CN115477634A - Compound for analgesia and medical application thereof - Google Patents
Compound for analgesia and medical application thereof Download PDFInfo
- Publication number
- CN115477634A CN115477634A CN202211221019.XA CN202211221019A CN115477634A CN 115477634 A CN115477634 A CN 115477634A CN 202211221019 A CN202211221019 A CN 202211221019A CN 115477634 A CN115477634 A CN 115477634A
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- CN
- China
- Prior art keywords
- propyl
- methyl
- butyl
- group
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 64
- 230000036592 analgesia Effects 0.000 title description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- -1 hydroxy, methoxy, ethoxy, propoxy, butoxy Chemical group 0.000 claims description 180
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 102000051367 mu Opioid Receptors Human genes 0.000 claims description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- 108020001612 μ-opioid receptors Proteins 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
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- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
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- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to compounds shown in a formula I or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds or the pharmaceutically acceptable salts thereof as active ingredients, and application of the compounds or the pharmaceutically acceptable salts thereof in preparing analgesic drugs.
Description
Technical Field
The invention relates to compounds for analgesia or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds or the pharmaceutically acceptable salts thereof as active ingredients, and application of the compounds or the pharmaceutically acceptable salts thereof in preparing analgesic drugs.
Background
While the treatment of pain has long been a major public health challenge, the current primary treatment for pain is the use of opioids, which are traditionally effective in relieving pain, but patients taking opioids are subject to drug addiction and high risk of overdose, with 13.3 deaths per 100,000 people in the united states resulting from opioid overdose.
The analgesic effect of opioids such as morphine is produced by signaling through Gi protein in G protein, and many adverse reactions, including respiratory depression and constipation, may occur by signaling through β -arrestin pathway downstream of Mu Opioid Receptor (MOR) activation. The MOR biased agonist can selectively activate a Gi protein pathway to avoid activating a beta-arrestin pathway, and experiments prove that a beta-arrestin-2 knockout mouse has better analgesic effect on morphine, is not easy to have drug tolerance and causes less respiratory depression and constipation compared with a wild mouse. Therefore, agonists specific for MOR and biased towards Gi signaling pathway are a new direction for perfect analgesics as therapeutic drugs. The first mu receptor agonist-biased analgesic novel TRV130 injection is approved by the US FDA to be marketed in 8 months in 2020, and has milestone significance for mu opioid receptor agonist-biased, but the TRV130 still has lower clinical adverse reaction.
PZM21 is a newly discovered novel skeleton molecule with a completely different chemical structure from the existing opioid analgesics, and experiments prove that PZM21 can strongly activate Gi/o and only cause very low beta-arrestin aggregation. Thus PZM21 is a highly potent MOR-biased agonist, and also has no significant addictive properties. However, the analgesic activity of PZM21 has yet to be further improved.
Disclosure of Invention
The invention designs and synthesizes a series of compounds shown as a formula I:
wherein R is 1 Is hydrogen atom, hydroxyl, C 1 –C 5 Alkoxy radical,Halogen (F, cl, br) or C 1 –C 5 Linear or branched alkyl of R 2 Is a hydrogen atom, an electron withdrawing group, including but not limited to-NO 2 ，-CN，-SO 3 H，-CF 3 ，-CCl 3 Halogen (F, cl, br), -CHO, -COOH, etc., electron donating groups including but not limited to-NH 2 ，-OH，C 1 –C 5 Alkoxy radical, C 1 –C 5 And n is an integer selected from 0 to 5, such as 0,1,2,3,4,5.
The activity evaluation result shows that the compound shown in the formula I has high in-vivo analgesic activity and G protein pathway biased selectivity, and has no activity on beta-arrestin 2 pathway.
Based on the above results, the present invention has been completed.
The present invention provides compounds represented by formula I or a pharmaceutically acceptable salt thereof:
in formula I: r 1 Is hydrogen atom, hydroxyl, C 1 –C 5 Alkoxy, halogen atoms (F, cl, br) or C 1 –C 5 Straight-chain or branched alkyl of R 2 Is a hydrogen atom, an electron withdrawing group, including but not limited to-NO 2 ，-CN，-SO 3 H，-CF 3 ，-CCl 3 Halogen (F, cl, br), -CHO, -COOH, etc., electron donating groups including but not limited to-NH 2 ，-OH，C 1 –C 5 Alkoxy radical, C 1 –C 5 And n is an integer selected from 0 to 5, such as 0,1,2,3,4,5.
In certain embodiments, the configuration of chiral carbon 2 in formula I is R or S.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxyl, C 1 –C 4 Alkoxy, halogen or C 1 –C 4 Linear or branched alkyl groups of (a).
In certain embodiments, formula (ilia) isIn I, R 1 Is a hydrogen atom, a hydroxyl group, C 1 –C 3 Alkoxy, halogen or C 1 –C 3 Linear or branched alkyl groups of (a).
In certain embodiments, R in formula I 1 Is a hydrogen atom, a hydroxyl group, C 1 –C 2 Alkoxy, halogen or C 1 –C 2 Linear or branched alkyl groups of (a).
