CN117800942A - Thiophene piperazine amide derivative, composition and application thereof - Google Patents

Thiophene piperazine amide derivative, composition and application thereof Download PDF

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CN117800942A
CN117800942A CN202311710358.9A CN202311710358A CN117800942A CN 117800942 A CN117800942 A CN 117800942A CN 202311710358 A CN202311710358 A CN 202311710358A CN 117800942 A CN117800942 A CN 117800942A
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ethyl
thiophen
piperazin
phenyl
ylmethyl
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曹旭东
范志远
施玉鑫
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Xuzhou Medical University
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Xuzhou Medical University
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Abstract

The invention discloses a thiophene piperazine amide derivative, a composition and application thereof, wherein the derivative is a compound shown in a structural general formula (I) or pharmaceutically acceptable salt thereof or optical isomer thereof or stereoisomer thereof; the composition comprises an acylated indoline derivative or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers. The invention also provides thiophene piperazine amide derivatives or medicines thereofUse of a pharmaceutically acceptable salt or an optical isomer or a stereoisomer thereof for the preparation of a medicament for the prophylaxis or treatment of pain disorders. The derivative may have sigma 1 The dual activity of the receptor antagonist and the mu receptor agonist can obviously improve the pain induced by formalin; the Chinese medicinal composition is applied to the treatment of pain, particularly neuralgia, has the characteristics of high response rate, small side effect, less adverse reaction and the like, and meets the requirements of clinical medication.

Description

Thiophene piperazine amide derivative, composition and application thereof
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a thiophene piperazine amide derivative, a thiophene piperazine amide derivative composition and application of thiophene piperazine amide derivative.
Background
Pain is an unpleasant subjective sensory and emotional experience associated with tissue damage or potential damage. Pain is a warning system in the organism, which can cause defensive reaction and has protective effect, but intense or lasting pain can cause disorder of physiological functions of the organism, and can directly affect human beings, such as appetite and sleep, quality of life reduction, labor loss, economic benefit reduction, medical expenditure increase and the like. Pain affects approximately 20% of the adult population, and many patients have no effective treatment and relief of pain.
Neuropathic pain refers to: pain directly caused by injury or disease of the somatosensory nervous system, including peripheral nerve fibers and the central nervous system, is one of the pain, and is characterized clinically by spontaneous pain, hyperalgesia, allodynia, and paresthesia. About 7-10% of people worldwide suffer from neuralgia and their incidence increases with age. The drugs currently used to treat or alleviate neuropathic pain are mainly: non-steroidal anti-inflammatory drugs (non-steriod anti-inflammatory drugNSAIDs), antidepressants, anticonvulsants, and opioids.
The treatment method of the neuralgia mainly comprises non-invasive means such as drug treatment auxiliary psychology and behavior therapy, and clinically commonly used drugs include anticonvulsants, antidepressants, 5-hydroxytryptamine (5-HT), norepinephrine reuptake inhibitors, local anesthetics, opioid analgesics, N-methyl-D-aspartate receptor (NMDA) antagonists and the like, wherein the former three drugs are the first choice drugs for treating the neuralgia. Current drugs used as first-line treatment for neuropathic pain include anticonvulsants (gabapentin and pregabalin) which are not metabolized by the liver and are excreted by the kidneys, and therefore patients with insufficient renal function or ongoing renal dialysis need careful medication, common side effects of sleepiness, dizziness, debilitation, weight gain and ataxia. Tricyclic antidepressants (e.g., amitriptyline, noramitriptyline, etc.) and 5-hydroxytryptamine and norepinephrineAntidepressants (such as venlafaxine, duloxetine and the like) are taken as the ingestion inhibitors, and have strong side effects and low response rate. Opioids (morphine, fentanyl, tramadol, etc.) are used as second-line drugs for the treatment of neuropathic pain, and have remarkable side effects, mainly manifested by respiratory depression, constipation, nausea, etc., and are prone to drug resistance and addiction after long-term administration. Sigma-1 (Sigma) 1 ) Receptors, H 3 Receptors, cannabinoid receptors, NOP receptors, etc. are new targets that have been studied in recent years, and biased mu receptor agonists are also the current research focus, but these targets have been studied very early and have entered few clinical trials. Therefore, searching for a new mechanism of action, and researching analgesic drugs with high analgesic activity and small side effects has great significance.
σ 1 Receptors are recently emerging new targets for neuropathic pain treatment, and many studies have shown that receptor antagonists themselves have analgesic effects. Sigma (sigma) 1 Mice with the receptor gene knocked out showed pain insensitivity to formalin experiments with sigma 1 Formalin-induced pain was significantly reduced when mice were pretreated with a receptor antagonist (haloperidol). Similarly, entrena et al found that wild-type (WT) mice induced mechanical allodynia, while σ in experiments with central sensitization to pain by intraplantar injection of capsaicin 1 Mice with the receptor gene knocked out have no apparent pain behavior, and σ 1 Receptor antagonists inhibit this pain behavior. In recent years people are based on sigma 1 The receptor antagonist synthesizes quinolinone, aryl pyrimidine and 6-hydroxy pyridazinone derivatives for the treatment of neuropathic pain. Compound S1RA was developed by espeve company in 2012, with the effect of treating neuropathic pain and enhancing the analgesic effect of opioids, and phase II clinical trials are currently underway. But still not based on sigma 1 The receptor is used for the drug on the market for resisting neuralgia.
σ 1 The initial use of the receptor for analgesia is derived from the anti-opioid system where Chien and pananak found that Sigma receptors are endogenous, agonists of Sigma-1 receptors counteract opioid receptor-mediated analgesia, whereas antagonists thereof (e.g., haloperidol)Strengthen the analgesic effect of opioid receptor agonist morphine. Carroll was equal to 1992 and found by in vitro survival that phenazocine and its derivatives had dual pharmacological activity of sigma-1 receptor and mu receptor, but no in vivo analgesic activity evaluation was performed. The Prezzavento subject group is based on the early-stage study of Carroll, researches the analgesic effect of phenazocine on a mechanical pain model, and experimental data show that the analgesic effect of the phenazocine can be realized by mu receptor antagonists of naloxone, naloxone methyl iodide and sigma 1 Antagonizing by the agonist PRE-084, proves that the phenazocine simultaneously acts sigma 1 The receptor and mu receptor act as analgesics. The compound has double pharmacological activities and better analgesic activity, and is expected to be used for treating pain. In 2019 Mwave nica GarcRia proposed to synthesize sigma-based compound by pharmacophore fusion method 1 The spiro undecane derivative with double target points of mu receptor has analgesic activity. Thus, find the sigma 1 The analgesic with dual pharmacological activities of receptor antagonist and mu receptor agonist has important scientific significance.
Disclosure of Invention
One of the objects of the present invention is to provide a thiophene piperazine amide derivative and a composition, the derivative can have sigma 1 The dual activity of the receptor antagonist and the mu receptor agonist can obviously improve the I pain induced by formalin; the Chinese medicinal composition is applied to the treatment of pain, particularly neuralgia, has the characteristics of high response rate, small side effect, less adverse reaction and the like, and meets the requirements of clinical medication.
The second object of the invention is to provide the application of thiophene piperazine amide derivatives or pharmaceutically acceptable salts thereof or optical isomers thereof or stereoisomers thereof in preparing medicaments for preventing or treating pain diseases.
