CN112759546B - 3- (dimethylaminomethyl) piperidin-4-ol derivatives, their preparation and their pharmaceutical use - Google Patents

3- (dimethylaminomethyl) piperidin-4-ol derivatives, their preparation and their pharmaceutical use Download PDF

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CN112759546B
CN112759546B CN201911076330.8A CN201911076330A CN112759546B CN 112759546 B CN112759546 B CN 112759546B CN 201911076330 A CN201911076330 A CN 201911076330A CN 112759546 B CN112759546 B CN 112759546B
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piperidin
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CN112759546A (en
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付伟
黄火明
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Abstract

The invention provides a compound of Formula (FWBH) or a pharmaceutically acceptable salt thereof, a preparation method 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) piperidine-4-ol piperidine derivative with a general Formula (FWBH) or a salt and a preparation method thereof, and application of the compound in treating opioid receptor mediated diseases.
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，EC 50 > 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 as an atypical opioid is different from other traditional opioids, has unique pharmacological characteristics, has strong analgesic effect and few adverse reactions, and is widely applied to pain treatment. However, clinical applications showThe analgesic effect of tramadol is slightly lower 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. After long-term administration, withdrawal reactions such as sweating, anxiety, poor sleep, pain and trembling of the body can also occur. In addition, there are studies that indicate that tramadol use is associated with increased risk of hyponatremia and hypoglycemia that require hospitalization. Therefore, there is a need for the development of analgesics having a stronger analgesic effect and less side effects.
Disclosure of Invention
The present invention provides a compound represented by Formula (FWBH), or a pharmaceutically acceptable salt thereof:
Figure BDA0002262562610000011
Figure BDA0002262562610000021
wherein, the first and the second end of the pipe are connected with each other,
R 1 selected from hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl C1-6 alkyl;
R 2 selected from C1-6 alkyl, cycloalkyl, substituted or unsubstituted endocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the substituent 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, 1,2, or 3;
R 3 selected from hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, chain alkenyl, cycloalkenyl, aryl C1-6 alkyl. In a preferred embodiment, R 1 Selected from methyl and trifluoromethyl.
In a preferred embodiment, R 2 Selected from methyl, ethyl, isopropyl, allyl, substituted or unsubstituted phenyl, substituted or unsubstituted bridged cycloalkaneAnd (4) a base. Wherein, the substituent in the substituted phenyl is preferably mono-substituted, the substituent is preferably selected from halogen, methyl, trifluoromethyl and nitro, and the substitution site can be ortho-position, meta-position and para-position. The substituted bridged cycloalkyl group is selected from the following groups:
Figure BDA0002262562610000022
in a preferred embodiment, R 3 Selected from hydrogen, fluoroalkyl. In a more preferred embodiment, R 3 Selected from hydrogen, fluoromethyl.
In a preferred embodiment, the compound of Formula (FWBH) is selected from:
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- ((3-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4-methylbenzyl) sulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenethylsulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3- (trifluoromethyl) benzyl) sulfonyl) piperidin-4-ol;
1- ((4-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- ((4-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- ((3-bromobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- ((2-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- (butylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3-nitrobenzyl) sulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenylsulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- (ethylsulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (propylsulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- (isopropylsulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- (allylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
(1R,4S) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1] heptan-2-one;
3- ((dimethylamino) methyl) -1- (((((1R, 4S) -2-hydroxy-7, 7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (methylsulfonyl) piperidin-4-ol;
(1S,4R) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1] heptan-2-one;
3- ((dimethylamino) methyl) -1- (((((1S, 4R) -2-hydroxy-7, 7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3- (trifluoromethoxy) phenyl) piperidin-4-ol;
1- (1- (benzylsulfonyl) -4- (difluoromethoxy) -4- (3-methoxyphenyl) piperidin-3-yl) -N, N-dimethylaminomethyl amine.
The invention also provides pharmaceutically acceptable salts of the compounds of Formula (FWBH), which may be formed with inorganic or organic acids, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogenphosphate, acetate, benzoate, tartrate, succinate, maleate, fumarate, lactate, citrate, gluconate, methanesulphonate, benzenesulphonate or p-toluenesulphonate salt, preferably the hydrochloride salt.
The invention also provides a pharmaceutically acceptable solvate or hydrate of the compound of Formula (FWBH).
The present invention also provides a pharmaceutical composition comprising: a compound of Formula (FWBH) 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 may be effected by administering to a subject a therapeutically effective amount of a compound of Formula (FWBH) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
The invention also provides a method for synthesizing the compound with the general Formula (FWBH), which comprises the steps of Mannich reaction, nucleophilic addition of a Grignard reagent, deprotection of Boc, protection group TES application, condensation with sulfonyl chloride, protection group removal, salt formation and the like.