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxy, methoxy, ethoxy, propoxy, butoxy, F, cl, br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxyl, methoxy, ethoxy, propoxy, butoxy, F, cl, br, methyl, ethyl, propyl, n-butyl or n-pentyl.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxyl, methoxyl, ethoxyl, propoxyl, F, cl, br, methyl, ethyl, propyl or n-butyl.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxyl, methoxyl, ethoxyl, F, cl, br, methyl, ethyl or propyl.
In certain embodiments, R in formula I 1 Is a hydrogen atom, a methyl group or an ethyl group.
In certain embodiments, R in formula I 1 Is hydroxyl, methoxy, ethoxy, F, cl or Br.
In certain embodiments, R in formula I 1 Is a hydrogen atom or a methyl group.
In certain embodiments, R in formula I 1 Is methoxy, ethoxy, propoxy or butoxy.
In certain embodiments, R in formula I 1 Is F, cl or Br.
In certain embodiments, R in formula I 1 Is a firstAlkyl, ethyl, propyl, n-butyl or n-pentyl.
In certain embodiments, R in formula I 2 Is hydrogen atom, halogen (F, cl, br), -OH, C 1 –C 5 Alkoxy radical, C 1 –C 5 Linear or branched alkyl groups of (a).
In certain embodiments, R in formula I 2 Is a hydrogen atom, F, cl, br, -OH or C 1 –C 5 An alkoxy group.
In certain embodiments, R in formula I 2 Is hydrogen atom, F, -OH or methoxyl.
In certain embodiments, n in formula I is 0,1,2,3, or 4.
In certain embodiments, n in formula I is 0,1,2, or 3.
In certain embodiments, n in formula I is 0,1 or 2.
In certain embodiments, n in formula I is 0 or 1.
In certain embodiments, the electron donating group is-NH 2 ，-OH，C 1 –C 4 Alkoxy or C 1 –C 4 Linear or branched alkyl groups of (a).
In certain embodiments, the electron donating group is-NH 2 ，-OH，C 1 –C 3 Alkoxy or C 1 –C 3 Linear or branched alkyl groups of (a).
In certain embodiments, the electron donating group is-NH 2 ，-OH，C 1 –C 2 Alkoxy or C 1 –C 2 Linear or branched alkyl groups of (a).
In certain embodiments, the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl or 1-ethyl-propyl.
In certain embodiments, the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, n-butyl or n-pentyl.
In certain embodiments, the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl or n-butyl.
In certain embodiments, the electron donating group is-NH 2 -OH, methoxy, ethoxy, methyl, ethyl or propyl.
In certain embodiments, the electron donating group is-NH 2 -OH, methyl or ethyl.
In certain embodiments, the electron donating group is-NH 2 -OH, methoxy or ethoxy.
In certain embodiments, the electron donating group is-OH or methoxy.
In certain embodiments, the electron donating group is methoxy, ethoxy, propoxy, or butoxy.
In certain embodiments, the electron donating group is-OH.
In certain embodiments, the electron donating group is methyl, ethyl, propyl, n-butyl, or n-pentyl.
In certain embodiments, the electron donating group is methyl or ethyl.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxyl, methoxy, ethoxy, F, cl, br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl or 1-ethyl-propyl.
In certain embodiments, the compound of formula I has a structure of formula Ia or Ib,
wherein R is 1 And R 2 As defined in any of the embodiments of the present invention.
In certain embodiments, the compound of formula I is selected from:
the invention also provides a pharmaceutical composition which is formed by taking the compound shown in the formula I or the pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable excipients or carriers. These pharmaceutical compositions may be solutions, tablets, capsules or injections. These pharmaceutical compositions may be administered by injection route or orally.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound shown in the formula I or pharmaceutically acceptable salt thereof as an active ingredient in preparing a medicament serving as an analgesic.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound shown in the formula I or pharmaceutically acceptable salt thereof as an active ingredient in preparation of a medicament serving as a mu opioid receptor bias agonist.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound shown in the formula I or pharmaceutically acceptable salt thereof as an active ingredient in preparing a medicament for treating pain.
The term "pharmaceutical composition" as used herein means a composition containing one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity. Vectors described herein include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, wool fat. The excipient is an additive except the main drug in the pharmaceutical preparation, has stable property, no incompatibility with the main drug, no side effect and no influence on curative effect, is not easy to deform, crack, mildew or moth eating at normal temperature, has no harm to a human body and no physiological effect, does not generate chemical or physical effect with the main drug, does not influence the content determination of the main drug, and the like. Such as binders, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juice, etc. in the Chinese medicinal pill; base portion in semisolid formulations ointments, creams; preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, tonicity adjusting agents, colorants and the like in liquid preparations can all be referred to as excipients.
The compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof may be administered by the following routes: parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes, or as inhalants.
The compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof may be formulated into various suitable dosage forms according to the administration route.
When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, aromatic or coloring agent can be added into the above oral preparation.