In order to achieve the above purpose, the invention adopts the following technical scheme: thiophene piperazine amide derivatives are compounds with a structural general formula (I) or pharmaceutically acceptable salts thereof or optical isomers thereof or stereoisomers thereof:
wherein Q is C or N; n and m are each 0, 1 or 2;
R 1 selected from halogen, C 1-5 Alkyl, halogen substituted C 1-5 One of the alkyl groups is used for the preparation of a catalyst,
R 2 、R 3 、R 4 、R 5 respectively selected from hydrogen, C 1-5 Alkoxy, substituted C 1-5 Alkoxy, halogen, C 1-5 Alkyl, substituted C 1-5 Alkyl, C 3-7 Cycloalkyl, substituted C 3-7 Cycloalkyl, phenyl, alkyl-substituted phenyl, heteroaryl ring.
Preferably, the C 1-5 The alkyl is selected from one of methyl, ethyl, propyl, butyl, isopropyl, tertiary butyl, amyl and isoamyl; the C is 1-5 The alkoxy is selected from one of methoxy, ethoxy, propoxy, butoxy and pentoxy.
Preferably, R 1 In (C) substituted by halogen 1-5 The alkyl is selected from one of dichloromethyl and trifluoromethyl.
Preferably, the substituted C 1-5 Alkoxy, substituted C 1-5 Alkyl, substituted C 3-7 The substituent groups in the cycloalkyl are respectively selected from one or more of amino, hydroxyl, methyl and halogen.
Preferably, the halogen is fluorine, chlorine, bromine or iodine.
Preferably, the salt is a pharmaceutically acceptable anion salt selected from one of hydrochloride, hydrobromide, hydroiodide, oxalate, citrate, acetate, maleate, fumarate, nitrate, sulfate, bisulfate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate. Preferably, the anionic salt is a hydrochloride or oxalate salt.
Preferably, the derivatives are:
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) propanamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) butanamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide,
2-methoxy-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide,
2-methyl-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide,
4-methoxy-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide,
4-fluoro-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide,
2-fluoro-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) acrylamide,
N- (4-fluorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide,
N- (4-chlorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide,
N- (4-methoxyphenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide,
N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) furan-2-carboxamide,
N- (4-fluorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-chlorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-methoxyphenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) thiophene-2-carboxamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acetamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) propanamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) butanamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
2-methoxy-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acetamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
2-methyl-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
4-methoxy-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
4-fluoro-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
2-fluoro-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
3-methyl-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) cyclopropanecarboxamide,
N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) acrylamide,
N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl-N- (p-tolyl) furan-2-carboxamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) thiophene-2-carboxamide.
The reaction general formula is as follows:
in another aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the thiophenepaperamide derivative or the pharmaceutically acceptable salt thereof or the optical isomer thereof or the stereoisomer thereof, and one or more pharmaceutically acceptable excipients (carrier, excipient, binder, disintegrant, lubricant or sweetener, etc.).
The auxiliary material such as excipient can be calcium hydrophosphate; the binder is selected from corn starch, gelatin, and gum arabic; disintegrants such as corn starch, potato starch or alginic acid; lubricants such as magnesium stearate; when the formulation is in the form of a capsule, a liquid carrier such as grease may be included in addition to the above-described types of raw materials.
The invention further provides application of the thiophen piperazine amide derivatives or pharmaceutically acceptable salts thereof or optical isomers thereof or stereoisomers thereof in preparing medicaments for preventing or treating pain diseases.
Preferably, the pain-based disorder is neuralgia, inflammatory pain, trigeminal neuralgia or cancer pain.
The synthesis method of the compound with the general formula I comprises the steps of synthesizing an amide compound by using an aniline compound and a carbon chain containing acyl chloride, linking the amide compound with a thiophene piperazine ring, and finally reducing carbonyl and acylating to obtain a thiophene piperazine series derivative.
An effective dose of a compound of the invention may be administered orally, e.g., with an inert diluent or with some carrier. It may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention may be used together with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like. These formulations should contain approximately 1% to 99% by weight of the active compound of the invention or a salt thereof, but the active content of these active compounds or salts thereof is preferably in the range of 4% to 70% depending on the dosage form.
The compounds of formula I or salts thereof of the present invention can provide about 0.01mg to 1000mg per unit dose of active ingredient, and the compounds containing formula I or salts thereof can be administered by common routes of administration, such as oral optional capsules, tablets, syrups, and the like; parenteral administration may take the form of an injection such as subcutaneous injection, intramuscular injection, intravenous injection, etc.; the topical application may be in the form of a paste or lotion or rectally in the form of a suppository, transdermally in the form of a patch delivery system, and the total daily dose is typically between about 0.05mg and 2000mg, depending on the specific condition of the patient, such as health, age, sex, weight and drug tolerance, and may be determined by the physician with respect to the type and severity of the disease or disorder. Effective dosages of commonly used CNS agents are well known to those skilled in the art and they are able to determine the appropriate dosage based on these or other factors. For parenteral administration, the compounds provided herein may be combined with sterile water or organic media to form injectable solutions or suspensions.
Furthermore, the compounds provided by the present invention and pharmaceutical compositions consisting of the compounds are useful for the treatment and prevention of pain, including acute pain: soft tissue and joint acute injury pain, postoperative pain, obstetrical pain, acute herpes zoster pain, gout and the like; chronic pain: soft tissue and joint strain or degeneration pain, intervertebral disc-derived pain, and nerve-derived pain; intractable pain: trigeminal neuralgia, postherpetic neuralgia, herniated disk and intractable headache; cancer pain: advanced tumor pain, tumor metastasis pain; specific pain classes: thromboangiitis pain, intractable angina, idiopathic chest and abdominal pain, etc.
In vitro receptor binding assays indicate that the derivatives provided by the invention have sigma 1 The dual activity of receptor antagonists and mu receptor agonists, and the results of animal experiments also showed that the results in formalin induced pain models showed that the ED of thiophenepiperazine derivatives 50 The value is lower than that of the positive medicine pregabalin, and the pregabalin has better analgesic activity. Thus, the derivatives provided by the invention have the potential to treat pain, in particular neuralgia. The Chinese medicinal composition is applied to the treatment of pain, particularly neuralgia, has the characteristics of high response rate, small side effect, less adverse reaction and the like, and meets the requirements of clinical medication.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide, the reaction formula:
the preparation process comprises the following steps:
1) 4- (thiophene-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 1):
4.37g of 2-thiophenecarboxylic acid, 6.07g of boc piperazine, 13.63g of HATU, 9.08mL of triethylamine, and 100mL of DMF were successively added to a 250mL single-necked flask, and stirred at room temperature overnight. After the reaction, adding water for quenching, extracting with EA, washing with saturated saline water, adding anhydrous sodium sulfate, stirring and drying, distilling under reduced pressure to remove the solvent, adding a proper amount of anhydrous ethanol and petroleum ether for heating and dissolving, cooling for crystallization, filtering, washing the filter cake with petroleum ether, and drying to obtain a white solid with the yield of about 80.7 percent.