Figure BDA0002262562610000041
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 "bridged cycloalkyl" refers to a cycloalkyl group in which any two carbocyclic rings share two carbon atoms not directly connected.
The term "substituted or unsubstituted endocyclic alkyl group" means that 0 or at least one hydrogen atom on the endocyclic alkyl group is replaced by a substituent selected from the group consisting of: hydroxy, oxo, halogen, C1-6 alkyl, nitrile, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluoro, nitro.
The term "aryl" refers to all carbon monocyclic or fused ring polycyclic aromatic groups containing 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, nitrile group, alkoxy, amino, nitro, alkylsulfonyl, ester group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl.
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 replaced by 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). Examples of heteroaryl groups include, but are not limited to, 6-membered ring substituents such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 5-membered heteroaryl groups such as triazolyl, imidazolyl, furyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2, 5-or 1,3, 4-oxadiazolyl, oxazolyl, thienyl, thiazolyl, isothiazolyl and pyrazolyl; 6/5 membered fused ring substituents such as indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzooxadiazolyl, benzothiazolyl, isobenzothienyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl (e.g., 5,6,7, 8-tetrahydro [1,2,4] triazolo [1,5-a ] pyridin-2-yl), and anthranoyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1, 4-benzoxazinyl.
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 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 phosphate and citrate.
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 (FWBH)" or "compound of Formula (FWBH)" 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 given for illustration only and do not limit the scope of the invention. The compounds of formula FWBH can be prepared as described in the general synthetic schemes and examples below.
Figure BDA0002262562610000081
Example 1
Preparation of intermediate 2
Figure BDA0002262562610000082
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 BDA0002262562610000083
boc-piperidone (35g, 175.66mmol, 1eq.) and acetonitrile (350ml) were added to a 1L single-neck flask with a thermometer, 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 hydrogencarbonate (250ml) was added thereto, followed by mixing, standing, layer 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 BDA0002262562610000091
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). 1 H 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 BDA0002262562610000092
250mboc-aminoalcohol (9.5g,26.06mmol, 1eq.)) and methanol (76ml) were added in a single vial, stirred, HCl/1, 4-dioxane solution (16.3ml, 65.15mmol, 2.5eq.) -added dropwise and the internal temperature was raised 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 reaction completion. 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%. 1 H NMR(400MHz,CD3OD),δ7.38(t,J＝8Hz,1H),7.15～7.16(m,1H),7.12(d,J＝8Hz,1H),6.92(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),3.83(s,3H),3.75(dd,J 1 ＝12Hz,J 2 ＝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
Preparation of intermediate 7:
a250 ml three-necked flask equipped with a nitrogen balloon, a constant pressure dropping funnel and a thermometer was charged with amino alcohol hydrochloride (10g,33.22mmol,1eq.), imidazole (20.35g,298.98mmol,9eq.), DCM (100ml) and dissolved with stirring. Cooling was carried out and triethylchlorosilane (35.06g,232.6mmol,7eq.) was added dropwise at 10 ℃. After the dropwise addition, the mixture was stirred for 5min, and then stirred overnight (26h) with the ice-water bath. TLC (DCM: MeOH ═ 10:1 and 4: 1) showed completion of the reaction. The reaction mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (100ml) under an ice-water bath, stirred for 10 minutes, and extracted with dichloromethane (25 ml). The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water (20ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled off under reduced pressure to give 36.72g of a pale yellow liquid, which was purified by alumina column chromatography to give 10.2g of a pale yellow liquid with a yield of 81%. LC-MS: ESI + [M+H] + 379.1。
Example 6
General procedure for condensation of intermediate 7 with sulfonyl chloride:
a 100ml single vial was charged with intermediate 7(1eq.), DCM (10ml), TEA (2eq.), stirred in an ice-water bath and sulphuryl chloride (1 eq.). Stirring for a certain time at 30 ℃. Adding water (30ml) and DCM, mixing, standing, layering, separating liquid. Aqueous phase was extracted with DCM (20 ml). The organic phases were combined and washed with water. And (5) evaporating under reduced pressure to obtain light yellow liquid. Was used in the next step without further purification.
Example 7
The general method for removing TES comprises the following steps:
a50 ml single-neck flask was charged with the starting materials (1eq.) and THF, dissolved with stirring, and TBAF (1.5eq.) was added. Stir at room temperature and monitor by LC-MS until the reaction is complete. THF was evaporated under reduced pressure, sodium bicarbonate solution (30ml) was added, and DCM was extracted. And combining organic phases, washing with water, drying by anhydrous magnesium sulfate, performing suction filtration, and performing reduced pressure distillation on the filtrate to obtain liquid. And (5) performing column chromatography purification to obtain a target product.