When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion, or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
Typically, an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000mg/kg body weight/day. Suitably, the dose is from about 0.01 mg/kg body weight/day to about 1000mg/kg body weight/day. The dosage range may be about 0.01 to 1000mg/kg of subject body weight per day, every second day, or every third day, more usually 0.1 to 500mg/kg of subject body weight. Exemplary treatment regimens are once every two days or once weekly or once monthly. The formulation is typically administered multiple times, and the interval between single doses may be daily, weekly, monthly or yearly. Alternatively, the formulation may be administered as a sustained release formulation, in which case less frequency of administration is required. The dose and frequency will vary depending on the half-life of the formulation in the subject. May also differ depending on whether prophylactic or therapeutic treatment is used. In prophylactic applications, relatively low doses are given chronically at relatively infrequent intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or halted, and preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which a prophylactic regimen can be administered to the patient.
In certain embodiments, the synthesis of compounds of formula Ia starts with L-3-benzothiophenylalanine (1 a) and reacts with thionyl chloride and ammonia to form benzothiophenylalanine amide (2 a), 2a undergoes reductive amination and borane reduction to form intermediate (4 a); 1-hydrocarbon substituted benzylamine (5 a) reacts with p-nitrophenyl chloroformate to generate an intermediate (6 a), and the 6a reacts with 4a and triethylamine to obtain a target product Ia.
The synthetic route for the compound of formula Ia is shown below:
in the formula Ia, R 1 And R 2 And n is as defined in any embodiment of the invention.
In some embodiments, the compound represented by formula Ib is synthesized by reacting L-3-benzothiophenylalanine (1 a) as a starting material with thionyl chloride and ammonia to form benzothiophenylalanine (2 a), and subjecting 2a to reductive amination and borane reduction to form intermediate (4 a); and (3) reacting the 1-position hydrocarbyl substituted phenethylamine (5 b) with p-nitrophenyl chloroformate to generate an intermediate (6 b), and reacting the 6b with the 4a and triethylamine to obtain a target product Ib.
The synthetic route for the compound of formula Ib is shown below:
in the formula Ib, R 1 And R 2 And n is as defined in any embodiment of the invention.
Detailed Description
The following examples are presented to further illustrate the essence of the present invention, and it should be understood that the following examples are only illustrative of the present invention, but not intended to limit the scope of the present invention. The following examples, which do not indicate specific conditions, were conducted according to conventional conditions or as recommended by the manufacturer. The raw materials are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
Although many of the materials and methods of operation used in the examples below are well known in the art, the invention is described in detail herein. It will be apparent to those skilled in the art that the materials and methods of operation used in the following examples are well known in the art, unless otherwise specified.
Example 1: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3-benzylurea (Ia-1)
1.1 Synthesis of (S) -2-amino-3- (3-benzothienyl) propanamide (2 a)
Taking a 500mL three-neck round-bottom flask, dissolving 10g (38.83 mmol) of L-3-benzothiophene alanine hydrochloride (1 a) in a methanol solution, slowly dropwise adding 9.5g (78.17 mmol) of thionyl chloride into 200mL of methanol under the condition of stirring in an ice water bath, mixing with the methanol solution of L-3-benzothiophene alanine hydrochloride after dropwise adding is finished, gradually raising the temperature of the reaction solution to room temperature, stirring, reacting for 10h, carrying out TLC detection, fully reacting, and stopping stirring. And (3) carrying out reduced pressure rotary evaporation on the reaction liquid to obtain a white solid, adding a proper amount of methanol to fully dissolve the white solid, concentrating the white solid to dryness again, and repeating the operation twice. Under the condition of stirring in an ice-water bath, slowly dropwise adding 400mL of ammonia water into a round-bottom flask, slowly dropwise adding methanol until the mixture is fully dissolved, heating the reaction solution to room temperature, stirring for 48h under the protection of argon, fully detecting by TLC, and stopping stirring. Silica gel was added to the round bottom flask to stir and column chromatography was performed using 200-300 mesh silica gel, using DCM: meOH =20, as eluent to give (S) -2-amino-3- (3-benzothienyl) propanamide (2 a) as a white solid 7.90g, 92.43% yield.
