthalenyl ring; when R1 and R3 are the same or different and represent halogen; R2=R4= H; m=n=1 , and R5=R7= -CH2-; and R6 is one of formula (VI) or (VII) then Rzi to Rzs are H; and when R1 and R3 are the same or different and represent halogen; R2=R4= H; m=n=1 , and R5=R7= -CH2-; and R6 is one of formula (XI) as defined in clause 1 , then Rp is H; when R1 and R3 are F; R2=R4= H; m=1 ; n=2, and R5=R7= -CH2-; then R6 is other than a 1/7-pyrrolo[2,3-b]pyridin-3-yl ring; and when R1 is ethoxy; R2=Rs= H; R4 is methyl; m=0; n=1 ; and R5=R7= -CH2-; then R6 is other than a phenyl ring.
Clause 23. The compound of clause 22, which is of formula (Ibis), R2 represents H, and R3 is as defined in any of the preceding clauses, provided that it is other than hydrogen.
Clause 24. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof, as defined in any of the clauses 22-23, together with one or more pharmaceutically acceptable salts.
Clause 25. A compound as defined in any one of the clauses 23-24 for use in therapy.
Clause 26. The compound for use according to any one of the preceding clauses 1-21 or 25, the compound according to any one of the clauses 22-23 or the pharmaceutical composition according to clause 24, wherein the compound is selected from the group consisting of:
1-benzyl- N-(2-fluoro-4-(pentafluoro-A6-sulfanyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-3-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide; and
1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4- carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide;
1-(4-chlorobenzyl)-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-(4-chlorobenzyl)-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4- carboxamide; N-(2,4-dichlorobenzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; 1-(4-iodobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-(4-fluorobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide; N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4- carboxamide; N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide, or a pharmaceutically acceptable salt, solvate or prodrug.
Clause 27. The compound 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide for use in the treatment or prevention of pain.
Clause 28. A process for preparing a compound of formula (I) as defined in any of the preceding clauses, wherein the process comprises the coupling reaction between:
- a compound of formula (VIII), either as a free base or in the form of a pharmaceutically acceptable salt in the presence of an amide coupling reagent and a base, wherein R1 to R?, n and m are as defined in any of the preceding clauses.
Clause 29. A process for preparing a compound of formula (I) as defined in any of the preceding clauses, which comprises the step of subjecting a compound of formula (X): (X) to a reductive alkylation with a benzaldehyde of formula (XI), in the presence of a reductor agent; or, alternatively, to a nucleophilic substitution with an alkylaryl halide of formula (XII) in the presence of a base, wherein “Hal” represents halogen, and R1 to R7, m and n are as defined in the preceding clauses, and w is 0 or 1.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treatment or prevention of pain, wherein: R1 is selected from the group consisting of: CN, halogen, (C1-C10)haloalkyl, -O-(C1- C10)alkyl, and -O-(C1-C10)haloalkyl;
R2 to R4 are the same or different and are independently selected from the group consisting of: H; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1- C10)alkyl substituted with one or more Sui; (C2-C10)alkenyl substituted with one or more SU2; (C2-C10)alkynyl substituted with one or more SU3; -0-(C1-C10)alkyl; -O-(C1-C10)alkyl substituted with one or more SU4; -O-(C1-C10)haloalkyl; -O-(C1-C10)haloalkyl substituted with one or more Sus; -SF5, -S(O)2Rg; -NR10R11; aryl; and heteroaryl. R5 is CRxR’x, being Rx and R’x the same or different and are independently selected from -H, (C1-C5)alkyl or (C1-C5)haloalkyl; or, alternatively, Rx and R’x together with the C atom to which they are attached, form a ring having from 3 to 6 members; R6 is an aromatic known ring system, which is selected from the group consisting of: a) an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRy, and N; Ry being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more Sue; (C2-C10)alkenyl substituted with one or more Su?; (C2-C10)alkynyl substituted with one or more Sus; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; SF5; S(O)2R13; NR14R15; CONRsR’s; and COOR24; b) an aromatic 5-membered ring system, wherein the members are selected from the group consisting of: CRZ, S, N, NH, and O; Rz being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(C1-C10)haloalkyl; SFs; S(O)2R17; NR18R19; CONR12R 12; and COOR24; c) an aromatic fused ring system consisting of two rings, each one of the aromatic rings having 6 members selected from CH or N; and d) an aromatic fused ring system of formula (XI) wherein Rn to Rt9 are selected from N, NRP, or CR’P; Rp being selected from the group consisting of H, (C1-C10)haloalkyl, S(O)2Rtw, CONRtuR’tn, and COOR’n2; and R’p being selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; O-(C1- C10)alkyl; -0-(C1-C10)haloalkyl; SFs; S(O)2R’17; NR’isR’19; CONR-isR’is; and COOR25;