Example 8
The general method for salt formation comprises the following steps:
adding the raw materials (1eq.) into a 50ml single-mouth bottle, adding dichloromethane, stirring to dissolve, and adding methyl tert-butyl ether. Adding HCl 1, 4-dioxane solution (1.2eq.) to precipitate solid, stirring for a certain time, vacuum-filtering, leaching filter cake methyl tert-butyl ether, and pumping by an oil pump to obtain the target product.
Example 9
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH6)
Figure BDA0002262562610000111
Obtained by salifying 1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol with the yield of 95.8 percent. 1 H NMR(400MHz,CDOD),δ7.50(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),7.36～7.44(m,3H),7.33(t,J＝8Hz,1H),7.07(s,1H),70.03(d,J＝8Hz,1H),6.85～6.87(m,1H),4.45(s,2H),3.79～3.83(m,4H),3.52～3.57(m,1H),3.12～3.20(m,2H),2.95～3.01(m,1H),2.60～2.69(m,1H),2.60(s,6H),2.29～2.35(m,1H),2.13～2.21(m,1H),1.65～1.70(m,1H).LC-MS-ESI + :[M+H] + 419.3.。
Example 10
1- ((3-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH7)
Figure BDA0002262562610000112
Is obtained by salifying 1- ((3-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidine-4-ol, and the yield is 92.1%. 1 H NMR(400MHz,CDOD),δ7.56～7.57(m,1H),7.41～7.47(m,3H),7.34(t,J＝8Hz,1H),7.10～7.11(m,1H),7.05(d,J＝12Hz,1H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,H),4.49(t,2H),3.89(dd,J 1 ＝12Hz,J 2 ＝4Hz,1H),3.82(s,3H),3.56～3.61(m,1H),3.18～3.25(m,2H),2.99～3.05(m,1H),2.71(s,6H),2.69～2.73(m,1H),2.53(s,3H),2.34～2.41(m,1H),2.15～2.23(m,1H),1.68～1.73(m,1H).LC-MS-ESI + :[M+H] + 453.2.。
Example 11
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4-methylbenzyl) sulfonyl) piperidin-4-ol hydrochloride (FWBH8)
Figure BDA0002262562610000121
Is obtained by salifying 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4-methylbenzyl) sulfonyl) piperidine-4-ol, and the yield is 96.8%. 1 H NMR(400MHz,CD3OD),δ7.31～7.38(m,3H),7.23～7.26(m,2H),7.02～7.07(m,2H),6.87(dd,J＝8Hz,J＝4Hz,1H),4.40(s,2H),3.81(s,3H),3.75～3.82(m,1H),3.51～3.56(m,1H),3.12～3.21(m,3H),2.95～3.01(m,1H),2.66～2.70(m,1H),2.60(s,6H),2.35(s,3H),2.28～2.37(m,1H),2.13～2.21(m,1H),1.65～1.70(m,1H).LC-MS-ESI + :[M+H] + 433.3.。
Example 12
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenethylsulfonyl) piperidin-4-ol hydrochloride (FWBH9)
Figure BDA0002262562610000122
From 3- ((dimethylamino)) The methyl) -4- (3-methoxyphenyl) -1- (phenethylsulfonyl) piperidine-4-ol is obtained by salifying, and the yield is 87.2%. 1 H NMR(400MHz,CD3OD),δ7.23～7.37(m,6H),7.11(s,1H),7.07(d,J＝8Hz,1H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,H),3.86～3.91(m,1H),3.82(s,3H),3.70(d,J＝12Hz,1H),3.39～3.43(m,2H),3.10～3.27(m,4H),3.01～3.06(m,1H),2.69～2.74(m,1H),2.65(s,6H),2.41～2.46(m,1H),2.21～2.29(m,1H),1.76(dd,J 1 ＝12Hz,J 2 ＝4Hz,H).LC-MS-ESI + :[M+H] + 433.3.。
Example 13
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3- (trifluoromethyl) benzyl) sulfonyl) piperidin-4-ol hydrochloride (FWBH10)
Figure BDA0002262562610000131
Is obtained by salifying 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3- (trifluoromethyl) benzyl) sulfonyl) piperidine-4-ol, and the yield is 90.6%. 1 H NMR(400MHz,CD3OD),δ7.70～7.81(m,3H),7.83(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.04～7.10(m,2H),6.87(d,J＝8Hz,1H),4.57(s,2H),3.82～3.87(m,1H),3.81(s,3H),3.58～3.61(m,1H),3.18～3.25(m,2H),2.96～3.04(m,1H),2.69～2.73(m,1H),2.62(s,6H),2.39(m,1H),2.18～2.26(m,1H),1.70～1.74(m,1H).LC-MS-ESI + :[M+H] + 487.2.。