2) Piperazin-1-yl (thiophen-2-yl) methanone (intermediate 2):
5.0g of tert-butyl 4- (thiophene-2-carbonyl) piperazine-1-carboxylate (intermediate 1) was dissolved in 10mL of dichloromethane and placed in an ice bath with stirring to 0 ℃;7.5mL of trifluoroacetic acid was slowly added dropwise and stirred at room temperature for 4 hours. After the reaction, the solvent and the excessive trifluoroacetic acid are removed by rotary evaporation, 100mL of water is added for quenching, and then saturated NaHCO is used 3 The solution was neutralized to neutrality, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate under stirring, and the solvent was distilled off under reduced pressure, followed by EA: pe=3:1 to 1:1 column chromatography gave a colorless oil in about 75.4% yield.
3) 2-chloro-N-phenylamide (intermediate 3):
3.0g of aniline, 8.9g of 8.9g K 2 CO 3 Dissolving in 10mL of acetone, and placing in an ice bath to stir to 0 ℃; chloroacetyl chloride 4.4g was slowly added dropwise and stirred at room temperature for 4 hours. Quenching with water after the reaction, extracting with EA, and thenWashing with dilute NaOH solution and saturated saline solution, adding anhydrous sodium sulfate, stirring, drying, distilling under reduced pressure to remove solvent, adding appropriate amount of anhydrous ethanol and petroleum ether, heating for dissolving, cooling for crystallization, filtering, washing filter cake with petroleum ether, and drying to obtain white solid with yield of about 65.8%.
4) N-phenyl-2- (4- (thiophene-2-carbonyl) piperazin-1-yl) acetamide (intermediate 4):
A single-necked flask was charged with 1.69g of piperazin-1-yl (thiophen-2-yl) methanone (intermediate 2), 150mL of acetone, 1.96g of 2-chloro-N-phenylamide (intermediate 3), and 4.07. 4.07g K 2 CO 3 The reaction was carried out at room temperature for 8 hours. After completion of the reaction, the mixture was quenched with water, extracted with an appropriate amount of EA, washed 3 times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and passed through a column with PE: ea=1:1 to give about 2.63g of a white solid with a yield of 79.9%.
5) N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) aniline (intermediate 5):
2.0g of intermediate 4 and 100mL of anhydrous THF are added into a single-neck flask, stirred in an ice bath for 15min, cooled to 0 ℃, and then 1.37g of LiAlH is slowly added 4 Transfer to an oil bath and reflux for 4h at 65 ℃. After the completion of the reaction, the reaction mixture was cooled in an ice bath, quenched by slow addition of ethanol, extracted with EA, washed with 5% naoh solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, followed by passing PE: ea=1:2 through a column to give 1.55g of colorless oil in 85.0% yield.
6) N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide
Into a single-neck flask, 0.35g of intermediate 5, 0.18g of triethylamine and 50mL of DCM were added, the mixture was stirred for 15min under ice-bath conditions, the temperature was lowered to 0℃and 0.13g of acetyl chloride was slowly added dropwise, followed by ice-bath stirring for 1h. After the reaction is finished, saturated NaHCO is added 3 Quench, extract with DCM and sequentially saturate NaHCO 3 Washing the solution and saturated saline water, drying by using anhydrous sodium sulfate, and spin-removing the solvent; washing with PE: ea=1:2 followed by DCM: meoh=25:1 gave 0.31g of a yellowish brown transparent oil in 77.5% yield.
1 H NMR(400MHz,Chloroform-d)δ7.38(dd,J＝8.2,6.5Hz,2H),7.34–7.28(m,1H),7.21–7.16(m,3H),6.92(dd,J＝5.0,3.4Hz,1H),6.88(dd,J＝3.4,1.1Hz,1H),3.81(t,J＝7.0Hz,2H),3.69(s,2H),2.47(t,J＝7.0Hz,10H),1.80(s,3H).MS(ESI)m/z＝344.2([M+H] + ).
Example 2
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) propanamide
The title compound was prepared by the procedure of example 1, except that "propionyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.42–7.27(m,3H),7.23–7.10(m,4H),6.94–6.87(m,2H),3.81(t,J＝7.1Hz,2H),3.75–3.63(m,2H),2.55–2.38(m,10H),2.01(q,J＝7.4Hz,2H),1.01(t,J＝7.4Hz,3H).MS(ESI)m/z＝358.2([M+H] + ).
Example 3
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) butanamide
The title compound was prepared by the procedure of example 1, except that "butyryl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.41–7.34(m,2H),7.34–7.28(m,1H),7.22–7.14(m,3H),6.92(dd,J＝5.0,3.4Hz,1H),6.88(dd,J＝3.4,1.1Hz,1H),3.81(t,J＝7.0Hz,2H),3.69(d,J＝0.8Hz,2H),2.65–2.24(m,10H),1.97(t,J＝7.4Hz,2H),1.56(h,J＝7.4Hz,2H),0.79(t,J＝7.4Hz,3H).MS(ESI)m/z＝372.2([M+H] + ).
Example 4
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide
The title compound was prepared by the procedure of example 1, except that "cyclopropylcarbonyl" was used instead of "acetylchloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.42–7.35(m,2H),7.34–7.28(m,1H),7.26–7.21(m,3H),6.96–6.92(m,2H),3.94–3.82(m,4H),2.83–2.53(m,10H),1.26(qd,J＝7.6,3.2Hz,1H),0.96(qd,J＝4.4,3.1Hz,2H),0.59(dq,J＝7.0,3.7Hz,2H).MS(ESI)m/z＝370.3([M+H] + ).
Example 5
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 1, except that "propenyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.44–7.26(m,3H),7.22–7.11(m,3H),6.95–6.83(m,2H),6.33(dd,J＝16.8,2.0Hz,1H),5.97(dd,J＝16.8,10.3Hz,1H),5.48(dd,J＝10.3,2.1Hz,1H),3.90(dd,J＝7.5,6.6Hz,2H),3.69(d,J＝0.8Hz,2H),2.59–2.30(m,10H).MS(ESI)m/z＝356.2([M+H] + ).
Example 6
Preparation of 2-methoxy-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide
The title compound was prepared by the procedure of example 1, except that "methoxyacetyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.42–7.33(m,3H),7.23(dd,J＝4.9,1.5Hz,1H),7.20–7.14(m,2H),6.95–6.90(m,2H),3.84(t,J＝6.9Hz,2H),3.81–3.77(m,2H),3.70(s,2H),3.30(s,3H),2.56(dd,J＝13.2,6.2Hz,10H).MS(ESI)m/z＝374.3([M+H] + ).
Example 7
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "benzoyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.28–7.23(m,2H),7.21(dd,J＝5.0,1.3Hz,1H),7.20–7.15(m,3H),7.15–7.09(m,3H),7.07–7.02(m,2H),6.92(dd,J＝5.0,3.4Hz,1H),6.89(dd,J＝3.5,1.1Hz,1H),4.04(t,J＝7.0Hz,2H),3.70(s,2H),2.73–2.31(m,10H).MS(ESI)m/z＝406.2([M+H] + ).
Example 8
Preparation of 2-methyl-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "o-methylbenzoyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.22(dd,J＝5.0,1.3Hz,1H),7.11(d,J＝7.4Hz,2H),7.03(q,J＝10.2,8.5Hz,5H),6.93(dd,J＝5.0,3.4Hz,2H),6.89(d,J＝3.8Hz,2H),4.10(dt,J＝16.5,8.2Hz,2H),3.71(s,2H),2.65–2.40(m,10H),2.34(s,3H).MS(ESI)m/z＝420.3([M+H] + ).