1.2 Synthesis of (S) -3- (3-benzothienyl) -2- (dimethylamino) propanamide (3 a)
Weighing 7g (31.81 mmol) of (S) -2-amino-3- (3-benzothienyl) propionamide (2 a) into a beaker, adding 200mL of methanol, stirring until fully dissolved, transferring the solution to a 500mL hydrogenation reaction flask, adding 4g 10% Pd/C, flushing the Pd/C on the wall of the flask with a small amount of methanol into the solution, rapidly adding 29mL (387.63 mmol) of 40% formaldehyde solution, hydrogenation reaction 7h, TLC to detect the completion of the reaction, stopping the hydrogenation reaction, filtering until the solution is clear, adding a small amount of silica gel powder to mix, performing column chromatography using 200-300 mesh silica gel, separating using an eluent of DCM: meOH =60, and finally obtaining 3.33g of (S) -3- (3-benzothienyl) -2- (dimethylamino) propionamide (3 a) as a white solid with a yield of 42.16%, 1 H NMR(500MHz,DMSO-d 6 )δ2.48(s,6H),3.16(dd,J＝14.8,5.9Hz,1H),3.29(dd,J＝14.8,8.2Hz,1H),3.60–3.67(m,1H),7.35–7.44(m,2H),7.51(s,1H),7.90(d,J＝7.8Hz,1H),7.96(d,J＝7.8Hz,1H)。
1.3 Synthesis of (S) -3- (3-benzothienyl) -2- (N, N-dimethylamino) propylamine hydrochloride (4 a)
Taking a 500mL three-neck round-bottom flask, transferring 3g (12.1 mmol) of (S) -3- (3-benzothienyl) -2- (dimethylamino) propionamide (3 a) into the three-neck flask, adding a proper amount of ultra-dry THF (tetrahydrofuran) into the three-neck flask under the protection of argon, slowly dropwise adding 73mL (73 mmol) of 1M borane-tetrahydrofuran complex solution under the stirring condition of an ice water bath, transferring into an oil bath, heating and refluxing for 18h, performing TLC detection, and completing the reaction. Stopping heating, cooling the reaction liquid to room temperature, slowly dropwise adding a proper amount of methanol solution under the stirring condition until no bubbles are generated, concentrating under reduced pressure to obtain an off-white solid, repeating twice, adding a small amount of methanol solution, heating, refluxing and stirring until the solution is sufficiently clear, slowly dropwise adding ethyl acetate into the solution until a large amount of white solid is generated, performing suction filtration, adding excessive concentrated hydrochloric acid into the filtrate to sufficiently salify, concentrating under reduced pressure to dry, adding a small amount of silica gel powder to mix, performing column chromatography separation and purification by using an eluent of DCM: meOH =30, and performing column chromatography separation by using an eluent of DCM: meOH =30 to obtain 1.98g of (S) -3- (3-benzothiophenyl) -2- (N, N-dimethylamino) propylamine hydrochloride (4 a) as a white solid with the yield of 60.43%.
1.4 Synthesis of 4-nitrophenylbenzyl carbamate (6 a-1)
0.5g (4.67 mmol) of benzylamine (5 a-1) is transferred to a round-bottom flask, 100mL of ultra-dry THF and 1.25mL (7.13 mmol) of triethylamine are slowly added under the condition of stirring in an ice-water bath, 1g (5 mmol) of 4-nitrophenyl chloroformate is dissolved in an appropriate amount of ultra-dry THF solution under the protection of argon, and the mixture is slowly dripped into the reaction solution, and white smoke is generated during the dripping. After the dropwise addition, the reaction solution is heated to room temperature and stirred, the white milky white color of the reaction solution is changed into yellow, the reaction is carried out for 8h, TLC detection is carried out, after the reaction is finished, the post-treatment operation is carried out, 100mL of DCM is used for diluting the reaction solution, the stirring is uniform, the suction filtration is carried out, the filtrate is respectively washed twice by using a saturated NaHCO3 solution and a saturated NaCl solution, a small amount of silica gel powder is added for mixing samples, column chromatography separation and purification are carried out by using 200-300-mesh silica gel, finally, an eluent of DCM: PE =5 is used for flushing the products, the products are combined, and after the vacuum concentration and the drying, the products are placed into an oven for drying, 6 a-1.07g of white solid is obtained, and the yield is 84.27%.
1.5 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3-benzylurea (Ia-1)
0.2g (0.74 mmol) of (S) -3- (3-benzothienyl) -2- (N, N-dimethylamino) propylamine hydrochloride (4 a) was placed in a round bottom flask, 50mL of acetonitrile was injected, stirred, 0.4mL (2.61 mmol) of triethylamine was slowly added dropwise, transferred to an oil bath, warmed to 60 ℃, and a solution of acetonitrile in which 0.3g (1.10 mmol) of 6a-1 was dissolved was added dropwise to the reaction solution, the solution rapidly changing from colorless to yellow. After the dropwise addition is completed, the solution is transferred toIn an oil bath kettle, the temperature in T is raised to 90 ℃, the reaction is stirred at high temperature for 7h, the TLC is used for monitoring the completion of the reaction, the reaction is closed, the mixture is shaken up and filtered, after the filtrate is concentrated under reduced pressure and dried, the mixture is fully dissolved and cleaned by using 30mL of isopropanol/ethyl acetate (1] + . 1 H-NMR(400MHz,CDCl 3 )δ2.48(s,6H),2.77(dd,J＝14.8,11.0Hz,1H),3.00–3.13(m,1H),3.14–3.27(m,2H),3.41(m,1H),4.30(d,J＝5.3Hz,2H),5.36(br s,1H),5.73(br s,1H),7.19–7.30(m,6H),7.33–7.40(m,2H),7.71(m1H),7.81–7.88(m,1H)。
Example 2: synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((S) -1-phenylethyl) urea (Ia-2)
2.1 4-Nitrobenzene (S) - (1-phenethyl) carbamate (6 a-2)
During the synthesis of intermediate 6a-2, benzylamine (5 a-1) was replaced with (S) -1-phenylethylamine (5 a-2), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-2.