R? is CRvR’v, being Rv and R’v the same or different and are independently selected from H, (C1-C5)alkyl, or (C1-C5)haloalkyl; or, alternatively, Rv and R’v together with the C atom to which they are attached, form a ring having from 3 to 6 members;
Rs and R’s are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;
R9, R13, R17 and Rtw are selected from the group consisting of: (C1-C10)alkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;
R10 and R11 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl;
R12 and R’12 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; and (C3-C8)cycloalkyl;
R14 and R15 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R2i;
R16 and R’16 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; and (C3-C8)cycloalkyl; R1s and R19 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C1-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R22; R’18 and R’19 are the same or different and are selected from the group consisting of: -H, (C1-C10)alkyl; (C3-C8)cycloalkyl; (C1-C10)haloalkyl; and -S(O)2R23;
Rtw and R’tw are the same or different and are selected from the group consisting of: - H, (C1-C10)alkyl; (C3-C8)cycloalkyl; (C1-C10)haloalkyl; and -S(O)2Rti3;
R21 to R23 and Rti3 are selected from the group consisting of (C1-C10)alkyl; (C3- C8)cycloalkyl; or (C1-C10)haloalkyl;
R24, R25, and R’n2 are selected from the group consisting of -H, (C1-C10)alkyl; (C3- C8)cycloalkyl; and (C1-C10)haloalkyl; m is an integer value selected from 0, 1 or 2; n is an integer value selected from 1 or 2;
“aryl” means an aromatic ring system comprising 6 CRc members, being Rc selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, or -O-(C1- Cs)haloalkyl;
“heteroaryl” means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl;
Sui to Su8 are independently selected from the group consisting of: halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1- C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3- C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl. provided that at least one of R2 to R4 is other than H.
2. The compound for use according to claim 1 , which is one of formula (Ibis): wherein R1 to R3, R6 and n are as defined in claim 1.
3. The compound for use according to any one of the preceding claims, wherein R2 is selected from the group consisting of: H, CN; halogen; -0-(C1-C10)alkyl; -O-(C1- C10)haloalkyl; and (C1-C10)haloalkyl.
4. The compound for use according to any one of the preceding claims, wherein R3 is selected from the group consisting of: H; CN; halogen; -0-(C1-C10)alkyl; -O-(C1- C10)haloalkyl; SF5; S(O)2Rg, wherein R9 is as defined above; particularly R9 is selected from (C1-C10)alkyl or aryl; particularly R9 is selected from (C1-C10)alkyl.
5. The compound for use according to any one of the preceding claims, wherein R6 is an aromatic 5- or 6-membered ring system, as defined in claim 1.
6. The compound for use according to any one of the preceding claims, wherein R6 is an aromatic 6-membered ring system selected from the group consisting of a system of formula (II) and of formula (III): wherein
Rya to Ryeare the same or different and are selected from the group consisting of: H; OH; CN; halogen; nitro; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (C1-C10)alkyl substituted with one or more Sus; (C2-C10)alkenyl substituted with one or more Sug; (C2- C10)alkynyl substituted with one or more Su™; -0-(C1-C10)alkyl; -0-(C1-C10)haloalkyl; - SF5; and -S(O)2R26; particularly Rya to Ryeare the same or different and are selected from the group consisting of: H, halogen, (C1-C10)alkyl,-0-(C1-C10)alkyl, and COOR24;
R26 is selected from the group consisting of: (C1-C10)alkyl; (C3-C8)cycloalkyl; (C2- C10)alkenyl; (C2-C10)alkynyl; aryl; and heteroaryl; and
Su8 to Suw are independently selected from the group consisting of: halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N- methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl.