Example 9
Preparation of 4-methoxy-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "p-methoxybenzoyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.26–7.16(m,5H),7.14–7.08(m,1H),7.07–7.03(m,2H),6.92(dd,J＝5.1,3.4Hz,1H),6.88(dd,J＝3.4,1.2Hz,1H),6.65–6.59(m,2H),4.05–3.98(m,2H),3.71(s,3H),3.69(d,J＝0.8Hz,2H),2.69–2.36(m,10H).MS(ESI)m/z＝436.2([M+H] + ).
Example 10
Preparation of 4-fluoro-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "p-fluorobenzoyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.25(q,J＝5.4,4.1Hz,2H),7.23–7.16(m,3H),7.16–7.09(m,1H),7.07–7.00(m,2H),6.95–6.87(m,2H),6.81(td,J＝8.8,2.6Hz,2H),4.02(q,J＝4.8,2.4Hz,2H),3.70(d,J＝2.6Hz,2H),2.75–2.23(m,10H).MS(ESI)m/z＝424.2([M+H] + ).
Example 11
Preparation of 2-fluoro-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "o-fluorobenzoyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.23–7.12(m,5H),7.09(d,J＝9.0Hz,3H),6.93(ddd,J＝13.2,11.6,5.5Hz,3H),6.77(t,J＝8.8Hz,1H),4.04(t,J＝7.1Hz,2H),3.71(s,2H),2.67–2.26(m,10H).MS(ESI)m/z＝424.2([M+H] + ).
Example 12
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 1, except that "2-furoyl chloride" was used instead of "acetyl chloride" in example 1, step 6).
1 H NMR(400MHz,Chloroform-d)δ7.42–7.32(m,3H),7.30(d,J＝1.7Hz,1H),7.26–7.21(m,2H),7.20(dd,J＝5.1,1.3Hz,1H),6.94–6.84(m,2H),6.15(dt,J＝3.3,1.5Hz,1H),5.64(d,J＝3.5Hz,1H),3.96(t,J＝7.0Hz,2H),3.68(s,2H),2.66–2.30(m,10H).MS(ESI)m/z＝396.2([M+H] + ).
Example 13
Preparation of N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) acrylamide
The title compound was prepared by the procedure of example 5, except that "p-toluidine" was used instead of "aniline" in example 5, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.20(dd,J＝13.4,6.4Hz,3H),7.07(d,J＝7.7Hz,2H),6.96–6.84(m,2H),6.32(d,J＝16.8Hz,1H),6.00(dd,J＝16.9,10.3Hz,1H),5.47(d,J＝10.3Hz,1H),3.88(t,J＝7.2Hz,2H),3.70(s,2H),2.51(dd,J＝17.9,9.8Hz,10H),2.37(s,3H).MS(ESI)m/z＝370.2([M+H] + ).
Example 14
Preparation of N- (4-fluorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 5, except that "para-fluoroaniline" was used instead of "aniline" in step 3) of example 5.
1 H NMR(400MHz,Chloroform-d)δ7.39–7.33(m,2H),7.22(dd,J＝5.1,1.3Hz,1H),7.20–7.14(m,2H),6.94(dd,J＝5.1,3.4Hz,1H),6.90(dt,J＝3.5,1.0Hz,1H),6.35(dd,J＝16.7,2.0Hz,1H),5.97(dd,J＝16.7,10.3Hz,1H),5.53(dd,J＝10.3,2.0Hz,1H),3.87(t,J＝6.8Hz,2H),3.70(d,J＝0.8Hz,2H),2.57–2.39(m,10H).MS(ESI)m/z＝374.2([M+H] + ).
Example 15
Preparation of N- (4-chlorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 5, except that "p-chloroaniline" was used instead of "aniline" in example 5, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.25–7.16(m,3H),7.12–7.03(m,2H),6.94(dd,J＝5.0,3.4Hz,1H),6.91–6.83(m,1H),6.35(dd,J＝16.8,2.0Hz,1H),5.96(dd,J＝16.8,10.4Hz,1H),5.52(dd,J＝10.3,2.0Hz,1H),3.87(t,J＝6.9Hz,2H),3.70(d,J＝0.8Hz,2H),2.58–2.36(m,10H).MS(ESI)m/z＝390.1([M+H] + ).
Example 16
Preparation of N- (4-methoxyphenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 5, except that "p-methoxyaniline" was used instead of "aniline" in example 5, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.23(d,J＝5.0Hz,1H),7.16–7.08(m,2H),6.97–6.87(m,4H),6.38–6.29(m,1H),6.06–5.96(m,1H),5.49(d,J＝10.3Hz,1H),3.92–3.85(m,2H),3.85(d,J＝2.3Hz,3H),3.72(d,J＝2.2Hz,2H),2.64–2.38(m,10H).MS(ESI)m/z＝386.2([M+H] + ).
Example 17
Preparation of N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 12, except that "p-toluidine" was used instead of "aniline" in example 12, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.33(s,1H),7.22–7.17(m,2H),7.12(dd,J＝8.3,2.2Hz,2H),6.96–6.87(m,2H),6.17(d,J＝3.6Hz,1H),5.63(s,1H),5.30(d,J＝2.2Hz,1H),3.98–3.91(m,2H),3.70(d,J＝2.2Hz,2H),2.66–2.42(m,10H),2.39(d,J＝2.2Hz,3H).MS(ESI)m/z＝410.2([M+H] + ).
Example 18
Preparation of N- (4-fluorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 12, except that "para-fluoroaniline" was used instead of "aniline" in step 3) of example 12.
1 H NMR(400MHz,Chloroform-d)δ7.35(d,J＝2.0Hz,1H),7.34(d,J＝2.2Hz,1H),7.30(dd,J＝1.7,0.8Hz,1H),7.23–7.20(m,2H),7.19(d,J＝2.1Hz,1H),6.93(dd,J＝5.1,3.3Hz,1H),6.89(dd,J＝3.4,1.2Hz,1H),6.24(dd,J＝3.5,1.7Hz,1H),5.97(d,J＝3.5Hz,1H),3.94(t,J＝6.8Hz,2H),3.70(d,J＝0.8Hz,2H),2.68–2.32(m,10H).MS(ESI)m/z＝414.2([M+H] + ).
Example 19
Preparation of N- (4-chlorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 12, except that "p-chloroaniline" was used instead of "aniline" in step 3) of example 12.
1 H NMR(400MHz,Chloroform-d)δ7.32(d,J＝1.7Hz,1H),7.27–7.21(m,3H),7.13–7.04(m,2H),6.94(dd,J＝5.0,3.4Hz,1H),6.90(dd,J＝3.5,1.1Hz,1H),6.22(dd,J＝3.6,1.7Hz,1H),5.82(s,1H),3.94(t,J＝6.8Hz,2H),3.71(s,2H),2.62–2.38(m,10H).MS(ESI)m/z＝430.1([M+H] + ).
Example 20
Preparation of N- (4-methoxyphenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 12, except that "p-methoxyaniline" was used instead of "aniline" in example 12, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.37(dd,J＝1.8,0.8Hz,1H),7.24(dd,J＝5.1,1.3Hz,1H),7.22–7.15(m,2H),6.98–6.89(m,4H),6.20(dd,J＝3.6,1.7Hz,1H),5.63(s,1H),3.96(t,J＝6.9Hz,2H),3.87(s,3H),3.73(d,J＝0.8Hz,2H),2.65–2.44(m,10H).MS(ESI)m/z＝426.2([M+H] + ).
