CN112759587A - 3- (dimethylamino methyl) piperidine-4-alcohol derivative and preparation method and pharmaceutical application thereof - Google Patents

3- (dimethylamino methyl) piperidine-4-alcohol derivative and preparation method and pharmaceutical application thereof Download PDF

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CN112759587A
CN112759587A CN201911076925.3A CN201911076925A CN112759587A CN 112759587 A CN112759587 A CN 112759587A CN 201911076925 A CN201911076925 A CN 201911076925A CN 112759587 A CN112759587 A CN 112759587A
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methyl
dimethylamino
hydroxy
methoxyphenyl
piperidin
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CN112759587B (en
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付伟
黄火明
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Fudan University
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Fudan University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides a compound of Formula (FWBE) or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical use thereof,

Description

3- (dimethylamino methyl) piperidine-4-alcohol derivative and preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the field of pharmacy, and relates to a 3- (dimethylaminomethyl) piperidin-4-ol derivative with a general Formula (FWBE) or a salt thereof, a preparation method thereof, and application of the compound in treating diseases mediated by opioid receptors.
Background
Pain is a common symptom occurring in the course of various diseases, is one of the main problems troubling patients, and is listed as the fifth vital sign following body temperature, pulse, respiration and blood pressure. At present, opioid analgesics, such as morphine, fentanyl, etc., have irreplaceable effects in the treatment of pain. However, the long-term use of the medicine can cause adverse reactions such as drug resistance, addiction, withdrawal reaction, respiratory depression and the like. Tramadol is an artificially synthesized opioid central system analgesic developed in 1977 by the Gr ü nenthal company under the trade name tramal. It is a relatively weak mu opioid receptor agonist (K at the mu opioid receptor)i＝2400nM，EC50> 1000nM) and inhibits reuptake of 5-hydroxytryptamine and norepinephrine. It is metabolized primarily by the liver and is almost completely excreted by the kidneys. Tramadol is an atypical opioid, is different from other traditional opioid drugs, has unique pharmacological characteristics, has strong analgesic effect and few adverse reactions, and is widely applied to pain treatment. However, clinical application shows that the analgesic effect of tramadol is slightly weaker than that of analgesics such as morphine and fentanyl. In addition, tramadol also has side effects such as respiratory depression, addiction, nausea, diarrhea, headache, dizziness, somnolence and constipation. The long-term administration of the medicine can also cause withdrawal reactions such as sweating, anxiety, poor sleep, pain, trembling and the like. In addition, there are studies that indicate that the use of tramadol is associated with an increased risk of hyponatremia and hypoglycemia that requires hospitalization. Therefore, there is a need for the development of analgesics with stronger analgesic effect and less side effects.
Disclosure of Invention
The present invention provides a compound represented by Formula (FWBE), or a pharmaceutically acceptable salt thereof:
Figure BDA0002262756560000011
wherein the content of the first and second substances,
R1selected from C1-6 alkyl, cycloalkyl, chain alkenyl, cycloalkenyl, substituted or unsubstituted aryl C1-6 alkyl;
R2selected from substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylcycloalkyl, wherein the substituents can be selected from aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl;
n is 0, 1, or 2.
In a preferred embodiment, R1Is methyl.
In preferred embodiments, the aryl group is selected from phenyl, naphthyl, anthracenyl; preferably naphthyl and phenyl; more preferably phenyl.
In a preferred embodiment, the substituents in the substituted aryl group are selected from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy. The substituents may be mono-, di-or tri-substituted.
In a preferred embodiment, the heteroaryl group is selected from thienyl, indolyl, tetrazolyl.
In a preferred embodiment, the alkyl group in the arylalkyl group is isopropyl.
In a preferred embodiment, the cycloalkyl group in the arylcycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In a preferred embodiment, the compound of Formula (FWBE) is selected from:
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-3-yl) ethyl-1-one;
2- (3, 5-bis (trifluoromethyl) phenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-phenylethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethyl) phenyl) ethyl-1-one;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (2,4, 5-trifluorophenyl) methanone;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethoxy) phenyl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-2-yl) ethyl-1-one;
2- (3-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -3- (3- (trifluoromethyl) phenyl) propyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-fluorophenyl) ethyl-1-one;
2- (3-bromophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-indol-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-2-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-1-yl) ethyl-1-one;
2- (3, 4-dichlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (2,4, 5-trifluorophenyl) ethyl-1-one;
2- (4-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
2- (2-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-nitrophenyl) ethyl-1-one;
3- (2- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-oxoethyl) benzonitrile;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopropyl) methanone;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-methyl-2-phenylprop yl-1-one;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopentyl) methanone;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclohexyl) methanone;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclobutyl) methanone.
The invention also provides pharmaceutically acceptable salts of the compounds of Formula (FWBE), which may be formed with inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, sulphates or sulphates, phosphates or hydrogen phosphates, acetates, benzoates, tartrates, succinates, maleates, fumarates, lactates, citrates, gluconates, methanesulphonates, benzenesulphonates or p-toluenesulphonates, preferably hydrochlorides.
The present invention also provides a pharmaceutical composition comprising: a compound of Formula (FWBE) or a pharmaceutically acceptable salt, solvate or hydrate thereof; and a pharmaceutically acceptable carrier.
The medicaments prepared from the compounds can be used for treating or improving diseases related to opioid receptors. The disorder may be selected from, but is not limited to, pain, gastrointestinal disorders, and depression. For example, pain may be selected from, but is not limited to, centrally mediated pain, peripherally mediated pain, pain associated with structural or soft tissue injury, pain associated with inflammation, pain associated with progressive disease, neuropathic pain, acute pain, and chronic pain.
Such a method can be effected by administering to a subject a therapeutically effective amount of a compound of Formula (FWBE) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
The invention also provides a method for synthesizing the compound with the general Formula (FWBE), which comprises the steps of Mannich reaction, nucleophilic addition of a Grignard reagent, deprotection of Boc, condensation, salt formation and the like.
Figure BDA0002262756560000041
The substituents and groups in the reaction schemes are as defined above.
Detailed Description
As used throughout this application, including the claims, the following terms have the meanings defined below as used herein, unless specifically indicated otherwise.
The term "C1-C6 alkyl" refers to a saturated branched or straight chain alkyl group containing 1 to 6 carbon atoms such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
The term "C1-6 mono-or poly-substituted alkyl" means that one or more hydrogen atoms in a C1-C6 alkyl group as defined above are replaced by a substituent selected from the group consisting of: OH, halogen, alkoxy, dialkylamino, or heterocyclyl, e.g., morpholinyl, piperidinyl, and the like.
The term "C1-6 mono-or poly-substituted alkanoyl" means "C1-6 mono-or poly-substituted alkyl" as defined above attached to the parent molecular moiety through the carbonyl group.