7. The compound for use according to any one of the preceding claims, wherein R2 represents -H.
8. The compound for use according to any one of the preceding claims 1-6, wherein R3 represents -H.
9. The compound for use according to any one of the preceding claims, wherein:
R1 is selected from the group consisting of halogen, CN, -0-(C1-C10)alkyl, (C1- C10)haloalkyl, and -O-(C1-C10)haloalkyl;
R2 represents H;
R3 is selected from the group consisting of -CN, halogen, -0-(C1-C10)alkyl, -O- (C1-C10)haloalkyl, -SF5, and -S(O)2Rg; and R6 is selected from the group consisting of:
(a) an aromatic 6-membered ring system, wherein the members are CRy, and each Ry is independently selected from the group consisting of: H; halogen; nitro; CN; (C1-C5)alkyl; (C1-C5)alkyl substituted with one or more halogens; -O-(C1- Cs)alkyl; -O-(C1-C5)haloalkyl; -SF5; -S(O)2Rg, -NR10R11, and -COOR23; particularly each Ry is independently selected from the group consisting of: H; halogen; (C1- C5)alkyl; -O-(C1-C5)alkyl; and -COOH;
(b) an aromatic 6-membered ring system, wherein one of the members is N and the remaining members are CRy, Ry being as defined in preceding claims; particularly, it corresponds to the system of formula (III) as defined in claim 7; and
(c) an aromatic 5-membered ring system wherein the members are selected from CRZ, N, and S, provided that at least one of the members is S; particularly, it corresponds to the system of formula (IV): or, alternatively,
R1 is selected from the group consisting of halogen; -0-(C1-C10)alkyl; (C1-C10)alkyl substituted with one or more halogen atoms; and -O-(C1-C10)haloalkyl; and
R3 is selected from the group consisting of CN, -0-(C1-C10)alkyl, -O-(C1- C10)haloalkyl, and halogen. or, alternatively, R1 is selected from the group consisting of halogen, (C1-C10)haloalkyl; and -O- (C1-C10)haloalkyl;
R2 is selected from the group consisting of halogen and (C1-C10)haloalkyl;
R3 represents -H; and R6 is a 6-membered aromatic ring system is a ring of formula (II) as defined in claim 7; particularly R6 represents phenyl.
10. The compound for use according to any one of the preceding claims, wherein the pain is post-operative pain; a pain induced by tissue damage; pain associated to inflammation, cancer pain; articular pain; chronic pain or any other pain condition involving allodynia and/or hyperalgesia.
11. A compound selected from the group consisting of: a compound of formula (I’): a compound of formula (Ibis) as defined in claim 2, or a pharmaceutically salt, solvate or prodrug thereof, wherein
R1, R2, R3, R4, R6, R7, m and n are as defined in any of the preceding claims 1-9, and R5’ represents CRfR’f, wherein Rf and R’f are the same or different and are selected from the group consisting of: H and (C1-C5)haloalkyl; or, alternatively, Rf and R’f, together with the C atom to which they are attached, form a ring having from 3 to 6 members provided that: at least one of R2 to R4 is other than hydrogen; R6 is other than a ring of formula (i): when R1 and R4 are the same and represent a -O-(C1-C10)alkyl or halogen; R2 and R3 are H; m= n=1 ; R5 is -CH2- and R?= -CH2- or CH(CH3)-; then Rs is other than: an aromatic 6-membered ring system, wherein all 6 members are CRy, as defined in claim 9, and a furyl; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 or 2; and R5= R7= -CH2-; then Rs is other than phenyl; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 ; and R5= R7= -CH2-; then Rs is other than a ring of formula (ii): wherein Ri= Me or Et; when R1 to R3 are the same and represent a -0-(C1-C10)alkyl; R4 is H; m= 1 ; n= 1 ; and R5= R7= -CH2-; then Rs is other than phenyl substituted by a (C1-C10)alkyl or one or more halogens; when R1 and R3are Cl; m=n= 1 ; R2=R4= H; and R5=R7= -CH2-; then Rs is other than a phenyl ring, a phenyl ring substituted with (C1-C10)alkyl, a meta-O-(C1-C10)alkyl, or one or more halogens, and a naphthalenyl ring; when R1 and R3 are the same or different and represent halogen; R2=R4= H; m=n=1 , and R5= R7= -CH2-; and Rs is one of formula (VI) or (VII) then Rz1 to Rz5 are H; and when R1 and R3 are the same or different and represent halogen; R2=R4= H; m=n=1 , and R5= R7= -CH2-; and R6 is one of formula (XI) as defined in claim 1 , then Rp is H; when R1 and R3 are F; R2=R4= H; m=1 ; n=2, and R5= R7= -CH2-; then R6 is other than a 1 /7-pyrrolo[2,3-jb]pyridin-3-yl ring; and when R1 is ethoxy; R2=R3= H; R4 is methyl; m = 0; n = 1 ; and R5 = R7 = -CH2-; then R6 is other than a phenyl ring.