2.2 Synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((S) -1-phenylethyl) urea (Ia-2)
In the synthesis process of Ia-2, 4-nitrophenyl benzyl carbamate (6 a-1) is replaced by 4-nitrobenzene (S) - (1-phenethyl) carbamate (6 a-2)) Otherwise the same procedure as for the synthesis of Ia-1 gave Ia-2 as a yellow oil. HRESIMS m/z:382.1956[ M + H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ1.23(d,J＝6.6Hz,3H),2.21(s,6H),2.73–2.88(m,2H),3.01–3.05(m,2H),3.19(m,1H),4.98(q,J＝6.6Hz,1H),5.37(br s,1H),5.75(br s,1H),7.19–7.28(m,6H),7.30–7.38(m,2H),7.64–7.70(m,1H),7.81–7.88(m,1H)。
Example 3: synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((R) -1-phenylethyl) urea (Ia-3)
3.1 4-Nitrobenzene (R) - (1-phenethyl) carbamate (6 a-3)
During the synthesis of intermediate 6a-3, benzylamine (5 a-1) was replaced with (R) -1-phenylethylamine (5 a-3), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-3.
3.2 Synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((R) -1-phenylethyl) urea (Ia-3)
The synthesis of Ia-3 was performed in the same manner as Ia-1 except that 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (R) - (1-phenylethyl) carbamate (6 a-3) to obtain Ia-3 as a yellow oil. HRESIMS m/z:382.1953[ 2 ] M + H] + . 1 H NMR(400MHz,DMSO-d 6 )δ1.24(d,J＝6.6Hz,3H),2.23(s,6H),2.75–2.89(m,2H),3.03–3.07(m,2H),3.19(m,1H),4.98(q,J＝6.6Hz,1H),5.38(br s,1H),5.76(br s,1H),7.19–7.28(m,6H),7.30–7.38(m,2H),7.64–7.70(m,1H),7.82–7.89(m,1H)。
Example 4: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-fluorobenzyl) urea (Ia-4)
4.1 Synthesis of 4-nitrophenyl (3-fluorobenzyl) carbamate (6 a-4)
During the synthesis of intermediate 6a-4, benzylamine (5 a-1) was replaced with 3-fluorobenzylamine (5 a-4), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-4.
4.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-fluorobenzyl) urea (Ia-4)
The synthesis of Ia-4 was performed in the same manner as Ia-1 except that 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-fluorobenzyl) carbamate (6 a-4) to obtain Ia-4 as a yellow oil. HRESIMS m/z of 386.1705[ m + H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.33(s,6H),2.67(dd,J＝14.2,9.0Hz,1H),2.87–3.01(m,2H),3.06(dd,J＝14.2,4.1Hz,1H),3.09–3.20(m,1H),4.25(d,J＝5.8Hz,2H),5.70–5.95(m,2H),6.97-7.18(m,3H),7.35–7.49(m,3H),7.50(s,1H),7.80–7.82(m,1H),7.97–7.99(m,1H)。
Example 5: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-fluorobenzyl) urea (Ia-5)
5.1 Synthesis of 4-nitrophenyl (4-fluorobenzyl) carbamate (6 a-5)
During the synthesis of intermediate 6a-5, benzylamine (5 a-1) was replaced with 4-fluorobenzylamine (5 a-5), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-5.
5.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-fluorobenzyl) urea (Ia-5)
The synthesis of Ia-5 was performed in the same manner as Ia-1 except that 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-fluorobenzyl) carbamate (6 a-5) to obtain Ia-5 as a yellow oil. HRESIMS m/z:386.1702[ m ] +H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.32(s,6H),2.67(dd,J＝14.2,9.0Hz,1H),2.87–3.01(m,2H),3.06(dd,J＝14.2,4.1Hz,1H),3.09–3.20(m,1H),4.25(d,J＝5.8Hz,2H),5.71–5.97(m,2H),6.97-7.18(m,3H),7.35–7.49(m,4H),7.80–7.82(m,1H),7.97–7.99(m,1H)。
Example 6: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-hydroxybenzyl) urea (Ia-6)
6.1 Synthesis of 4-nitrophenyl (3-hydroxybenzyl) carbamate (6 a-6)
During the synthesis of intermediate 6a-6, benzylamine (5 a-1) was replaced with 3-hydroxybenzylamine (5 a-6), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-6.
6.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-hydroxybenzyl) urea (Ia-6)
The 4-nitrophenylbenzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-hydroxybenzyl) carbamate (6 a-6) during the synthesis of Ia-6, and the same procedure as for the synthesis of Ia-1 gave Ia-6 as a yellow oil. HRESIMS m/z 384.1748[ 2 ], [ M ] +H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.34(s,6H),2.67–2.89(m,2H),2.92–3.02(m,1H),3.07–3.21(m,2H),4.03(d,J＝5.8Hz,2H),5.75(d,J＝7.1Hz,1H),6.48(t,J＝5.8Hz,1H),6.67–6.77(m,3H),7.03(t,J＝8.0Hz,1H),7.35–7.42(m,2H),7.50(s,1H),7.79–7.82(m,1H),7.97–7.99(m,1H),9.32(s,1H)。
Example 7: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-hydroxybenzyl) urea (Ia-7)
7.1 Synthesis of 4-nitrophenyl (4-hydroxybenzyl) carbamate (6 a-7)
During the synthesis of intermediate 6a-7, benzylamine (5 a-1) was replaced with 4-hydroxybenzylamine (5 a-7), and the other operations were the same as in the synthesis of 6a-1, giving white solid 6a-7.