The term "cycloalkyl" refers to a cyclic saturated monovalent monocyclic or bicyclic hydrocarbon group of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. The cycloalkyl group may be optionally substituted with one, two or three substituents selected from halogen atoms, hydroxy groups, aryl groups.
The term "linear alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond, including a straight or branched chain group having at least one carbon-carbon double bond. For example having 2 to 6 carbon atoms. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. When the compounds of the invention contain a C2-C6 chain alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.
The term "cycloalkenyl" refers to a corresponding cycloalkenyl group formed by the removal of an additional hydrogen atom from a cycloalkyl group to form a double bond group.
The term "aryl" refers to all carbon monocyclic or fused ring polycyclic aromatic groups containing from 6 to 10 carbon atoms and having a conjugated pi-electron system, such as phenyl or naphthyl.
The term "substituted or unsubstituted aryl" means that 0 to 3 hydrogen atoms on the aryl group are replaced by a substituent selected from the group consisting of: aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluoro, nitro, phenolic hydroxy.
The term "substituted or unsubstituted arylcycloalkyl" means that one hydrogen on the carbon atom of the cycloalkyl group attached to the parent molecule as defined above is replaced with a substituted or unsubstituted aryl group.
The term "halo" or "halogen" refers to a chlorine, fluorine, bromine or iodine atom.
The term "substituted or unsubstituted arylacyl" means a "substituted or unsubstituted aryl" as defined above attached to the parent molecular moiety through a carbonyl group.
The term "substituted or unsubstituted arylalkyl" means that one or more hydrogen atoms in a C1-C6 alkyl group, as defined above, is substituted with a "substituted or unsubstituted aryl group," as defined above.
The term "heteroaryl" refers to a monocyclic or fused ring polycyclic aromatic heterocyclic group in which one or more heteroatom ring members (ring-forming atoms) in at least one ring are each independently selected from oxygen (O), sulfur (S), and nitrogen (N).
The term "substituted or unsubstituted heteroaryl" means that 0 to 3 hydrogen atoms on the heteroaryl are replaced by a substituent selected from the group consisting of: aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluoro, nitro, phenolic hydroxy.
Unless otherwise specified, all occurrences of a compound in the present invention are intended to include all possible isomers, such as tautomers, enantiomers, diastereomers, and mixtures thereof.
"therapeutically effective amount" refers to an amount of a compound that will alleviate one or more symptoms of the condition being treated to some extent.
The term "pharmaceutically acceptable carrier" refers to carriers that can be used in the preparation of pharmaceutical compositions, which are generally safe, non-toxic, not biologically or otherwise undesirable, and includes carriers that are pharmaceutically acceptable to animals and humans. As used in the specification and claims, a "pharmaceutically acceptable carrier" includes one or more of such carriers.
The pharmaceutical compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner appropriate to the route of administration employed. The pharmaceutical composition of the present invention can be administered in the following manner: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, and the like.
Oral pharmaceutical compositions may be solid, gel or liquid. Examples of solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solutions, acacia mucilage, gelatin solutions, sucrose and starch pastes; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose.
The pharmaceutical compositions of the present invention are administered parenterally, typically by injection, including subcutaneous, intramuscular, or intravenous injection. Injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that may be used in the injections of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents, and other pharmaceutically acceptable materials. Examples of aqueous carriers include sodium chloride injection, ringer's injection, isotonic glucose injection, sterile water injection, dextrose and lactated ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, and the like; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
The pharmaceutical compositions of the present invention may also be prepared as sterile lyophilized powders for injection, which are prepared by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by sterile filtration of the solution under standard conditions known to those skilled in the art, followed by lyophilization to provide the desired formulation.
The term "compound of Formula (FWBE)" or "compound of Formula (FWBE)" may be referred to as "compound of the present invention". Such terms are also defined to include all forms of the compounds of the present invention, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphous forms, polymorphs and metabolites thereof.
The compounds of the invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations well known to those skilled in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hours, "r.t." for room temperature).
The invention is illustrated by the following examples, which are intended to be illustrative only and are not limiting to the scope of the invention. The compounds of Formula (FWBE) may be prepared as described in the following general synthetic schemes and examples.
Figure BDA0002262756560000071
Example 1
Preparation of intermediate 2:
Figure BDA0002262756560000072
A1L three-necked flask equipped with a nitrogen balloon, a thermometer and a constant pressure dropping funnel was charged with N, N, N ', N' -tetramethylmethanediamine (60g, 587.2mmol,1eq.) and methyl t-butyl ether (500ml), cooled to 0 ℃ and acetyl chloride (46.1g, 587.2mmol,1eq., about 20min) was added dropwise at 30 ℃. After the dropwise addition, stirring for 30 minutes, carrying out suction filtration, adding acetonitrile (100ml) and MTBE (25ml) into the filter cake, stirring for 10 minutes, carrying out suction filtration, and evaporating the filter cake under reduced pressure (55 ℃), so that 46g of off-white solid (extremely easy to absorb moisture) is obtained, and the yield is 83.7%.
Example 2
Preparation of intermediate 3:
Figure BDA0002262756560000073
boc-piperidone (35g, 175.66mmol, 1eq.) and acetonitrile (350ml) were added to a 1L single-neck flask with a thermometer and nitrogen balloon, dissolved with stirring, and intermediate 2(19.72g, 210.8mmol, 1.2eq.) was added. The reaction is carried out at an internal temperature of 30-35 ℃ for 24h, and TLC shows that the reaction is basically complete after 24 h. The acetonitrile was evaporated under reduced pressure, DCM (300ml) was added, and saturated sodium bicarbonate (250ml) was added, followed by mixing, standing, separation and liquid separation. Aqueous phase was extracted with DCM (200+100 ml). The organic phases were combined, washed with water (50ml), dried over anhydrous magnesium sulphate, filtered with suction and the filtrate was evaporated off under reduced pressure to give 43.3g of a reddish brown viscous liquid with a yield of 93.5%.