Example 21
Preparation of N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) thiophene-2-carboxamide
The title compound was prepared by the procedure of example 1, except that "2-thiophenecarboxyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.39–7.34(m,3H),7.29–7.24(m,3H),7.20(dd,J＝5.0,1.2Hz,1H),6.92(dd,J＝5.0,3.4Hz,1H),6.88(dt,J＝3.4,1.0Hz,1H),6.75(dd,J＝5.0,3.8Hz,1H),6.64(dd,J＝3.8,1.2Hz,1H),3.97(dd,J＝7.6,6.6Hz,2H),3.69(d,J＝0.8Hz,2H),2.66–2.35(m,10H).MS(ESI)m/z＝412.2([M+H] + ).
Example 22
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acetamide
The title compound was prepared as in example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiopheneacetic acid" in example 1, step 1).
1 HNMR(400MHz,CDCl 3 )δ7.13–7.05(m,4H),6.97–6.87(m,4H),3.83(s,3H),3.81–3.73(m,2H),2.85(d,J＝11.4Hz,2H),2.51–2.41(m,4H),1.90(t,J＝10.8Hz,2H),1.81(s,3H),1.57(d,J＝12.5Hz,2H),1.50–1.38(m,1H),1.28–1.17(m,2H).MS(ESI)m/z＝358.2([M+H] + ).
Example 23
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) propanamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "propionyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,CDCl 3 )δ7.43–7.36(m,2H),7.36–7.27(m,1H),7.19(dd,J＝5.1,3.2Hz,2H),7.06(dd,J＝8.7,5.2Hz,2H),6.93–6.85(m,2H),3.83(t,J＝7.1Hz,2H),2.85(d,J＝11.1Hz,2H),2.46(t,J＝7.4Hz,4H),2.03(q,J＝7.3Hz,2H),1.90(t,J＝11.1Hz,2H),1.56(d,J＝12.6Hz,2H),1.48–1.39(m,1H),1.27–1.14(m,2H),1.03(t,J＝7.4Hz,3H).MS(ESI)m/z＝372.2([M+H] + ).
Example 24
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) butanamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "butyryl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.42–7.35(m,2H),7.35–7.28(m,1H),7.21–7.16(m,2H),7.10(dd,J＝5.1,1.2Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.82–6.76(m,1H),3.83(t,J＝7.0Hz,2H),2.99(dd,J＝9.0,6.9Hz,2H),2.72–2.28(m,12H),1.98(t,J＝7.4Hz,2H),1.57(q,J＝7.4Hz,2H),0.80(t,J＝7.4Hz,3H).MS(ESI)m/z＝386.3([M+H] + ).
Example 25
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "cyclopropylcarbonyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.40(t,J＝7.6Hz,2H),7.36–7.24(m,3H),7.10(dd,J＝5.2,1.2Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.79(d,J＝3.5Hz,1H),3.86(t,J＝7.1Hz,2H),3.00(q,J＝8.9,8.2Hz,2H),2.78–2.27(m,12H),1.32–1.22(m,1H),0.98(dp,J＝6.5,3.7,3.3Hz,2H),0.58(dq,J＝7.0,3.7Hz,2H).MS(ESI)m/z＝384.3([M+H] + ).
Example 26
Preparation of 2-methoxy-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acetamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "methoxyacetyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.45–7.32(m,3H),7.23–7.16(m,2H),7.10(dd,J＝5.1,1.2Hz,1H),6.90(dd,J＝5.1,3.4Hz,1H),6.80(dt,J＝3.4,1.0Hz,1H),3.84(t,J＝6.8Hz,2H),3.72(s,2H),3.31(s,3H),3.05–2.95(m,2H),2.73–2.63(m,2H),2.51(dd,J＝15.5,8.7Hz,10H).MS(ESI)m/z＝388.3([M+H] + ).
Example 27
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "acryloyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.47–7.29(m,3H),7.17(d,J＝7.6Hz,2H),7.11(d,J＝5.1Hz,1H),6.90(dd,J＝5.2,3.4Hz,1H),6.80(d,J＝3.5Hz,1H),6.33(dd,J＝16.9,2.0Hz,1H),5.97(dd,J＝16.8,10.3Hz,1H),5.50(dd,J＝10.3,2.0Hz,1H),3.93(t,J＝7.1Hz,2H),3.08–3.02(m,2H),2.78–2.56(m,12H).MS(ESI)m/z＝370.2([M+H] + ).
Example 28
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "benzoyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.30–7.23(m,2H),7.23–7.16(m,3H),7.16–7.08(m,4H),7.07–7.02(m,2H),6.90(dd,J＝5.1,3.4Hz,1H),6.81(dt,J＝3.3,1.1Hz,1H),4.07(t,J＝7.0Hz,2H),3.02(dd,J＝8.7,7.1Hz,2H),2.74–2.34(m,12H).MS(ESI)m/z＝420.2([M+H]+).
Example 29
Preparation of 2-methyl-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "o-methylbenzoyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.19–7.09(m,3H),7.09–6.97(m,5H),6.97–6.85(m,3H),6.81(d,J＝3.4Hz,1H),4.07(d,J＝7.0Hz,2H),3.01(t,J＝7.8Hz,2H),2.61(dt,J＝33.9,8.6Hz,12H),2.37(s,3H).MS(ESI)m/z＝434.3([M+H]+).
Example 30
Preparation of 4-methoxy-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "p-methoxybenzoyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.26–7.19(m,4H),7.16–7.09(m,2H),7.09–7.04(m,2H),6.90(dd,J＝5.1,3.4Hz,1H),6.81(dt,J＝3.4,1.0Hz,1H),6.66–6.60(m,2H),4.04(t,J＝7.1Hz,2H),3.72(s,3H),3.00(dd,J＝9.0,6.7Hz,2H),2.68–2.41(m,12H).MS(ESI)m/z＝450.2([M+H] + ).
Example 31
Preparation of 4-fluoro-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "p-methylchloroformyl" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.29–7.22(m,2H),7.22–7.18(m,2H),7.17–7.13(m,1H),7.13–7.09(m,1H),7.07–7.02(m,2H),6.90(dd,J＝5.1,3.4Hz,1H),6.85–6.77(m,3H),4.05(t,J＝7.0Hz,2H),3.02(dd,J＝9.0,6.8Hz,2H),2.74–2.41(m,12H).MS(ESI)m/z＝438.3([M+H] + ).
Example 32
Preparation of 2-fluoro-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "p-fluoroformyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.24–7.05(m,8H),6.95(t,J＝7.6Hz,1H),6.92–6.88(m,1H),6.79(dd,J＝16.2,6.2Hz,2H),4.05(t,J＝6.9Hz,2H),3.07–2.95(m,2H),2.75–2.34(m,12H).MS(ESI)m/z＝438.3([M+H]+).
Example 33
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "2-furoyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.41–7.35(m,3H),7.31(dd,J＝1.8,0.8Hz,1H),7.26(d,J＝2.1Hz,1H),7.24(t,J＝1.8Hz,1H),7.11(dd,J＝5.1,1.2Hz,1H),6.90(dd,J＝5.1,3.4Hz,1H),6.80(dt,J＝3.4,1.1Hz,1H),6.16(dd,J＝3.5,1.7Hz,1H),5.65(d,J＝3.4Hz,1H),3.98(t,J＝7.0Hz,2H),2.99(dd,J＝8.9,6.8Hz,2H),2.68–2.35(m,12H).MS(ESI)m/z＝410.2([M+H] + ).