7.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-hydroxybenzyl) urea (Ia-7)
In the synthesis of Ia-7, 4-nitrophenyl benzylamino-methylThe acid ester (6 a-1) was replaced with 4-nitrophenyl (4-hydroxybenzyl) carbamate (6 a-7), and the other procedures were the same as for the synthesis of Ia-1, to give Ia-7 as a yellow oil. HRESIMS m/z of 384.1745[ 2 ] M + H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.36(s,6H),2.67–2.89(m,2H),2.92–3.02(m,1H),3.07–3.21(m,2H),4.02(d,J＝5.7Hz,2H),5.91(br s,1H),6.50(br s,1H),6.66(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),7.35–7.42(m,2H),7.50(s,1H),7.79–7.82(m,1H),7.97–7.99(m,1H),9.24(s,1H)。
Example 8: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-methoxybenzyl) urea (Ia-8)
8.1 Synthesis of 4-nitrophenyl (3-methoxybenzyl) carbamate (6 a-8)
During the synthesis of intermediate 6a-8, benzylamine (5 a-1) was replaced with 3-methoxybenzylamine (5 a-8), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-8.
8.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-methoxybenzyl) urea (Ia-8)
The same procedure as for the synthesis of Ia-1 was repeated except that 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-methoxybenzyl) carbamate (6 a-8) during the synthesis of Ia-8 to give Ia-8 as a yellow oil. HRESIMS m/z:398.1903[ 2 ] M + H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.34(s,6H),2.67–2.89(m,2H),2.92–3.02(m,1H),3.07–3.21(m,2H),3.65(s,3H),4.05(d,J＝5.8Hz,2H),5.75(d,J＝7.1Hz,1H),6.48(t,J＝5.8Hz,1H),6.71–6.81(m,3H),7.10(t,J＝8.0Hz,1H),7.35–7.42(m,2H),7.50(s,1H),7.79–7.82(m,1H),7.97–7.99(m,1H)。
Example 9: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-methoxybenzyl) urea (Ia-9)
9.1 Synthesis of 4-nitrophenyl (4-methoxybenzyl) carbamate (6 a-9)
During the synthesis of intermediate 6a-9, benzylamine (5 a-1) was replaced with 4-methoxybenzylamine (5 a-9), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6a-9.
9.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-methoxybenzyl) urea (Ia-9)
The same procedure as for the synthesis of Ia-1 was repeated except that 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-methoxybenzyl) carbamate (6 a-9) during the synthesis of Ia-9 to give Ia-9 as a yellow oil. HRESIMS m/z:398.1902[ M ] +H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.36(s,6H),2.67–2.89(m,2H),2.92–3.02(m,1H),3.07–3.21(m,2H),3.64(s,3H),4.10(d,J＝5.7Hz,2H),5.75(d,J＝7.1Hz,1H),6.48(t,J＝5.7Hz,1H),6.76(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,2H),7.35–7.42(m,2H),7.52(s,1H),7.79–7.82(m,1H),7.97–7.99(m,1H)。
Example 10: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3-phenethylurea (Ib-1)
10.1 Synthesis of 4-nitrophenylphenethylcarbamate (6 b-1)
During the synthesis of intermediate 6b-1, benzylamine (5 a-1) was replaced with (S) -1-phenylethylamine (5 b-1), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-1.
10.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3-phenethylurea (Ib-1)
During the synthesis of Ib-1, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced by 4-nitrophenyl phenethyl carbamate (6 b-1), and the other operations were the same as those for the synthesis of Ia-1, giving Ib-1 as a yellow oil. HRESIMS m/z 382.1956[ M ] +H] + . 1 H NMR(400MHz,DMSO-d 6 )δ2.35(s,6H),2.58–2.61(m,1H),2.73–2.91(m,2H),3.15–3.27(m,1H),3.32–3.41(m,2H),3.57–3.63(m,3H),5.36(br s,1H),5.73(br s,1H),7.07–7.16(m,3H),7.17–7.25(m,2H),7.33–7.40(m,2H),7.48(s,1H),7.71–7.76(m,1H),7.81–7.88(m,1H)。
Example 11: synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((S) -1-phen-en-2-yl) urea (Ib-2)
11.1 4-Nitrobenzene (S) - (1-Phenylpropan-2-yl) carbamate (6 b-2)
During the synthesis of intermediate 6b-2, benzylamine (5 a-1) was replaced with (S) -1-phenylprop-2-amine (5 b-2), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-2.