12. The compound of claim 11 , which is of formula (Ibis), R2 represents H, and R3 is as defined in any of the preceding claims, provided that it is other than hydrogen.
13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I’), (Ibis), or a pharmaceutically salt thereof, as defined in any one of the claims 11-12, together with one or more pharmaceutically acceptable salts.
14. A compound as defined in any one of the claims 11-12 for use in therapy.
15. The compound for use according to any one of the preceding claims 1-9 or 14, the compound according to any one of the claims claim 11-12 or the pharmaceutical composition according to claim 13, wherein the compound is selected from the group consisting of:
1-benzyl-N-(2-fluoro-4-(pentafluoro-A6-sulfanyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-3-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide; and
1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(3-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide; 1-benzyl-N-(3-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4-carboxamide;
1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4- carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide;
1-(4-chlorobenzyl)-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide;
1-(4-chlorobenzyl)-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide; N-(2,4-dichlorobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4- carboxamide; N-(2,4-dichlorobenzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide; N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide; N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide; N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide;
1-(4-iodobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide;
1-(4-fluorobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide; N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4- carboxamide; N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4- carboxamide, or a pharmaceutically acceptable salt, solvate or prodrug; or, alternatively, the compound 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide, or a pharmaceutically acceptable salt, solvate or prodrug, for use in the treatment or prevention of pain.
EP23806325.9A 2022-11-18 2023-11-17 Dual inhibitors of sigma-1 receptor and soluble epoxide hydrolase and their use in the treatment of pain Pending EP4618985A1 (en)

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WO2007098352A2 (en) 2006-02-16 2007-08-30 Boehringer Ingelheim International Gmbh Substituted pyridineamide compounds useful as soluble epoxide hydrolase inhibitors
PT2214487E (en) 2007-10-11 2014-02-20 Glaxosmithkline Llc Novel seh inhibitors and their use
US8642660B2 (en) * 2007-12-21 2014-02-04 The University Of Rochester Method for altering the lifespan of eukaryotic organisms
US20100311776A1 (en) 2008-01-30 2010-12-09 Smithkline Beecham Corporation Novel sEH Inhibitors and their Use
FI120985B (en) 2008-02-07 2010-05-31 Pekka Leskinen A device for evenly distributing flow with two or more objects
WO2010042225A2 (en) * 2008-10-10 2010-04-15 Dana Farber Cancer Institute Chemical modulators of pro-apoptotic bax and bcl-2 polypeptides
WO2010080183A1 (en) * 2009-01-08 2010-07-15 The Trustees Of Columbia University In The City Of New York Potent non-urea inhibitors of soluble epoxide hydrolase
WO2010096722A1 (en) 2009-02-20 2010-08-26 Takeda Pharmaceutical Company Limited 3-oxo-2, 3-dihydro- [1,2, 4] triazolo [4, 3-a]pyridines as soluble epoxide hydrolase (seh) inhibitors

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