Example 14
1- ((4-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH11)
Figure BDA0002262562610000132
Is obtained by salifying 1- ((4-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidine-4-ol, and the yield is 68.4 percent. 1 H NMR(400MHz,CD3OD),δ7.41～7.50(m,4H),7.30～7.37(m,1H),7.04～7.09(m,2H),6.85～6.88(m,1H),4.44～4.46(m,2H),3.80～3.84(m,4H),3.59(m,1H),3.14～3.24(m,3H),2.96～3.03(m,1H),2.69～2.71(m,4H),2.54(s,3H),2.35(s,1H),2.16～2.23(m,1H),1.68～1.72(m,1H).LC-MS-ESI + :[M+H] + 453.2.。
Example 15
3- ((dimethylamino) methyl) -1- ((4-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH12)
Figure BDA0002262562610000141
Is obtained by salifying 3- ((dimethylamino) methyl) -1- ((4-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidine-4-ol, and the yield is 98.33%. 1 H NMR(400MHz,CD3OD),δ7.50～7.54(m,2H),7.31～7.35(m,1H),7.14～7.19(m,2H),7.09(s,1H),7.05(d,J＝8Hz,1H),6.87(d,J＝8Hz,1H),4.45(s,2H),3.82～3.84(m,1H),3.81(s,3H),3.54～3.59(m,1H),3.15～3.21(m,1H),2.97～3.03(m,1H),2.68～2.72(m,1H),2.62(s,6H),2.34～2.40(m,1H),2.16～2.24(m,1H),1.67～1.72(m,1H).LC-MS-ESI + :[M+H] + 437.2.。
Example 16
1- ((3-bromobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH13)
Figure BDA0002262562610000142
Is obtained by salifying 1- ((3-bromobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol with the yield of 85 percent. 1 H NMR(400MHz,CD3OD),δ7.57～7.58(m,1H),7.43(d,J＝8Hz,1H),7.35(d,J＝8Hz,1H),7.18～7.24(m,2H),6.90～6.98(m,2H),6.72～6.76(m,1H),4.33(s,2H),3.68～3.75(m,1H),3.67(s,3H),3.45(dd,J 1 ＝16Hz,J 2 ＝8Hz,1H),3.03～3.11(m,2H),2.84～2.90(m,1H),2.54～2.59(m,1H),2.48(s,6H),2.19～2.24(m,1H),2.01～2.09(m,1H),1.55～1.59(m,1H).LC-MS-ESI + :[M+H] + 497.2.。
Example 17
3- ((dimethylamino) methyl) -1- ((2-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH14)
Figure BDA0002262562610000143
Is obtained by salifying 3- ((dimethylamino) methyl) -1- ((2-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidine-4-ol, and the yield is 94%. 1 H NMR(400MHz,CD3OD),δ7.54～7.60(m,1H),7.41～7.49(m,1H),7.32～7.38(m,1H),7.19～7.29(m,2H),7.04～7.11(m,2H),6.86～6.91(m,1H),4.52(s,2H),3.82～3.87(m,1H),3.81(s,3H),3.54～3.57(m,1H),3.20～3.27(m,2H),2.99～3.06(m,1H),2.67～2.73(m,1H),2.62(s,6H),2.36～2.41(m,1H),2.15～2.25(m,1H),1.61～1.74(m,1H).LC-MS-ESI + :[M+H] + 437.2.。
Example 18
1- (Butylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH15)
Figure BDA0002262562610000151
Obtained by salifying 1- (butylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol salt with a yield of 88.6%. 1 H NMR(400MHz,CD3OD),δ7.32～7.39(m,1H),7.08～7.15(m,2H),6.86～6.92(m,1H),3.87～3.91(m,1H),3.81(s,3H),3.67～3.72(m,1H),3.20～3.27(m,1H),3.03～3.16(m,3H),2.70～2.77(m,1H),2.65(s,6H),2.45～2.50(m,1H),2.25～2.33(m,1H),1.76～1.84(m,3H),1.46～1.56(m,2H),0.91～1.04(m,3H).LC-MS-ESI + :[M+H] + 385.2.。
Example 19
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3-nitrobenzyl) sulfonyl) piperidin-4-ol hydrochloride (FWBH22)
Figure BDA0002262562610000152
The yield of the salified product of 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3-nitrobenzyl) sulfonyl) piperidin-4-ol is 98.4%. 1 H NMR(400MHz,CD3OD),δ8.28～8.34(m,2H),7.74～7.80(m,2H),7.32～7.40(m,1H),7.05～7.13(m,2H),6.86～6.92(m,1H),4.62～4.66(m,2H),3.81～3.88(m,4H),3.60～3.69(m,2H),3.18～3.27(m,3H),2.98～3.08(m,1H),2.64～2.74(m,7H),2.40～2.48(m,1H),2.19～2.28(m,1H),1.70～1.77(m,1H).LC-MS-ESI + :[M+H] + 464.2.。