Example 3
Preparation of intermediate 5:
Figure BDA0002262756560000081
A1L four-necked flask equipped with a nitrogen balloon, a constant pressure dropping funnel, a condenser tube and a thermometer was charged with a solution of magnesium turnings (11g, 451.68mmol, 3eq.), THF (300ml), 3 iodine pellets, a small amount of m-bromoanisole (84.5g, 451.68mmol, 3eq.) in THF (70ml), and the mixture was brought to reflux at elevated temperature. After the yellow color faded, the heating was stopped. A THF solution of m-bromoanisole was slowly added dropwise (about 1h) until the addition was complete. After the dropwise addition, the mixture is stirred and naturally cooled to room temperature. After 30min, a solution of intermediate 3(37.76g, 1eq.) in THF (100ml) was added dropwise at 25 ℃. After the addition, the ice-water bath was removed and the mixture was stirred overnight at room temperature (18 h). The reaction mixture was poured into a mixture of an aqueous ammonium chloride solution (200ml) and ice (about 100g), stirred for 5min, and THF was evaporated under reduced pressure (30 ℃ C.). Ethyl acetate (300ml) was added thereto, followed by stirring, standing, layer separation and liquid separation. Aqueous phase was extracted with ethyl acetate (300 ml). The organic phases were combined, washed with water (100ml), dried over anhydrous magnesium sulfate, filtered, the filtrate was distilled off under reduced pressure to give 76.5g of a yellow liquid, which was purified by column chromatography to give 21.4g of a pale yellow viscous liquid with a yield of 38.9% (two steps, based on boc-piperidone).1H NMR(400MHz,CD3OD),δ7.26(t,J＝8Hz,1H),7.04～7.05(m,1H),6.98(d,J＝8Hz,1H),6.81(dd,J＝8Hz,J＝4Hz,1H),4.20～4.25(m,1H),3.96～4.00(m,1H),3.79(s,3H),3.35(s,1H),3.03～3.22(m,2H),2.31～2.37(m,1H),2.07～2.11(m,1H),2.04(s,6H),1.94～2.01(m,1H),1.78～1.81(m,1H),1.58～1.62(m,1H),1.50(s,9H).。
Example 4
Preparation of intermediate 6:
Figure BDA0002262756560000082
5(9.5g,26.06mmol, 1eq.) and methanol (76ml) were added to a 250ml single-neck flask, followed by stirring, dropwise addition of HCl/1, 4-dioxane solution (16.3ml, 65.15mmol, 2.5eq.) and internal temperature rise to about 36 ℃. After stirring for 2 hours, TLC showed a large amount of starting material. The temperature was raised to 50 ℃ and stirred, after 2 hours TLC showed substantial completion of the reaction. MTBE (150ml) was added and stirred to gradually precipitate a solid which was stirred overnight (24 h). And (3) carrying out suction filtration, leaching a filter cake MTBE (20ml), and carrying out rotary evaporation, reduced pressure and rotary drying to obtain 8.63g of off-white solid with the yield of 98.3%.1H NMR(400MHz,CD3OD),δ7.38(t,J＝8Hz,1H),7.15～7.16(m,1H),7.12(d,J＝8Hz,1H),6.92(dd,J1＝8Hz,J2＝4Hz,1H),3.83(s,3H),3.75(dd,J1＝12Hz,J2＝4Hz,1H),3.41～3.43(m,3H),3.09～3.15(m,1H),2.85～2.92(m,1H),2.75(s,3H),2.75～2.78(m,1H),2.57(s,3H),2.54～2.62(m,1H),1.89～1.94(m,1H).。
Example 5
General method of condensation:
a 100ml single vial was charged with intermediate 6(1eq.), carboxylic acid (1eq.), EDCI-HCl (1.5eq.), HOBT (1.5eq.), DMF (6ml), NMM (4eq.), stirred at room temperature until TLC indicated completion of the reaction. Water and sodium bicarbonate solution were added and extracted with DCM. And combining organic phases, washing with water, drying with anhydrous magnesium sulfate, performing suction filtration, and evaporating the filtrate under reduced pressure to obtain a residue. And purifying the obtained residue by using an aluminum oxide column chromatography to obtain a target product.
Example 6
The general method for salt formation comprises the following steps:
adding dichloromethane into 100ml of single-mouth bottle free alkali (1eq.), stirring to dissolve and clarify, and adding methyl tert-butyl ether; HCl in 1, 4-dioxane was slowly added dropwise (1.2eq.) to precipitate a solid. Stirring, filtering, leaching filter cake methyl tert-butyl ether (2ml), and pumping by an oil pump to obtain the target product.
Example 7
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-3-yl) ethyl-1-one
Figure BDA0002262756560000091
2- (thiophene-3-yl) acetic acid is used as a raw material to obtain a target product with the yield of 34 percent.1H NMR(400MHz,CD3OD),δ7.40～7.43(m,1H),7.20～7.26(m,2H),7.06～7.09(m,1H),6.93～6.97(m,1H),6.87～6.91(m,1H),6.76～6.79(m,1H),4.48～4.72(m,1H),3.75～4.12(m,4H),3.78(s,3H),3.28～3.51(m,1H),3.04～3.01,2.90～2.96(m,1H),2.98(s,1H),2.85(s,1H),2.24～2.40(m,1H),2.07(s,3H),1.84～2.02(m,3H),1.91(m,1H),1.47～1.51,1.70～1.73(m,1H),1.62～1.66(m,1H).LC-MS-ESI+:[M+H]+389.。
Example 8
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-3-yl) ethyl-1-one hydrochloride (FWBE2)
Figure BDA0002262756560000101
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophene-3-yl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 59.6 percent.1H NMR(400MHz,CD3OD),δ7.42～7.45(m,1H),7.28～7.37(m,2H),7.08～7.14(m,1H),6.94～7.07(m,2H),6.83～6.87(m,1H),4.53～4.66(m,1H),3.92～4.01m,1H),3.79(s,3H),3.78～3.86(m,1H),3.40～3.59(m,1H),3.95～3.14(m,1H),2.60～2.73(q,6H),2.29(s,1H),2.16～2.23(m,1H),2.08～2.16,1.75～1.86(m,1H),1.59～1.75(m,1H).LS-MS-ESI+:[M+H]+389.。
Example 9
2- (3, 5-bis (trifluoromethyl) phenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one hydrochloride (FWBE1)
Figure BDA0002262756560000102
3, 5-bis (trifluoromethyl) phenylacetic acid is taken as a raw material to obtain a target product with the yield of 34 percent.1H NMR(400MHz,CD3OD),δ7.91～7.93(d,2H),7.87(s,1H),7.24(t,J＝8Hz,1H),7.04(t,J＝4Hz,1H),6.94～6.98(m,1H),6.80(dd,J1＝8Hz,J2＝4Hz,1H),4.48～4.73(m,1H),3.93～4.15(m,3H),3.79(s,3H),3.33～3.61(m,1H),2.93～3.13(m,1H),2.27～2.39(m,1H),1.93～2.11(m,2H),2.04(s,3H),1.96(s,3H),1.74～1.87(m,1H),1.63～1.69(m,1H).LC-MS-ESI+:[M+H]+519.0.