11.2 Synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((S) -1-phenylpropan-2-yl) urea (Ib-2)
During the synthesis of Ib-2, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (S) - (1-phenylprop-2-yl) carbamate (6 b-2), and the other operations were the same as for the synthesis of Ia-1, giving Ib-2 as a yellow oil. HRESIMS m/z of 396.2112[ m ] +H] + . 1 H NMR(400MHz,DMSO-d 6 )δ1.23(d,J＝6.6Hz,3H),2.21(s,6H),2.58–2.88(m,4H),3.06–3.11(m,1H),3.28–3.32(m,1H),3.38–3.41(m,1H),4.21–4.32(m,1H),5.37(br s,1H),5.75(br s,1H),7.19–7.28(m,5H),7.30–7.38(m,2H),7.45(s,1H),7.64–7.70(m,1H),7.81–7.88(m,1H)。
Example 12: synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((R) -1-phenylpropan-2-yl) urea (Ib-3)
12.1 4-Nitrobenzene (R) - (1-Phenylpropan-2-yl) carbamate (6 b-3)
During the synthesis of intermediate 6b-3, benzylamine (5 a-1) was replaced with (R) -1-phenylprop-2-amine (5 b-3), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-3.
12.2 Synthesis of 1- ((S) -3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- ((R) -1-phen-en-2-yl) urea (Ib-3)
During the synthesis of Ib-3, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (R) - (1-phenylprop-2-yl) carbamate (6 b-3), and the other operations were the same as those for the synthesis of Ia-1, giving Ib-3 as a yellow oil. HRESIMS m/z:396.2113[ alpha ], [ M + H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ1.24(d,J＝6.6Hz,3H),2.22(s,6H),2.59–2.88(m,4H),3.06–3.11(m,1H),3.28–3.32(m,1H),3.38–3.41(m,1H),4.21–4.32(m,1H),5.39(br s,1H),5.76(br s,1H),7.19–7.28(m,5H),7.30–7.37(m,2H),7.46(s,1H),7.64–7.68(m,1H),7.81–7.87(m,1H)。
Example 13: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-fluorophenethyl) urea (Ib-4)
13.1 Synthesis of 4-nitrophenyl (3-fluorophenethyl) carbamate (6 b-4)
During the synthesis of intermediate 6b-4, benzylamine (5 a-1) was replaced with 3-fluorophenylethylamine (5 b-4), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-4.
13.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-fluorophenethyl) urea (Ib-4)
During the synthesis of Ib-4, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced by 4-nitrophenyl (3-fluorophenethyl) carbamate (6 b-4), and the other operations were the same as those for the synthesis of Ia-1, giving a yellow oilIb-4。HRESIMS m/z:400.1861[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.33(s,6H),2.67–2.71(m,2H),2.87–3.01(m,3H),3.06–3.11(m,1H),3.09–3.20(m,1H),3.47–3.51(m,2H),5.68(br s,1H),5.91(br s,1H),6.97-7.18(m,3H),7.33–7.41(m,3H),7.45(s,1H),7.75–7.79(m,1H),7.91–7.95(m,1H)。
Example 14: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-fluorophenethyl) urea (Ib-5)
14.1 Synthesis of 4-nitrophenyl (4-fluorophenethyl) carbamate (6 b-5)
During the synthesis of intermediate 6b-5, benzylamine (5 a-1) was replaced with 4-fluorophenylethylamine (5 b-5), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-5.
14.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-fluorophenethyl) urea (Ib-5)
During the synthesis of Ib-5, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-fluorophenethyl) carbamate (6 b-5), otherwise the same procedure was followed as for the synthesis of Ia-1, yielding Ib-5 as a yellow oil. HRESIMS m/z 400.1861[ m ] +H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.32(s,6H),2.57–2.61(m,1H),2.87–3.01(m,3H),3.06–3.09(m,1H),3.20–3.24(m,1H),3.56–3.62(m,3H),5.97(br s,2H),6.97-7.18(m,4H),7.35–7.49(m,2H),7.43(s,1H),7.78–7.80(m,1H),7.92–7.95(m,1H)。
Example 15: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-hydroxyphenylethyl) urea (Ib-6)
15.1 Synthesis of 4-nitrophenyl (3-hydroxyphenylethyl) carbamate (6 b-6)
During the synthesis of intermediate 6b-6, benzylamine (5 a-1) was replaced with 3-hydroxyphenylethylamine (5 b-6), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-6.
6.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-hydroxyphenylethyl) urea (Ib-6)
During the synthesis of Ib-6, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-hydroxyphenylethyl) carbamate (6 b-6), otherwise the same procedure was followed as for the synthesis of Ia-1, yielding Ib-6 as a yellow oil. HRESIMS m/z:398.1903[ 2 ] M + H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.32(s,6H),2.67–2.89(m,2H),2.92–3.02(m,2H),3.07–3.21(m,2H),3.57–3.63(m,3H),5.75(br s,1H),6.48(br s,1H),6.67–6.77(m,3H),7.03(t,J＝8.0Hz,1H),7.35–7.42(m,2H),7.52(s,1H),7.79–7.82(m,1H),7.97–7.99(m,1H),9.35(s,1H)。
Example 16: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-hydroxyphenylethyl) urea (Ib-7)
16.1 Synthesis of 4-nitrophenyl (4-hydroxyphenylethyl) carbamate (6 b-7)
During the synthesis of intermediate 6b-7, benzylamine (5 a-1) was replaced with 4-hydroxyphenylethylamine (5 b-7), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-7.