Example 20
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenylsulfonyl) piperidin-4-ol hydrochloride (FWBH16)
Figure BDA0002262562610000161
Obtained by salifying 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenylsulfonyl) piperidin-4-ol with the yield of 92.3 percent. 1 H NMR(400MHz,CD3OD),δ7.89(d,J＝8Hz,1H),7.72～7.76(m,1H),7.65～7.69(m,2H),7.32(t,J＝8Hz,1H),7.02～7.06(m,2H),6.84～6.87(m,1H),3.98(dd,J 1 ＝12Hz,J 2 ＝4Hz,1H),3.79(s,3H),3.71～3.73(m,1H),2.95～3.01(m,1H),2.53～2.77(m,10H),2.29～2.36(m,1H),1.73～1.77(m,1H).LC-MS-ESI + :[M+H] + 405.2.。
Example 21
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidin-4-ol hydrochloride (FWBH17)
Figure BDA0002262562610000162
Is obtained by salifying 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidine-4-ol, and the yield is 98.5%. 1 H NMR(400MHz,CD3OD),δ7.69～7.75(m,4H),7.31～7.36(m,1H),7.04～7.10(m,2H),6.86～6.89(m,1H),4.56(s,2H),3.82～3.88(m,1H),3.81(s,3H),3.58～3.62(m,1H),3.22(t,J＝8Hz,2H),2.98～3.05(m,1H),2.69～2.74(m,1H),2.63(s,6H),2.35～2.41(m,1H),2.17～2.25(m,1H),1.69～1.74(m,1H).LC-MS-ESI + :[M+H] + 487.2.。
Example 22
3- ((dimethylamino) methyl) -1- (ethylsulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH18)
Figure BDA0002262562610000171
Obtained by salifying 3- ((dimethylamino) methyl) -1- (ethylsulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol with the yield of 98.7 percent. 1 H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.13(s,1H),7.09(d,J＝8Hz,1H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),3.91(dd,J 1 ＝12Hz,J 2 ＝8Hz,1H),3.82(s,3H),3.70(dd,J 1 ＝12Hz,J 2 ＝4Hz,1H),3.22～3.36(m,2H),3.13～3.18(m,2H),3.03～3.09(m,1H),2.74(s,3H),2.70～2.73(m,1H),2.58(s,3H),2.45～2.51(m,1H),2.25～2.33(m,1H),1.75～1.80(m,1H),1.37(t,J＝8Hz,3H).LC-MS-ESI + :[M+H] + 357.3.。
Example 23
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (propylsulfonyl) piperidin-4-ol hydrochloride (FWBH19)
Figure BDA0002262562610000172
Is obtained by salifying 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (propylsulfonyl) piperidine-4-ol, and the yield is 80%. 1 H NMR(400MHz,CD3OD),δ7.32～7.36(m,1H),7.08～7.13(m,2H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),3.87～3.91(m,1H),3.81(s,3H),3.66～3.71(m,1H),3.19～3.33(m,2H),3.03～3.12(m,3H),2.61～2.75(m,7H),2.45～2.51(m,1H),2.25～2.33(m,1H),1.82～1.89(m,2H),1.76～1.81(m,1H),1.08～1.12(m,3H).LC-MS-ESI + :[M+H] + 371.2.。
Example 24
3- ((dimethylamino) methyl) -1- (isopropylsulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH20)
Figure BDA0002262562610000173
Is obtained by salifying 3- ((dimethylamino) methyl) -1- (isopropylsulfonyl) -4- (3-methoxyphenyl) piperidine-4-ol, and the yield is 85.5%. 1 H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.04～7.11(m,2H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),3.89～3.93(m,1H),3.81(s,3H),3.70～3.75(m,1H),3.34～3.44(m,3H),3.03～3.09(m,1H),2.61～2.73(m,7H),2.41～2.45(m,1H),2.22～2.30(m,1H),1.71～1.76(m,1H),1.37(d,J＝4Hz,6H),.LC-MS-ESI + :[M+H] + 371.3.。
Example 25
1- (allylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH21)
Figure BDA0002262562610000181
Obtained by salifying 1- (allylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol with 89% of yield. 1 H NMR(400MHz,CD3OD),δ7.32～7.36(m,1H),7.07～7.12(m,2H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),5.91～6.02(m,1H),5.45～5.53(m,2H),3.94(d,J＝8Hz,3H),3.82(s,3H),3.70～3.75(m,1H),3.25～3.39(m,3H),3.02～3.08(m,1H),2.74(s,3H),2.57(s,3H),2.42～2.47(m,1H),2.23～2.31(m,1H),1.77(dd,J 1 ＝16Hz,J 2 ＝4Hz,1H).LC-MS-ESI + :[M+H] + 369.2.。