Salifying with 2- (3, 5-bis (trifluoromethyl) phenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one as raw material, the target product was obtained with a yield of 95.3%.1H NMR(400MHz,CD3OD),δ7.92～7.95(d,2H),7.86～7.88(d,1H),7.31～7.35(m,1H),7.05～7.16(m,2H),6.87(dd,J1＝8Hz,J2＝4Hz,1H),4.44～4.86(m,2H),4.16～4.31(q,1H),4.10(s,1H),4.00～4.07(m,1H),3.81～3.82(d,3H),3.48～3.54,3.71～3.79(m,1H),3.59～3.66(m,1H),3.01～3.30(m,3H),2.63～2.81(m,3H),2.45～2.60(m,3H),2.29～2.45(m,1H).2.12～2.34(m,1H),1.75(t,J＝8Hz,1H).LC-MS-ESI+:[M+H]+519.0.。
Example 10
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-phenylethyl-1-one
Figure BDA0002262756560000111
The target product is obtained by taking phenylacetic acid as a raw material, and the yield is 38.2%.1H NMR(400MHz,CD3OD),δ7.30～7.37(m,4H),7.19～7.27(m,2H),6.84～6.95(m,2H),6.75～6.79(m,1H),4.50～4.73(m,1H),3.88～3.94(m,1H),3.72～3.86(m,2H),3.77(s,3H),3.26～3.49(m,1H),2.89～3.11(m,1H),2.21～2.37(m,1H),2.04(s,3H),1.80～2.01(m,3H),1.85(s,3H),1.65～1.69(m,1H),1.42～1.63(m,1H).LC-MS-ESI+:[M+H]+383.。
Example 11
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-phenylethyl-1-one hydrochloride (FWBE3)
Figure BDA0002262756560000112
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-phenylethyl-1-ketone is used as a raw material to obtain a target product with the yield of 99 percent.1H NMR(400MHz,CD3OD),δ7.25～7.40(m,7H),6.92～7.06(m,2H),6.83～6.87(m,1H),4.27～4.32,4.63～4.67(m,1H),3.94～4.07,4.54～4.58(m,2H),3.80(s,3H),3.39～3.54(m,1H),2.94～3.14(m,2H),2.59～2.73(m,7H),2.08～2.24(m,1H),1.56～1.85(m,2H).LC-MS-ESI+:[M+H]+383.。
Example 12
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethyl) phenyl) ethyl-1-one
Figure BDA0002262756560000121
2- (3- (trifluoromethyl) phenyl) acetic acid is used as a raw material to obtain a target product with the yield of 58%.1H NMR(400MHz,CD3OD),δ7.47(s,1H),7.35～7.43(m,3H),7.03～7.08(m,1H),6.81～6.83(m,1H),6.73(dd,J1＝16Hz,J2＝8Hz,1H),6.62(dd,J1＝8Hz,J2＝4Hz,1H),4.33～4.57(m,1H),3.71～3.95(m,3H),3.61(s,3H),2.89～2.96,3.34～3.38(m,1H),2.68～2.81(q,3H),2.07～2.20(m,2H),1.86(s,3H),1.72～1.84(m,2H),1.72(s,3H),1.36～1.40,1.54～1.58(m,1H),1.47～1.53(m,1H).。
Example 13
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethyl) phenyl) ethyl-1-one hydrochloride (FWBE4)
Figure BDA0002262756560000122
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethyl) phenyl) ethyl-1-one is used as a raw material, and the yield is 97.6%.1H NMR(400MHz,CD3OD),δ7.55～7.66(m,4H),7.29～7.34(q,1H),6.97～7.13(m,2H),6.84～6.88(m,1H),4.52～4.67(m,1H),4.03～4.41(m,1H),3.99～4.03(m,2H),3.80～3.81(d,3H),3.44～3.60(m,1H),3.04～3.12(m,2H),2.86～3.02(m,1H),2.41～2.73(q,6H),1.98～2.18(m,1H),1.67～1.76(m,1H).LC-MS-ESI+:[M+H]+451.1。
Example 14
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (2,4, 5-trifluorophenyl) methanone
Figure BDA0002262756560000131
2,4, 5-trifluoro-benzoic acid is used as raw material to obtain the target product with 47 percent of yield.1H NMR(400MHz,CD3OD),δ7.30～7.37(m,1H),7.24～7.28(m,1H),7.12～7.22(m,1H),7.00～7.10(m,2H),6.81(dd,J1＝8Hz,J2＝4Hz H),4.55～4.87(m,1H),3.79(s,3H),3.57～3.69(m,1H),3.34～3.44(m,1H),3.09～3.30(m,1H),2.23～2.27,2.39～2.45(m,1H),1.99～2.04,2.11～2.22(m,2H),2.08(s,3H),1.88(s,3H),1.58～1.86(m,3H).LC-MS-ESI+:[M+H]+423.。
Example 15
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (2,4, 5-trifluorophenyl) methanone hydrochloride (FWBE5)
Figure BDA0002262756560000132
The target product is obtained by taking (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (2,4, 5-trifluorophenyl) methanone as a raw material with the yield of 86%.1H NMR(400MHz,CD3OD),δ7.55(s,1H),7.32～7.39(m,2H),7.08～7.13(m,2H),6.87(dd,J＝8Hz,1H),4.60～4.80(m,1H),3.81(s,3H),3.58～3.78(m,2H),3.48～3.53(m,1H),3.26～3.34(m,1H),3.12～3.20(m,1H),2.73～2.77(m,3H),3.61～3.68(d,3H),2.41～2.48(m,2H),2.13～2.21(m,1H),1.67～1.84(m,1H).。
Example 16
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethoxy) phenyl) ethyl-1-one
Figure BDA0002262756560000141
2- (3- (trifluoromethoxy) phenyl) acetic acid is used as a raw material to obtain a target product, and the yield is 77%.1H NMR(400MHz,CD3OD),δ7.42～7.47(m,1H),7.31～7.34(m,1H),7.08～7.26(m,3H),6.96～7.02(m,1H),6.86～6.92(m,H),6.76～6.80(m,1H),4.49～4.87(m,1H),3.88～4.11(m,3H),3.78(s,3H),3.28～3.53(m,1H),2.91～3.12(m,1H),3.23～3.38(m,1H),2.00～2.04(d,3H),1.92～1.98(m,1H),1.90(m,3H),1.51～1.85(m,2H).LC-MS-ESI+:[M+H]+467.0.。
Example 17
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethoxy) phenyl) ethyl-1-one hydrochloride (FWBE6)
Figure BDA0002262756560000142
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethoxy) phenyl) ethyl-1-ketone is used as a raw material to obtain a target product, and the yield is 94.2%.1H NMR(400MHz,CD3OD),δ7.42～7.48(m,1H),7.26～7.38(m,3H),7.17～7.21(m,1H),6.96～7.07(m,2H),6.84～6.88(m,1H),4.34～4.66(m,1H),4.00～4.14(m,1H),3.94～3.97(m,2H),3.80～3.81(3H),3.42～3.59(m,1H),2.97～3.41(m,2H),2.39～2.77(m,7H),2.21～2.39(m,2H),1.94～218(m,1H),1.66～1.76(m,1H).LC-MS-ESI+:[M+H]+467.0.。
Example 18
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethyl-1-one
Figure BDA0002262756560000151