Example 34
Preparation of 3-methyl-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "3-methylfuran-2-carbonyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.31–7.24(m,2H),7.22–7.16(m,1H),7.13–7.09(m,3H),6.93–6.87(m,2H),6.81–6.79(m,1H),6.12(d,J＝1.7Hz,1H),4.02–3.94(m,2H),3.04–2.97(m,2H),2.68–2.44(m,12H),2.21(s,3H).MS(ESI)m/z＝424.3([M+H] + ).
Example 35
Preparation of N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide
The title compound was prepared by the procedure of example 25, substituting "p-chloroaniline" for "aniline" in example 25, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.37(d,J＝8.6Hz,2H),7.28–7.22(m,2H),7.11–7.09(m,1H),6.90–6.88(m,1H),6.81–6.76(m,1H),3.82(t,J＝6.9Hz,2H),3.05–2.94(m,2H),2.72–2.59(m,2H),2.47(dd,J＝12.0,5.2Hz,10H),1.31–1.17(m,1H),1.05–0.94(m,2H),0.63–0.59(m,2H).MS(ESI)m/z＝418.3([M+H] + ).
Example 36
Preparation of N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide
The title compound was prepared by the procedure of example 25, except that "p-methoxyaniline" was used instead of "aniline" in example 25, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.23–7.16(m,2H),7.10–7.07(m,1H),6.93–6.86(m,3H),6.80–6.78(m,1H),5.58(s,1H),3.81(s,5H),3.05–2.96(m,2H),2.67–2.60(m,2H),2.58–2.38(m,10H),1.33–1.22(m,1H),1.01–0.92(m,2H),0.59–0.54(m,2H).MS(ESI)m/z＝414.3([M+H] + ).
Example 37
Preparation of N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide
The title compound was prepared by the procedure of example 25, except that "para-fluoroaniline" was used instead of "aniline" in step 3) of example 25.
1 H NMR(400MHz,Chloroform-d)δ7.34–7.23(m,2H),7.14–7.04(m,3H),6.90–6.87(m,1H),6.80–6.78(m,1H),3.82(t,J＝7.0Hz,2H),2.99(dd,J＝8.6,7.1Hz,2H),2.72–2.59(m,2H),2.57–2.34(m,10H),1.26–1.20(m,,1H),1.00–0.96(m,2H),0.62–0.57(m,2H).MS(ESI)m/z＝402.2([M+H] + ).
Example 38
Preparation of N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) cyclopropanecarboxamide
The title compound was prepared by the procedure of example 25, except that "p-toluidine" was used instead of "aniline" in example 25, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.23–7.12(m,4H),7.09(dd,J＝5.1,1.2Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.80–6.78(m,1H),3.86–3.79(m,2H),3.02–2.94(m,2H),2.65–2.59(m,2H),2.56–2.42(m,10H),2.36(s,3H),1.34–1.22(m,1H),0.98–0.96(m,2H),0.59–0.54(m,2H).MS(ESI)m/z＝398.3([M+H] + ).
Example 39
Preparation of N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 27, substituting "p-chloroaniline" for "aniline" in example 27, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.38–7.31(m,2H),7.20–7.13(m,2H),7.13–7.07(m,2H),6.90–6.88(m,1H),6.83–6.77(m,1H),6.37–6.32(m,1H),6.00–5.93(m,1H),5.53–5.50(m,1H),3.87(t,J＝6.8Hz,2H),3.00–2.96(m,2H),2.64–2.60(m,2H),2.66–2.48(m,12H).MS(ESI)m/z＝404.0([M+H] + ).
Example 40
Preparation of N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 27, substituting "p-methoxyaniline" for "aniline" in example 27, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.14–7.05(m,3H),6.96–6.85(m,3H),6.81–6.76(m,1H),6.31(dd,J＝16.8,2.1Hz,1H),5.99(dd,J＝16.8,10.3Hz,1H),5.47(dd,J＝10.3,2.1Hz,1H),3.87(t,J＝7.0Hz,2H),3.82(s,3H),3.02–2.95(m,2H),2.67–2.38(m,12H).MS(ESI)m/z＝400.2([M+H] + ).
Example 41
Preparation of N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide
The title compound was prepared by the procedure of example 27, substituting "p-fluoroaniline" for "aniline" in example 27, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.23–7.15(m,2H),7.13–7.02(m,3H),6.89(dd,J＝5.1,3.4Hz,1H),6.80–6.78(m,1H),6.34(dd,J＝16.8,2.0Hz,1H),5.95(dd,J＝16.8,10.3Hz,1H),5.50(dd,J＝10.3,2.0Hz,1H),3.87(t,J＝6.8Hz,2H),3.05–2.91(m,2H),2.73–2.26(m,12H).MS(ESI)m/z＝388.3([M+H] + ).
Example 42
Preparation of N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) acrylamide
The title compound was prepared by the procedure of example 27, substituting "p-toluidine" for "aniline" in example 27, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.18(d,J＝8.1Hz,2H),7.14–6.98(m,3H),6.89(dd,J＝5.1,3.4Hz,1H),6.79(dd,J＝3.4,1.1Hz,1H),6.32(dd,J＝16.8,2.1Hz,1H),5.99(dd,J＝16.8,10.3Hz,1H),5.46(dd,J＝10.3,2.1Hz,1H),3.88(t,J＝7.1Hz,2H),2.98(dd,J＝8.5,7.2Hz,2H),2.70–2.58(m,2H),2.52(dd,J＝12.9,5.9Hz,10H),2.36(s,3H).MS(ESI)m/z＝384.3([M+H] + ).
Example 43
Preparation of N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 33, substituting "p-chloroaniline" for "aniline" in example 33, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.38–7.26(m,3H),7.22–7.14(m,2H),7.09(d,J＝4.9Hz,1H),6.92–6.86(m,1H),6.79(d,J＝3.6Hz,1H),6.22(d,J＝3.6Hz,1H),5.96(d,J＝3.7Hz,1H),3.93(t,J＝6.7Hz,2H),2.98(t,J＝7.9Hz,2H),2.70–2.33(m,12H).MS(ESI)m/z＝444.0([M+H] + ).
Example 44
Preparation of N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 33, substituting "p-methoxyaniline" for "aniline" in example 33, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.34–7.32(m,1H),7.18–7.13(m,2H),7.10–7.08(m,1H),6.92–6.86(m,3H),6.80–6.78(m,1H),6.17–6.14(m,1H),3.93(t,J＝6.8Hz,2H),3.83(s,3H),2.99(t,J＝6.8Hz,2H),2.66–2.44(m,12H).MS(ESI)m/z＝440.3([M+H] + ).
Example 45
Preparation of N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 33, substituting "p-fluoroaniline" for "aniline" in example 33, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.30–7.28(m,1H),7.26–7.21(m,2H),7.12–7.04(m,3H),6.91–6.87(m,1H),6.81–6.78(m,1H),6.20(dd,J＝3.6,1.6Hz,1H),5.84(s,1H),3.94(t,J＝6.8Hz,2H),3.04–2.95(m,2H),2.67–2.42(m,12H).MS(ESI)m/z＝428.3([M+H] + ).
Example 46
Preparation of N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl-N- (p-tolyl) furan-2-carboxamide
The title compound was prepared by the procedure of example 33, substituting "p-toluidine" for "aniline" in example 33, step 3).