Example 26
(1R,4S) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1] hept-2-one hydrochloride (FWBH24)
Figure BDA0002262562610000182
From (1R,4S) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1]Salifying heptan-2-ketone to obtain the product with the yield of 84.4 percent. 1 H NMR(400MHz,CD3OD),δ7.32～7.37(m,1H),7.07～7.13(m,2H),6.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,H),3.92～3.95(m,1H),3.82(s,3H),3.73～3.77(m,1H),3.46(t,J＝16Hz,1H),3.20～3.35(m,2H),2.96～3.12(m,2H),2.39～2.75(m,10H),2.24～2.35(m,1H),2.06～2.14(m,2H),1.98(dd,J 1 ＝20Hz,J 2 ＝4Hz,1H),1.80(dd,J 1 ＝12Hz,J 2 ＝4Hz,1H),1.62～1.70(m,1H),1.45～1.53(m,1H),1.15(d,J＝4Hz,3H),0.93(d,J＝4Hz,3H).LC-MS-ESI + :[M+H] + 479.3.。
Example 27
3- ((dimethylamino) methyl) -1- (((((1R, 4S) -2-hydroxy-7, 7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH26)
Figure BDA0002262562610000191
From 3- ((dimethylamino) methyl) -1- ((((1R,4S) -2-hydroxy-7, 7-dimethylbicyclo [ 2.2.1)]Hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol is salified with a yield of 84.2%. 1 H NMR(400MHz,CD3OD),δ7.32～7.39(m,1H),7.09～7.17(m,2H),6.87～6.93(m,1H),4.03～4.07(m,1H),3.92～3.97(m,1H),3.72～3.86(m,4H),3.46～3.52(m,1H),3.18～3.35(m,2H),3.05～3.10(m,1H),2.05～2.77(m,8H),2.28～2.36(m,1H),1.73～1.86(m,5H),1.43～1.48(m,1H),1.08～1.23(m,5H),0.99～1.00(m,1H),0.90～0.95(m,3H).LC-MS-ESI + :[M+H] + 481.3.。
Example 28
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (methylsulfonyl) piperidin-4-ol hydrochloride (FWBH23)
Figure BDA0002262562610000192
Is obtained by salifying 3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (methylsulfonyl) piperidine-4-ol, and the yield is 94%. 1 H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.09～7.14(m,2H),6.86～6.89(m,1H),3.88(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),3.82(s,3H),3.65～3.70(m,1H),3.11～3.25(m,2H),3.03～3.09(m,1H),2.95(s,3H),2.72～2.78(m,1H),2.65(s,6H),2.49～2.55(m,1H),2.29～2.37(m,1H),1.79～1.84(m,1H).LC-MS-ESI + :[M+H] + 343.2.。
Example 29
(1S,4R) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1] hept-2-one hydrochloride (FWBH25)
Figure BDA0002262562610000201
From (1S,4R) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1]The heptan-2-ketone is salified, and the yield is 76.3%. 1 H NMR(400MHz,CD3OD),δ7.34(t,J＝8Hz,1H),7.07～7.13(m,2H),7.86～7.89(m,1H),3.95(d,J＝12Hz,1H),3.82(s,3H),3.74(t,J＝8Hz,1H),3.42～3.50(m,1H),3.20～3.35(m,2H),3.06～3.12(m,1H),2.97～3.03(m,1H),2.68～2.74(m,7H),2.39～2.57(m,3H),2.23～2.35(m,1H),2.06～2.15(m,2H),1.98(dd,J 1 ＝20Hz,J 2 ＝4Hz,1H),1.80(d,J＝16Hz,1H),1.62～1.70(m,1H),1.45～1.53(m,1H),1.14(d,J＝8Hz,3H),0.93(d,J＝8Hz,3H).LC-MS-ESI + :[M+H] + 479.3.。
Example 30
3- ((dimethylamino) methyl) -1- (((((1S, 4R) -2-hydroxy-7, 7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol hydrochloride (FWBH27)
Figure BDA0002262562610000202
From 3- ((dimethylamino) methyl) -1- ((((1S,4R) -2-hydroxy-7, 7-dimethylbicyclo [ 2.2.1)]Hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol is salified with a yield of 88.6%. 1 H NMR(400MHz,CD3OD),δ7.32～7.38(m,1H),7.09～7.14(m,2H),6.89(dd,J 1 ＝8Hz,J 2 ＝4Hz,1H),4.02～4.07(m,1H),3.93～3.99(m,1H),3.82(s,3H),3.72～3.78(m,1H),3.46～3.52(m,1H),3.18～3.30(m,2H),3.05～3.11(m,1H),2.87～2.93(m,1H),2.50～2.75(m,8H),2.28～2.36(m,1H),1.73～1.86(m,5H),1.43～1.148(m,1H),0.91～1.20(m,8H).LC-MS-ESI + :[M+H] + 481.3.。