2- (1H-tetrazole-1-yl) acetic acid is used as a raw material to obtain a target product with the yield of 56%.1H NMR(400MHz,CD3OD),δ9.17(s,1H),7.25～7.29(m,1H),7.03～7.05(m,1H),7.08～7.09(m,1H),6.82(dd,J1＝8Hz,J2＝4Hz,1H),5.61～5.79(m,2H),4.38～4.66(m,1H),3.82～4.04(m,1H),3.80(s,3H),3.43～3.69(m,1H),3.01～3.20(m,1H),2.22～2.40(m,2H),2.14～2.21(m,1H),2.00～2.09(m,7H),1.83～1.87(m,1H),1.65～1.76(m,1H).LC-MS-ESI+:[M+H]+375.1.。
Example 19
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethyl-1-one hydrochloride (FWBE7)
Figure BDA0002262756560000152
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 99 percent.1H NMR(400MHz,CD3OD),δ9.21(s,1H),9.34(t,J＝8Hz,1H),7.11～7.17(m,2H),6.88(dd,J1＝8Hz,J2＝4Hz,1H),5.63～6.08(m,2H),4.32～4.37,4.57～4.62(m,1H),3.90～3.94,4.42～4.46(m,1H),3.82(s,3H),3.54～3.60,3.66～3.73(m,1H),2.99～3.21(m,2H),2.65～2.86(m,5H),2.51～2.59(d,2H),2.15～2.44(m,1H),1.72～1.91(m,1H).LC-MS-ESI+:[M+H]+375.1.。
Example 20
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-2-yl) ethyl-1-one
Figure BDA0002262756560000161
2- (thiophene-1-radical) acetic acid is taken as a raw material to obtain a target product, and the yield is 76％.1H NMR(400MHz,CD3OD),δ7.30～7.32(m,1H),7.21～7.26(m,1H),6.95～7.01(m,3H),6.88～6.93(m,1H),6.77～6.80(m,1H),5.49(s,1H),4.47～4.71(m,1H),3.92～4.17(m,2H),3.78(s,3H),3.29～3.59(m,1H),2.91～3.12(m,1H),2.25～2.39(m,1H),2.05(s,3H),1.83～1.96(m,5H),1.71～1.76(m,1H),1.51～1.69(m,1H).LC-MS-ESI+:[M+H]+389.。
Example 21
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-2-yl) ethyl-1-one hydrochloride (FWBE8)
Figure BDA0002262756560000162
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophene-2-yl) ethyl-1-ketone is used as a raw material to obtain a target product, and the yield is 84.5 percent.1H NMR(400MHz,CD3OD),δ7.28～7.34(m,2H),6.95～7.07(m,4H),6.84～6.87(m,1H),4.51～4.63(m,1H),4.16～4.32(m,1H),4.01～4.12(m,1H),3.79(s,3H),3.45～3.60(m,1H),2.97～3.14(m,2H),2.37～2.74(m,8H),2.19～2.25(m,1H),1.87～2.16(m,1H),1.62～1.75(m,1H).LC-MS-ESI+:[M+H]+389.。
Example 22
2- (3-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one
Figure BDA0002262756560000171
The target product is obtained by using m-chlorophenylacetic acid as a raw material, and the yield is 58%.1H NMR(400MHz,CD3OD),δ7.23～7.37(m,5H),6.98～6.99(m,1H),6.89～6.92(m,1H),6.77～6.80(m,1H),4.49～4.71(m,1H),3.88～4.11(m,2H),3.78(s,3H),3.74～3.86(m,2H),3.28～3.53(m,1H),2.93～3.12(m,1H),2.25～2.47(m,1H),2.13(m,3H),1.91(s,3H),1.85～2.08(m,2H),1.70～1.78(m,1H),1.51～1.68(m,1H),1.21～1.30(m,1H).LC-MS-ESI+:[M+H]+417.0,419.0.。
Example 23
2- (3-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one hydrochloride (FWBE9)
Figure BDA0002262756560000172
The target product is obtained by taking 2- (3-chlorphenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-ketone as a raw material with the yield of 84.7 percent.1H NMR(400MHz,CD3OD),δ7.25～7.41(m,5H),6.97～7.11(m,2H),6.84～6.87(m,1H),3.34～3.38,4.62～4.66(m,1H),3.95～3.97,4.51～4.55(m,1H),3.96～4.09(m,1H),3.89(s,1H),3.81(s,3H),3.41～3.59(m,1H),2.97～3.14(m,2H),2.34～2.73(m,7H),2.22～2.28(m,1H),1.92～2.17(m,1H),1.64～1.75(m,1H).LC-MS-ESI+:[M+H]+417.0,419.0.。
Example 24
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -3- (3- (trifluoromethyl) phenyl) propyl-1-one hydrochloride (FWBE10)
Figure BDA0002262756560000181
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -3- (3- (trifluoromethyl) phenyl) propyl-1-ketone is used as a raw material to obtain a target product, and the yield is 84.2%.1H NMR(400MHz,CD3OD),δ7.56～7.63(m,2H),7.46～7.54(m,2H),7.31(t,J＝8Hz 1H),7.05～7.09(m,1H),6.94～7.03(m,1H),6.86(dd,J1＝8Hz,J2＝4Hz H),4.25～4.28,4.58～4.62(m,1H),3.86～3.90,4.48～4.52(m,1H),3.80(s,3H),3.33～3.51(m,1H),3.05～3.08(m,3H),2.73～3.02(m,4H),2.70,2.73(d,3H),2.44,2.60(d,3H),2.13～2.32(m,1H),1.92～2.09(m,1H),1.66～1.72(m,1H).LC-MS-ESI+:[M+H]+465.。
Example 25
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-fluorophenyl) ethyl-1-one hydrochloride (FWBE12)
Figure BDA0002262756560000182
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-fluorophenyl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 92 percent.1H NMR(400MHz,CD3OD),δ7.34～7.40(m,1H),7.29～7.33(m,1H),7.02～7.19(m,4H),6.97～7.00(m,1H),6.84～6.86(m,1H),4.30～4.35,4.62～4.66(m,1H),3.90～4.10,4.52～4.56(m,3H),3.80(s,3H),3.41～3.56(m,1H),2.97～3.13(m,2H),2.36～2.73(m,7H),2.23～2.33(m,1H),1.90～2.17(m,1H),1.63～1.75(m,1H).LC-MS-ESI+：[M+H]+401.3。
Example 26
2- (3-bromophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one
Figure BDA0002262756560000191
The target product is obtained by using m-bromobenzoic acid as a raw material, and the yield is 78.43%.1H NMR(400MHz,CD3OD),δ7.50～7.52(m,1H),7.41～7.44(m,1H),7.21～7.32(m,3H),6.97～6.99(m,1H),6.87～6.92(m,1H),6.78(dd,J1＝8Hz,J2＝4Hz,1H),4.49～4.73(m,1H),3.79～4.10(m,3H),3.77(s,3H),3.26～3.33,3.44～3.52(m,1H),2.90～2.96,3.04～3.12(m,1H),2.23～2.37(m,1H),1.80～2.03(m,3H),2.03(s,3H),1.88(s,3H),1.49～1.73(m,2H).LC-MS-ESI+:[M+H]+463.2.。
Example 27
2- (3-bromophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one hydrochloride (FWBE11)
Figure BDA0002262756560000192
2- (3-bromophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 94%.1H NMR(400MHz,CD3OD),δ7.51～7.55(m,1H),7.42～7.46(m,1H),7.26～7.36(m,3H),6.97～7.10(m,2H),6.84～6.88(m,1H),4.29～4.33,4.61～4.65(m,1H),3.88～4.06,4.52～4.56(m,3H),3.81(s,3H),3.42～3.59(m,1H),2.98～3.14(m,2H),2.35～2.73(m,7H),2.22～2.31(m,1H),1.91～2.17(m,1H),1.63～1.75(m,1H).LC-MS-ESI+：[M+H]+463.。