1 H NMR(400MHz,Chloroform-d)δ7.33–7.31(m,1H),7.21–7.15(m,2H),7.14–7.07(m,3H),6.91–6.88(m,1H),6.81–6.79(m,1H),6.18–6.15(m,1H),5.62(s,1H),3.95(t,J＝7.2Hz,2H),3.07–2.93(m,2H),2.72–2.44(m,12H),2.39(s,3H).MS(ESI)m/z＝424.3([M+H] + ).
Example 47
Preparation of N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) thiophene-2-carboxamide
The title compound was prepared by the procedure of example 1, except that "2-thiopheneacetic acid" was used instead of "2-thiophenecarboxylic acid" in step 1) of example 1, and "2-thiophenecarboxyl chloride" was used instead of "acetyl chloride" in step 6) of example 1.
1 H NMR(400MHz,Chloroform-d)δ7.38(td,J＝4.6,2.6Hz,3H),7.31–7.26(m,3H),7.10(dd,J＝5.1,1.3Hz,1H),6.90(dd,J＝5.2,3.4Hz,1H),6.80(dd,J＝3.4,1.1Hz,1H),6.75(dd,J＝5.0,3.7Hz,1H),6.64(dd,J＝3.9,1.2Hz,1H),3.99(t,J＝7.0Hz,2H),3.03–2.96(m,2H),2.72–2.37(m,12H).MS(ESI)m/z＝426.2([M+H] + ).
The structural formula of the compound prepared in the above example is shown in table 1 below:
TABLE 1 structural formulas of Compounds prepared in examples 1-47, respectively
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Example 48
Preparation of sigma-1 (cell) receptor membranes and determination of ligand affinity
Preparation of sigma-1 (cell) receptor membranes: taking out cell CHO-sigma-1 by a refrigerator at-80 ℃, naturally thawing, centrifuging 1000g for 10min, adding the precipitate into homogenate A, uniformly mixing by a vortex mixer, centrifuging at 50000g for 15min at 4 ℃, discarding the supernatant, taking the precipitate, adding buffer solution A again for washing, repeating the centrifugation for three times, discarding the supernatant after the centrifugation is finished, and storing the precipitate at-80 ℃ for later use.
Receptor binding assay materials: isotopic ligands 3 H-Pentazocine (cat# NET 1056), MICROSICINT PS scintillation fluid (cat# 94-1249C) available from Perkin-Elmer; fine GF/C filters (cat# 1822-047), available from Whatman; haloperidol, tris purchased from Sigma-Aldrich; the cells were cell lines cultured in a pharmacological laboratory cell house, and hamster ovary cells were transfected with the corresponding receptor proteins, purchased from Perkin-Elmer and Kirsrui.
Experimental instrument: PH meter (model PHS-3C) was purchased from Shanghai Seisaceae; precision electronic balance (model MS105 DU) was purchased from METTLER tolio; liquid scintillation counters (model 425-304) were purchased from HIDEX, finland; microBeta liquid flash instrument (model 2450-0010) was purchased from Perkin-Elmer company; high speed disperser (model IKA-T10) was purchased from IKA.
Experimental method
(I) Preparation of solutions required for experiments
For the preparation of sigma-1, μ:50mM Tris-HCl buffer: 96.8g Tris was dissolved in double distilled water to a total volume of 4000ml, pH adjusted to 7.5 with HCl, diluted to 16000mL, pH=7.4;
(II) CHO-sigma-1 receptor competitive binding assay
The first step: firstly, preparing a suspension of 8mg/ml membrane by using homogenate A for later use;
and a second step of: 100 μl of the membrane preparation was added to each reaction tube;
and a third step of: total binding Tube (TB) was filled with 100. Mu.l of A solution, nonspecific binding tube (NB) was filled with 100. Mu.l of haloperidol (final concentration 1.0X10) -5 M) 100 μl of test compound was added to each test compound tube (SB);
fourth step: the respective reaction tubes were charged with radioligand 4nM 3 H]-Pentazocine 10μl；
Fifth step: incubating each reaction tube at 25 ℃ for 120min, after the reaction is finished, rapidly filtering the combined ligand through decompression, soaking a Whatman test paper GF/C plate with 0.5% PEI for more than 1h in advance, drying a filter membrane at 60 ℃ after filtering, adding 45 mu l of scintillation liquid after attaching a bottom membrane, sealing the upper membrane, and standing;
sixth step: the scintillation vial was placed into a liquid scintillation counter for counting.
(III) data processing and statistical analysis
TB: total binding constant
NB: non-specific binding constant
SB: binding constant of the compound
Example 49
mu (cell) receptor functional assay
Experimental materials: DAMGO (Sigma-Aldrich), IBMX (SIGMA), DPBS (Ficus ficus-Tikouav), HTRF kit (Cisbio Bioassays,62AM9 PEC). CHO-K1 cells stably expressing human MOR.
Preparing a solution:
(A) Cell growth medium: 10% FBS,1% PBS and G418 were added to 90% DMEM to a final concentration of 500. Mu.g/mL and stored at 4℃for further use.
(B) Frozen stock solution: just prior to use, 5% DMSO was added to 95% FBS.
(C) Assay buffer: just prior to use, IBMX was added to DPBS at a final concentration of 0.5 mM.
(D) cAMP-d2 working solution: cAMP-d2 working solution was prepared by diluting cAMP-d2 mother liquor 20-fold with lysis binding buffer. The working solution may be left at 4℃for 24h.
(E) Anti-cAMP Anti-cryptate working solution: anti-cAMP with lysis binding buffer
The Anti-cAMP Anti-cryptate working solution is prepared after the Anti-cryptate mother solution is diluted 20 times; the working solution may be left at 4℃for 24h.
The experimental method comprises the following steps:
cells were thawed in a sterile water bath at 37℃and gently shaken until the ice was completely thawed (approximately 1 min). The cells to be resuscitated are transferred to sterile centrifuge tubes and 5-10mL of complete medium, preheated at 37 c, is added, without selection antibiotic G418. After the cells are naturally precipitated for 5min, the cells are centrifuged for 5min at 900r/min, and the culture medium is discarded. The centrifuged cells were resuspended in fresh medium and cultured in a 37℃incubator containing 5% CO2 until the cells reached 80-90%, after which they were subcultured or ready for drug screening assays. CHO-K1 cells were suspended in PBS buffer and centrifuged at 2000r/min for 10min. The cell pellet was resuspended in HAMF12 medium containing 0.5mM IBMX and added to 96-well ProxiPlates (5. Mu.L/well, 3000 cells/well). 0.5. Mu.M forskolin (1. Mu.L/well) and the target compound (4. Mu.L/well, 0.5% DMSO) were added sequentially, the final volume was 10. Mu.L, and incubated at 37℃for 45min. mu.L of cAMP-d2 working solution and 5. Mu.LAnti-cAMP anti-cryptate working solution were added to the corresponding wells of the reaction plate with a micropipette, covered and incubated at room temperature in the absence of light for 1h. Put into a reader for reading. Final number The value is the ratio of OD665nm to OD620 nm. At the same time as the detection of the compounds, cAMP standard curves were prepared as described in the kit. The results in Table 1 show that the compounds prepared in example 5, example 12, example 25 and example 27 have very good agonism to mu receptor, "+". ++'s representing EC (EC) 50 The value is less than 500nM and, "+". ++'s representing EC (EC) 50 The value 500-1000nM, "++" represents EC 50 Values of 1000-10000nM, "+" means EC 50 Values greater than 10000nM. At the same time, the compound has the concentration of 10 mu M for sigma 1 The affinity of the receptor is better.