Example 31
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3- (trifluoromethoxy) phenyl) piperidin-4-ol hydrochloride (FWBH29)
Figure BDA0002262562610000211
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3- (trifluoromethoxy) phenyl) piperidin-4-ol can be prepared by the same route as for 1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol by replacing 3- (methoxy) phenylmagnesium bromide in example 3 with 3- (trifluoromethoxy) phenylmagnesium bromide. Obtained by salifying 1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3- (trifluoromethoxy) phenyl) piperidin-4-ol with the yield of 91.4%. 1 H NMR(400MHz,CD3OD),δ7.49～7.55(m,4H),7.47(s,1H),7.39～7.44(m,3H),7.25(d,J＝8Hz,1H),4.46(s,2H),3.82(dd,J 1 ＝12Hz,J 2 ＝4Hz,1H),3.54～3.59(m,1H),3.12～3.21(m,2H),3.00～3.07(m,1H),2.58～2.63(m,7H),2.35～2.41(m,1H),2.13～2.22(m,1H),1.68～1.73(m,1H).LC-MS-ESI + :[M+H] + 473.2.。
Example 32
1- (1- (benzylsulfonyl) -4- (difluoromethoxy) -4- (3-methoxyphenyl) piperidin-3-yl) -N, N-dimethylaminomethylamine
Figure BDA0002262562610000212
Adding raw materials (100mg, 0.24mmol, 1eq.) and dichloromethane (0.5ml), water (0.5ml) and KOAc (188.43mmol, 1.92mmol, 8eq.) into a 25ml single-mouth bottle, and adding TMSCF 2 Br (195mg, 0.96mmol, 4 eq.). The solid was precipitated by stirring at room temperature, and methylene chloride (0.5ml) and water (0.5ml) were added thereto. LC-MS monitoring until the reaction is complete. And (4) carrying out suction filtration, washing a filter cake with water, and drying to obtain about 115mg of off-white solid. Methanol and ethyl acetate (0.4 ml: 0.6ml) were crystallized to give 90mg of an off-white solid with a yield of 80.4%.
1- (1- (benzylsulfonyl) -4- (difluoromethoxy) -4- (3-methoxyphenyl) piperidin-3-yl) -N, N-dimethylaminomethylamine hydrochloride (FWBH30)
Figure BDA0002262562610000221
Obtained by salifying 1- (1- (benzylsulfonyl) -4- (difluoromethoxy) -4- (3-methoxyphenyl) piperidin-3-yl) -N, N-dimethylaminomethyl amine in 84% yield. 1 H NMR(400MHz,CD3OD),δ7.485～7.501(m,2H),7.339～7.421(m,4H),7.107～7.148(m,2H),6.890～6.914(m,2H),6.838(s,J＝58.4Hz,1H),4.456(s,2H),3.823(s,3H),3.765(d,J＝13.2Hz,2H),3.564(d,J＝12.8Hz,1H),3.117～3.362(m,2H),2.977(s,3H),2.637(s,3H),2.482～2.504(m,1H),2.326～2.395(m,1H),1.715(d,J＝14.8Hz,1H).LC-MS-ESI+:
[M+H] + 469.2.。
Example 33
Preparation of Membrane receptors
CHO cells expressing mu opioid receptor, delta opioid receptor and kappa opioid receptor respectively are planted in 10cm 2 Culturing 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 on the bottom of the dish; adding PBS/EDTA solution (0.1M NaCl, 0.01M NaH) 2 PO 4 ,0.04％EDTA) Digesting 3ml for 3-5min, blowing with a suction tube to completely drop cells, collecting the cells in a 40ml centrifuge tube, centrifuging at 5000rpm for 5min, and removing 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; adding a proper amount of 50mM Tris-HCl, pH 7.4 buffer solution into the obtained precipitate, homogenizing, and subpackaging in a centrifuge tube, and storing 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, the mixture is incubated for 30min at 30 ℃, 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 and PERKIN ELMER PRI-CARB 2910 liquid scintillation counter to measure the radioactive intensity, calculating the inhibition rate, repeating the experiment for more than three times, and each group of three tubes.