Example 28
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-indol-3-yl) ethyl-1-one (FWBE13)
Figure BDA0002262756560000201
2- (1H-indole-3-yl) acetic acid is used as a raw material to obtain a target product with the yield of 54.8%.1H NMR(400MHz,CD3OD),δ7.65～7.71(m,1H),7.34～7.40(m,1H),7.03～7.21(m,4H),6.08～6.80(m,3H),4.53～4.67(m,1H),4.05～4.13(m,2H),3.81～3.95(m,2H),3.70(s,3H),3.03～3.09,3.37～3.43(m,1H),2.58～2.97(m,1H),2.30(s,3H),1.71～2.12(m,1H),1.83(s,1H),1.54～1.61(m,1H),1.05～1.26(m,3H).LC-MS-ESI+:[M+H]+422.3.。
Example 29
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-indol-1-yl) ethyl-1-one hydrochloride (FWBE14)
Figure BDA0002262756560000202
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidine-1-yl) -2- (1H-indole-1-yl) ethyl-1-ketone is used as a raw material to obtain a target product, and the yield is 98%.1H NMR(400MHz,CD3OD),δ7.55～7.59(t,1H),7.35～7.43(t,1H),7.23～7.35(m,2H),7.17(t,J＝8Hz H),6.77～7.11(m,4H),6.50～6.52(m,1H),5.16～5.52(m,2H),4.29～4.33,4.57～4.61(m,1H),4.94～4.98,4.43～4.46(m,1H),3.81(s,3H),3.47～3.65(m,1H),2.92～3.13(m,2H),2.57～2.74(m,6H),1.88～2.14(m,2H),1.62～1.74(m,1H).LC-MS-ESI+:[M+H]+422.3.。
Example 30
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-2-yl) ethyl-1-one
Figure BDA0002262756560000211
2- (naphthalene-2-yl) acetic acid is used as a raw material to obtain a target product with the yield of 42%.1H NMR(400MHz,CD3OD),δ7.78～7.87(m,4H),7.42～7.50(m,3H),7.11～7.19(m,1H),6.82～6.86(m,1H),6.71～6.76,6.89～6.90(m,2H),4.55～4.75(m,1H),3.91～4.41(m,3H),3.71(s,3H),3.27～3.50(m,1H),2.91～3.13(m,1H),2.16～2.39(m,1H),1.73～2.06(m,5H),1.51～1.68(m,5H),1.27～1.43(m,2H).。
Example 31
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-2-yl) ethyl-1-one hydrochloride (FWBE15)
Figure BDA0002262756560000212
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalene-2-yl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 88 percent.1H NMR(400MHz,CD3OD),δ7.81～7.90(m,4H),7.44～7.52(m,3H),7.20～7.29(m,1H),6.94～6.95(m,1H),6.79～6.85,7.02～7.03(m,2H),4.58～4.69(m,1H),4.01～4.32(m,3H),3.76(d,3H),3.42～3.59(m,1H),2.90～3.17(m,2H),2.56～2.72(m,6H),2.18～2.23(m,1H),1.78～2.16(m,2H),1.54～1.76(m,1H).LC-MS-ESI+:[M+H]+433.3.。
Example 32
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-1-yl) ethyl-1-one hydrochloride (FWBE16)
Figure BDA0002262756560000221
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidine-1-yl) -2- (naphthalene-1-yl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 99 percent.1H NMR(400MHz,CD3OD),δ8.03～8.09(m,1H),7.89～7.93(m,1H),7.83(d,J＝8Hz,1H),7.46～7.59(m,3H),7.41～7.45(m,1H),7.28～7.36(m,1H),7.02～7.06(m,1H),6.83～6.88,7.10～7.11(m,2H),4.58～4.69(m,1H),4.34～4.48(m,2H),3.98～4.27(m,1H),3.81(s,3H),3.49～3.54(m,1H),2.92～3.20(m,2H),2.54～2.69(m,6H),1.87～2.32(m,3H),1.56～1.78(m,1H).LC-MS-ESI+:[M+H]+433.3.。
Example 33
2- (3, 4-dichlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one hydrochloride (FWBE17)
Figure BDA0002262756560000222
2- (3, 4-dichlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-ketone is used as a raw material to obtain a target product with the yield of 88%.1H NMR(400MHz,CD3OD),δ7.48～7.54(m,2H),7.23～7.35(m,2H),7.00～7.13(m,2H),6.84～6.88(m,1H),4.31～4.35,4.60～4.65(m,1H),3.94～4.06,4.50～4.54(m,2H),3.88(s,1H),3.81(s,3H),3.43～3.60(m,1H),2.98～3.13(m,2H),2.65～2.69(m,6H),2.24～2.45(m,2H),1.68～2.18(m,2H).LC-MS-ESI+:[M+H]+451.2.。
Example 34
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (2,4, 5-trifluorophenyl) ethyl-1-one hydrochloride (FWBE18)
Figure BDA0002262756560000231
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (2,4, 5-trifluorophenyl) ethyl-1-ketone is used as a raw material to obtain a target product, and the yield is 94.6%.1H NMR(400MHz,CD3OD),δ7.26～7.36(m,2H),7.06～7.22(m,3H),6.87(d,J＝8Hz,1H),4.47～4.65(m,1H),3.84～4.43(m,3H),3.81(s,3H),3.50～3.67(m,1H),3.02～3.15(m,2H),2.67～2.82(m,6H),2.29～2.57(m,2H),2.11～2.27(m,1H),1.71～1.81(m,1H).LC-MS-ESI+:[M+H]+437.2.。
Example 35
2- (4-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one hydrochloride (FWBE19)
Figure BDA0002262756560000232
The target product is obtained by taking 2- (4-chlorphenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-ketone as a raw material with the yield of 97.7 percent.1H NMR(400MHz,CD3OD),δ7.29～7.38(m,5H),6.97～7.10(m,2H),6.83～6.87(m,1H),4.51～4.66(m,1H),3.87～4.38(m,3H),3.81(s,3H),3.40～3.57(m,1H),3.96～3.13(m,2H),2.60～2.73(m,6H),2.22～2.42(m,1H),1.90～2.18(m,1H),1.63～1.75(m,1H).LC-MS-ESI+:[M+H]+417.2、419.2.。
Example 36
2- (2-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one hydrochloride (FWBE20)
Figure BDA0002262756560000241
2- (2-chlorphenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-ketone is used asRaw materials are adopted to obtain the target product with the yield of 84 percent.1H NMR(400MHz,CD3OD),δ7.41～7.44(m,1H),7.25～7.38(m,4H),7.02～7.13(m,2H),6.85～6.89(m,1H),4.31～4.35,4.61～4.63(m,1H),3.94～4.41,4.51～4.54(m,3H),3.81(s,3H),3.52～3.65(m,1H),3.02～3.20(m,2H),2.60～2.80(m,6H),2.25～2.48(m,2H),2.11～2.20(m,1H),1.71～1.77(m,1H).LC-MS-ESI+:[M+H]+417；419.。