TABLE 1 results of functional experiments on mu receptor and on sigma for target compounds 1 Affinity results for receptors (inhibition of each receptor at a compound concentration of 10. Mu.M)
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Example 50
Formalin induced pain model
(1) Information of experimental animal
SD male rats, 230-280g 6-8 weeks old, supplied by Shanghai Sipuler-BiKai laboratory animal Co.
(2) Main reagent
Test positive drug: pregabalin; purified water purchased from Hangzhou baby haha; PEG400, available from wil chemical; normal saline, purchased from Shijia village; formaldehyde solution, purchased from Sigma-Adrich.
(3) Experimental instrument
Electronic balance (model: TP 6001N) was purchased from Shanghai precision scientific instruments Co., ltd;
Precision electronic balance (model: BS224 s) was purchased from cerdolischen instruments (beijing);
an automatic pain analysis system (model: ANTE) was purchased from Anhua Huaihai Zhenghua.
(4) Experimental method
Male SPF SD rats with qualified weight are randomly divided into a model group (namely a solvent group), a control group and each dose group of the compound to be tested, wherein 8 SD rats are selected from each group. According to different dosages of each group, solutions with different concentrations are prepared for administration, corresponding solvents are given to the model group, and corresponding positive control medicines are given to the control group.
Rats were acclimatized in the experimental set-up for 10min prior to experimental testing. The right hind paw of the rat after 1h of administration was subcutaneously injected with 5% formalin solution (containing 1.85% formaldehyde) in 75 μl of the molding to form a skin dome as a standard for molding success, and the animal was discarded if the injection had enough blood.
The software automatically records the number of times of lifting feet by taking 1min as a time period between 0-60min after molding, and then respectively analyzes and calculates the sum of the number of times of lifting feet of the rats in the first phase (1-10 min) and the second phase (10-60 min) according to the result of the software.
(5) Data processing
Dose-analgesic effect curves can be analyzed using GraphPad Prism 6.0 software nonlinear fitting methods, and ED calculated, with the dose-effect exhibiting pronounced dose dependence 50 。
(6) Experimental results
TABLE 2 acute toxicity test of preferred Compounds results of formalin induced pain test
The results show that the compounds prepared in example 5, example 12, example 25, example 27, respectively, all showed good analgesic effect in formalin induced pain experiments, ED, compared to pregabalin 50 Are all lower.
C. Formulation examples
Example 51: tablet formulation
Sieving the raw materials with 80 mesh sieve for use, weighing the active ingredient with prescription amount, microcrystalline cellulose, lactose and povidone K30, adding into a high-speed mixing pelleter, stirring at low speed, mixing well, adding appropriate amount of purified water, stirring at low speed, cutting at high speed, granulating, drying wet granules at 60deg.C for 3h, sieving with 24 mesh sieve, granulating, and adding sodium carboxymethyl starch with prescription amount. Silica and magnesium stearate, blended, and tableted by a rotary tablet press.
Example 52: injection preparation
Parenteral compositions are prepared by stirring 1.5% by weight of the active ingredient of the present invention in 10% by volume of propylene glycol and water.

Claims (10)

1. Thiophene piperazine amide derivatives are compounds with a structural general formula (I) or pharmaceutically acceptable salts thereof or optical isomers thereof or stereoisomers thereof:
Wherein Q is C or N; n and m are each 0, 1 or 2;
R 1 selected from halogen, C 1-5 Alkyl, halogen substituted C 1-5 One of the alkyl groups is used for the preparation of a catalyst,
R 2 、R 3 、R 4 、R 5 respectively selected from hydrogen, C 1-5 Alkoxy, substituted C 1-5 Alkoxy, halogen, C 1-5 Alkyl, substituted C 1-5 Alkyl, C 3-7 Cycloalkyl, substituted C 3-7 Cycloalkyl, phenyl, alkyl-substituted phenyl, heteroaryl ring.
2. A thiophenepiperazine amide derivative according to claim 1, characterized in thatCharacterized in that the C 1-5 The alkyl is selected from one of methyl, ethyl, propyl, butyl, isopropyl, tertiary butyl, amyl and isoamyl; the C is 1-5 The alkoxy is selected from one of methoxy, ethoxy, propoxy, butoxy and pentoxy.
3. The thiophenepiperazine amide derivative according to claim 1, wherein R 1 In (C) substituted by halogen 1-5 The alkyl is selected from one of dichloromethyl and trifluoromethyl.
4. A thiophene piperazine amide derivative according to claim 1, wherein the substituted C 1-5 Alkoxy, substituted C 1-5 Alkyl, substituted C 3-7 The substituent groups in the cycloalkyl are respectively selected from one or more of amino, hydroxyl, methyl and halogen.
5. The thiophene piperazine amide derivative according to claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine.
6. The thiophene piperazine amide derivative according to claim 1, wherein the salt is a pharmaceutically acceptable anion salt selected from one of hydrochloride, hydrobromide, hydroiodide, oxalate, citrate, acetate, maleate, fumarate, nitrate, sulfate, bisulfate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.
7. The thiophenepiperazine amide derivative according to claim 1, wherein the derivative is:
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) propanamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) butanamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide,
2-methoxy-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acetamide, N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide,
2-methyl-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide, 4-methoxy-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide, 4-fluoro-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide, 2-fluoro-N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) benzamide, N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide, N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) acrylamide, N- (4-fluorophenyl) -N- (2- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide, N- (4-chlorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide, N- (4-methoxyphenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) acrylamide, N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) furan-2-carboxamide, N- (4-fluorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide, N- (4-chlorophenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide, N- (4-methoxyphenyl) -N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) furan-2-carboxamide, N-phenyl-N- (2- (4- (thiophen-2-ylmethyl) piperazin-1-yl) ethyl) thiophen-2-carboxamide, N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acetamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) propanamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) butanamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide, 2-methoxy-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acetamide, N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide, N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide, 2-methyl-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide, 4-methoxy-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide, 4-fluoro-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
2-fluoro-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) benzamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
3-methyl-N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) cyclopropanecarboxamide,
N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) cyclopropanecarboxamide,
N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) acrylamide,
N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) -N- (p-tolyl) acrylamide,
N- (4-chlorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-methoxyphenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (4-fluorophenyl) -N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) furan-2-carboxamide,
N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl-N- (p-tolyl) furan-2-carboxamide,
N-phenyl-N- (2- (4- (2- (thiophen-2-yl) ethyl) piperazin-1-yl) ethyl) thiophene-2-carboxamide.
8. A pharmaceutical composition comprising a therapeutically effective amount of a thiophenepaperamide derivative of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
9. The use of a thiophenepiperazine amide derivative according to any of claims 1-5 or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof for the preparation of a medicament for the prophylaxis or treatment of pain diseases.
10. The use according to claim 9, wherein the pain disorder is neuralgia, inflammatory pain, trigeminal neuralgia or cancer pain.
CN202311710358.9A 2023-12-13 2023-12-13 Thiophene piperazine amide derivative, composition and application thereof Pending CN117800942A (en)

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