The inhibition ratio (or called binding ratio) (total binding ratio dpm-sample tube dpm)/(total binding tube dpm-nonspecific binding tube dpm) is 100%
IC was calculated using Graphpad Prism 5.0 software 50 . The Ki value, Ki ═ IC, was calculated as follows 50 /(1+[L]/K d )，[L]As concentration of the labeled ligand added, K d Equilibrium dissociation parameters for labeled ligands
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 BDA0002262562610000231
Figure BDA0002262562610000241
Figure BDA0002262562610000251
Figure BDA0002262562610000261
Figure BDA0002262562610000271
a. Inhibition or binding at 0.1. mu.M.
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 of the present invention all exhibit greater or comparable affinity for opioid receptors than tramadol.
Example 34
In vivo hot plate analgesia test
Female mice weighing about 20g are placed on a hot plate apparatus preheated to 55 ℃, and the latency period of the foot reaction after the mice lick is taken as the pain threshold index. 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-intraperitoneal administration. The percentage of analgesic effect (% MPE) is calculated according to the following formula: percentage analgesic effect (% MPE). ED50 values were calculated using Graphpad prism 5.0 software based on percent analgesic efficacy.
TABLE 25 percent maximum analgesic efficacy on Hot plates of Compounds at mg/kg dose or ED50 value
Figure BDA0002262562610000272
Figure BDA0002262562610000281
Figure BDA0002262562610000291
Figure BDA0002262562610000301
Figure BDA0002262562610000311
"% MPE or ED of Table 2 50 In the column, the values expressed as percentages refer to% MPE and the values in mg/kg refer to ED 50 。
As can be seen from table 2, the compounds of the present invention all showed stronger in vivo analgesic effect than tramadol.

Claims (9)

1. A compound of Formula (FWBH), or a pharmaceutically acceptable salt thereof:
Figure FDA0003680294140000011
wherein the content of the first and second substances,
R 1 selected from hydrogen, C1-6 alkyl, trifluoromethyl;
R 2 selected from C1-6 alkyl, allyl, phenyl unsubstituted or substituted by halogen, C1-6 alkyl, nitro or trifluoromethyl,
Figure FDA0003680294140000012
n is 0, 1,2, or 3;
R 3 selected from hydrogen, C1-6 alkyl, fluoromethyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is 1 Selected from methyl and trifluoromethyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is 2 Selected from methyl, ethyl, isopropyl, allyl, phenyl unsubstituted or substituted by halogen, C1-6 alkyl, nitro or trifluoromethyl,
Figure FDA0003680294140000013
4. the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is 3 Selected from hydrogen, fluoromethyl.
5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that the compound of Formula (FWBH) is selected from:
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- ((3-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4-methylbenzyl) sulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenethylsulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3- (trifluoromethyl) benzyl) sulfonyl) piperidin-4-ol;
1- ((4-chlorobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- ((4-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- ((3-bromobenzyl) sulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- ((2-fluorobenzyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- (butylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((3-nitrobenzyl) sulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (phenylsulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -1- (ethylsulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (propylsulfonyl) piperidin-4-ol;
1- (allylsulfonyl) -3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) piperidin-4-ol;
(1R,4S) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1] heptan-2-one;
3- ((dimethylamino) methyl) -1- (((((1R, 4S) -2-hydroxy-7, 7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
3- ((dimethylamino) methyl) -4- (3-methoxyphenyl) -1- (methylsulfonyl) piperidin-4-ol;
(1S,4R) -1- (((3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl) sulfonyl) methyl) -7, 7-dimethylbicyclo [2.2.1] heptan-2-one;
3- ((dimethylamino) methyl) -1- (((((1S, 4R) -2-hydroxy-7, 7-dimethylbicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) -4- (3-methoxyphenyl) piperidin-4-ol;
1- (benzylsulfonyl) -3- ((dimethylamino) methyl) -4- (3- (trifluoromethoxy) phenyl) piperidin-4-ol;
1- (1- (benzylsulfonyl) -4- (difluoromethoxy) -4- (3-methoxyphenyl) piperidin-3-yl) -N, N-dimethylaminomethyl amine.
6. A pharmaceutical composition, comprising: a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
7. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an indication associated with an opioid receptor.
8. The use of claim 7, wherein the indication associated with an opioid receptor is pain, irritable bowel syndrome, pruritus, addiction, depression.
9. The use of claim 8, wherein the pain comprises treatment or alleviation of pain during surgery, chronic pain, neuropathic pain, cancer pain.
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