Example 37
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-nitrophenyl) ethyl-1-one hydrochloride (FWBE22)
Figure BDA0002262756560000242
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-nitrophenyl) ethyl-1-ketone is used as a raw material to obtain a target product, and the yield is 96.8%.1H NMR(400MHz,CD3OD),δ8.13～8.25(m,2H),7.71～7.77(m,1H),7.57～7.63(m,1H),7.29～7.35(m,1H),7.02～7.14(m,2H),6.84～6.88(m,1H),4.39～4.44,4.63～4.67(m,1H),4.00～4.17,4.51～4.55(m,3H),3.81(s,3H),3.47～3.65(m,1H),3.01～3.15(m,2H),2.46～2.79(m,7H),2.28～2.33,2.50～2.55(m,1H),2.08～2.20(m,1H),1.71～1.76(m,1H).LC-MS-ESI+:[M+H]+428.3.。
Example 38
3- (2- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-oxoethyl) benzonitrile hydrochloride (FWBE21)
Figure BDA0002262756560000251
3- (2- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-oxoethyl) benzonitrile is used as a raw material to obtain a target product with the yield of 89.5%.1H NMR(400MHz,CD3OD),δ7.62～7.73(m,2H),7.50～7.56(m,1H),7.30～7.35(m,1H),7.02～7.14(m,2H),6.85～6.88(m,1H),4.38～4.42,4.61～4.66(m,1H),3.96～4.15,4.50～4.54(m,3H),3.81(m,3H),2.99～3.13(m,2H),2.44～2.78(m,7H),2.27～2.33,2.47～2.49(m,1H),2.05～2.19(m,1H),1.70～1.75(m,1H).LC-MS-ESI+:[M+H]+408.3.。
Example 39
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopropyl) methanone hydrochloride (FWBE24)
Figure BDA0002262756560000252
The target product is obtained by taking (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopropyl) methanone as a raw material with the yield of 80 percent.1H NMR(400MHz,CD3OD),δ7.24～7.41(m,6H),6.83～6.98(m,3H),4.64～4.67(m,1H),4.10～4.25(m,1H),3.81(s,3H),3.30～3.33(m,1H),2.95～3.23(m,1H),2.46～2.77(m,6H),2.24～2.28(m,1H),1.65～1.86(m,3H),1.00～1.46(m,4H).LC-MS-ESI+:[M+H]+409.3.。
Example 40
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-methyl-2-phenylpropyl-1-one hydrochloride (FWBE23)
Figure BDA0002262756560000253
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-methyl-2-phenylpropyl-1-ketone is used as a raw material to obtain a target product with the yield of 85.7 percent.1H NMR(400MHz,CD3OD),δ7.36～7.45(m,4H),7.25～7.33(m,2H),6.97(s,1H),6.91(d,J＝8Hz,1H),6.84(d,J＝1Hz,1H),4.69(d,J＝8Hz,1H),3.80(s,3H),3.47(s,1H),3.01～3.13(m,3H),2.71(s,6H),2.20(s,1H),1.64(s,3H),1.56(s,3H),1.12～1.41(m,2H).LC-MS-ESI+:[M+H]+411.3.。
EXAMPLE 41
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopentyl) methanone hydrochloride (FWBE26)
Figure BDA0002262756560000261
The target product was obtained with (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopentyl) methanone as the starting material in a yield of 72.4%.1H NMR(400MHz,CD3OD),δ7.35～7.42(m,4H),7.24～7.31(m,2H),6.82～6.91(m,3H),4.63～4.66(m,1H),3.79(s,3H),3.61～3.66(m,1H),2.99～3.21(m,3H),2.75(s,3H),2.65(s,3H),2.62～2.69(m,1H),2.13～2.34(m,3H),1.70～1.88(m,6H),1.10～1.22(m,1H).LC-MS-ESI+:[M+H]+437.3.。
Example 42
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclohexyl) methanone hydrochloride (FWBE27)
Figure BDA0002262756560000262
The target product was obtained with (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclohexyl) methanone as the starting material in 55.8% yield.1H NMR(400MHz,CD3OD),δ7.43(d,J＝4Hz,4H),7.23～7.31(m,2H),6.89(s,1H),6.83(dd,J1＝8Hz,J2＝4Hz,2H),4.55(s,1H),3.79(s,3H),3.59～3.65(m,1H),3.02～3.20(m,3H),2.74(s,3H),2.69(s,3H),2.40～2.74(m,3H),1.81～2.06(m,4H),1.31～1.40(m,1H),1.03(m,1H).LC-MS-ESI+:[M+H]+451.3.。
Example 43
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclobutyl) methanone hydrochloride (FWBE25)
Figure BDA0002262756560000271
With (3- ((dimethylamino) methyl) -4-hydroxy groupThe target product is obtained by taking (E) -4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclobutyl) ketone as a raw material with the yield of 84.9 percent.1H NMR(400MHz,CD3OD),δ7.43～7.58(m,4H),7.24～7.32(m,2H),6.77～6.91(m,3H),4.60(d,J1＝8Hz,J2＝4Hz,H),3.78(s,3H),3.39～3.42(m,1H),2.99～3.22(m,4H),2.61～2.75(m,8H),2.23～2.29(m,1H),1.92～2.09(m,4H),1.08～1.23(m,2H).LC-MS-ESI+:[M+H]+423.3.。
Example 44
Preparation of Membrane receptors
CHO cells expressing mu opioid receptor, delta opioid receptor and kappa opioid receptor respectively are planted in 10cm2Culturing in a culture dish (F-12 culture medium + 10% newborn calf serum) for several days, and sucking out the culture solution after the cells grow to fill the bottom of the dish; adding PBS/EDTA solution (0.1M NaCl, 0.01M NaH)2PO40.04% EDTA)3ml for 3-5min, blowing with a suction tube to make the cells fall off completely, collecting the cells in a 40ml centrifuge tube, centrifuging at 5000rpm for 5min, and removing the supernatant; adding ice-cold homogenate (50mM HEPES pH 7.4, 3mM MgCl,1mM EGTA) into the centrifuge tube, transferring the solution and pellet to a homogenizer for homogenization; then transferring the homogenate liquid into a centrifugal tube, centrifuging for 15min at 18000rpm, and centrifuging for 2 times; the obtained precipitate was added with an appropriate amount of 50mM Tris-HCl, pH 7.4 buffer solution to homogenate and subpackaged in centrifuge tubes and stored in a refrigerator at-70 ℃ for later use.
Competitive binding assays
The total binding tube is added with 20-30 mug of expressed membrane receptor protein and [3H ] labeled ligand (1-2nM), the corresponding non-specific binding tube is added with 1 muM of corresponding ligand, the sample tube is added with various screened opioid ligand drugs with different concentrations, the final volume is 100 muL, incubation is carried out at 30 ℃ for 30min, and the reaction is stopped in ice water. The samples were suction filtered through GF/C (whatman) glass fiber filter paper on a Millipore sample collector. Washing with 4ml 50mM Tris-HCl (pH 7.4) for three times, drying the filter paper, placing the filter paper in a 0.5ml Eppendorf tube, adding 0.5ml lipophilic scintillation fluid, measuring the radioactivity intensity by a liquid scintillation counter of PERKIN ELMER PRI-CARB 2910, calculating the inhibition rate, and repeating the experiment for more than three times, wherein each group of three tubes is provided with three tubes.
The inhibition ratio (or called binding ratio) is (total binding ratio dpm-sample tube dpm)/(total binding tube dpm-nonspecific binding tube dpm) × 100%
IC was calculated using Graphpad Prism5.0 software50. The Ki value, Ki ═ IC, was calculated as follows50/(1+[L]/Kd)，[L]Kd is the equilibrium dissociation parameter of the labeled ligand, as the concentration of labeled ligand added
Table 1 shows the affinity constant Ki values for representative compounds for opioid receptors, expressed as the mean ± standard deviation of three independent measurements.
TABLE 1 opioid receptor binding Rate or Ki at 1. mu.M concentration of the Compound
Figure BDA0002262756560000281
Figure BDA0002262756560000291
Figure BDA0002262756560000301
Figure BDA0002262756560000311
Figure BDA0002262756560000321
In the column of "binding rate (%) or Ki (nM)" in Table 1, the numerical value in percent means the binding rate, and the numerical value in nM means Ki.
As can be seen from table 1, the compounds have a higher affinity for the three opioid receptors than tramadol and may exhibit a stronger analgesic effect in vivo.
Example 45
In vivo hot plate analgesia test
Placing female mouse with weight of 20g on hot plate apparatus preheated to 55 deg.C, and placing the mouseThe latency of the response to licking is indicative of the pain threshold. Animals are screened before the experiment, and animals with the response latency period less than 5s or more than 30s are rejected. To prevent foot burn, the maximum observation time was set to 60 s. The basal pain threshold is the average of 2 measurements separated by 5 min. Pain thresholds were determined for each group of mice at 15min, 30min, 60 min and 120 min post-i.p. administration. The percentage of analgesic effect (% MPE) is calculated according to the following formula: percentage analgesic effect (% MPE). ED was calculated using Graphpad prism5.0 software based on percent analgesic efficacy50The value is obtained.
TABLE maximum% analgesic efficacy (% MPE) on compound Hot plates or ED at 210 mg/kg dose50Value of
Figure BDA0002262756560000331
Figure BDA0002262756560000341
Figure BDA0002262756560000351
Figure BDA0002262756560000361
Figure BDA0002262756560000371
"% MPE or ED of Table 250In the column, the values expressed as percentages refer to% MPE and the values in mg/kg refer to ED50。
As can be seen from Table 2, the compounds obtained by the present invention all have stronger analgesic effect compared with tramadol.

Claims (10)

1. A compound of Formula (FWBE), or a pharmaceutically acceptable salt thereof:
Figure FDA0002262756550000011
wherein the content of the first and second substances,
R1selected from C1-6 alkyl, cycloalkyl, chain alkenyl, cycloalkenyl, substituted or unsubstituted aryl C1-6 alkyl;
R2selected from substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylcycloalkyl;
n is 0, 1, or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is1Is methyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is2Is substituted or unsubstituted aryl, and the substituent in the substituted aryl is selected from halogen, trifluoromethyl, nitro, cyano and trifluoromethoxy.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is2Selected from thienyl, indolyl and tetrazolyl.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is2Is selected from substituted or unsubstituted aryl cycloalkyl, wherein the cycloalkyl in the aryl cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (FWBE) is selected from:
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-3-yl) ethyl-1-one;
2- (3, 5-bis (trifluoromethyl) phenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-phenylethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethyl) phenyl) ethyl-1-one;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (2,4, 5-trifluorophenyl) methanone;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3- (trifluoromethoxy) phenyl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (thiophen-2-yl) ethyl-1-one;
2- (3-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -3- (3- (trifluoromethyl) phenyl) propyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-fluorophenyl) ethyl-1-one;
2- (3-bromophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (1H-indol-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-2-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (naphthalen-1-yl) ethyl-1-one;
2- (3, 4-dichlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (2,4, 5-trifluorophenyl) ethyl-1-one;
2- (4-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
2- (2-chlorophenyl) -1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) ethyl-1-one;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2- (3-nitrophenyl) ethyl-1-one;
3- (2- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-oxoethyl) benzonitrile;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopropyl) methanone;
1- (3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) -2-methyl-2-phenylprop yl-1-one;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclopentyl) methanone;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclohexyl) methanone;
(3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) (1-phenylcyclobutyl) methanone.
7. A pharmaceutical composition, comprising: a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and a pharmaceutically acceptable carrier.
8. Use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for the treatment of an indication associated with an opioid receptor.
9. Use according to claim 8, wherein the indication related to opioid receptors is pain, irritable bowel syndrome, pruritus, addiction, depression.
10. The use of claim 9, wherein the pain comprises treatment or relief of intraoperative pain, chronic pain, neuropathic pain, cancer pain.
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