16.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-hydroxyphenylethyl) urea (Ib-7)
During the synthesis of Ib-7, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-hydroxyphenylethyl) carbamate (6 b-7), otherwise the same procedure was followed as for the synthesis of Ia-1, yielding Ib-7 as a yellow oil. HRESIMS m/z:398.1905[ 2 ] M + H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.33(s,6H),2.67–2.89(m,2H),2.92–3.02(m,2H),3.07–3.21(m,2H),3.57–3.63(m,3H),5.91(br s,1H),6.50(br s,1H),6.66(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),7.35–7.42(m,2H),7.50(s,1H),7.79–7.82(m,1H),7.97–7.99(m,1H),9.24(s,1H)。
Example 17: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-methoxyphenethyl) urea (Ib-8)
17.1 Synthesis of 4-nitrophenyl (3-methoxyphenylethyl) carbamate (6 b-8)
During the synthesis of intermediate 6b-8, benzylamine (5 a-1) was replaced with 3-methoxyphenethylamine (5 b-8), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-8.
17.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (3-methoxyphenethyl) urea (Ib-8)
In the synthesis of Ib-8, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-methoxyphenethyl) carbamate (6 b-8), and the same procedure as for the synthesis of Ia-1 was followed to give Ib-8 as a yellow oil. HRESIMS m/z:412.2057[ 2 ], [ M + H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.32(s,6H),2.67–2.89(m,2H),2.92–3.02(m,2H),3.07–3.21(m,2H),3.57–3.63(m,3H),3.65(s,3H),5.73(br s,1H),6.45(br s,1H),6.67–6.77(m,3H),7.10(t,J＝8.0Hz,1H),7.35–7.42(m,2H),7.50(s,1H),7.79–7.82(m,1H),7.96–7.98(m,1H)。
Example 18: synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-methoxyphenethyl) urea (Ib-9)
18.1 Synthesis of 4-nitrophenyl (4-methoxyphenethyl) carbamate (6 b-9)
During the synthesis of intermediate 6b-9, benzylamine (5 a-1) was replaced with 4-methoxyphenethylamine (5 b-9), and the other operations were the same as in the synthesis of 6a-1, to give white solid 6b-9.
18.2 Synthesis of (S) -1- (3- (benzothien-3-yl) -2- (dimethylamino) propyl) -3- (4-methoxyphenethyl) urea (Ib-9)
During the synthesis of Ib-9, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-methoxyphenethyl) carbamate (6 b-9), otherwise the same procedure was followed as for the synthesis of Ia-1, giving Ib-9 as a yellow oil. HRESIMS m/z:412.2056[ M + H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ:2.36(s,6H),2.67–2.89(m,2H),2.92–3.02(m,1H),3.07–3.21(m,2H),3.64(s,3H),3.57–3.63(m,4H),5.75(br s,1H),6.48(br s,1H),6.76(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,2H),7.35–7.42(m,2H),7.51(s,1H),7.79–7.82(m,1H),7.96–7.98(m,1H)。
Example 19: evaluation of mouse acetic acid writhing model
ICR (CD-1) male mice (weighing 22-25 g) were randomly divided into a blank group, a positive group, and a test compound group of 8 mice per group, provided by Schbefu (Beijing) Biotechnology Inc. (license number: SCXK (Beijing) 2016-0002), and then each group was subcutaneously administered (positive drug PZM21 and test drug: 20 mg/kg), and the blank group was administered with the same volume of vehicle (physiological saline). After 30min of administration, the mice were injected intraperitoneally with 10mL/kg of a 1% acetic acid solution. The number of writhing times within 20min after intraperitoneal injection of acetic acid was recorded.
Percent (%) pain "= (number of writhing in blank group-number of writhing in administered group)/number of writhing in blank group × 100%.
TABLE 1 acetic acid writhing model test results
Note: ** p<0.01vs.control
as is clear from the results in Table 1, the compounds of the present invention showed a strong analgesic activity at a dose of 20mg/kg, which is significantly higher than that of the positive drug PZM21.
Example 20: evaluation of hot plate licking experiment in mice
24-26 g of C57 female mice, provided by Schbefu (Beijing) laboratory animals Co., ltd., license number: SCXK (Jing) 2019-0010. The test compound groups were divided into 8 groups each, a blank group, a positive group, and a test compound group, and then each group was subcutaneously administered (positive drug PZM21 and test drug), and the blank group was subcutaneously administered with the same volume of vehicle (physiological saline). The pain threshold before administration and the pain threshold of mice 15, 30, 60, 90 and 120min after administration were determined for each mouse, and the duration of each determination was determined to be 60s.
Percent (%) analgesia = (pain threshold-pain threshold before administration)/(60-pain threshold before administration) × 100%.
TABLE 2 Hot plate model test results
| Compound (I) | Dosage (mg/kg) | Percentage of analgesia (%) |
| Ia-1 | 40 | 93.8 ** |
| Ia-2 | 40 | 98.7 ** |
| Ia-3 | 40 | 92.6 ** |
| Ia-4 | 40 | 99.2 ** |
| Ia-5 | 40 | 93.6 ** |
| Ia-6 | 40 | 99.9 ** |
| Ia-7 | 40 | 94.3 ** |
| Ia-8 | 40 | 95.7 ** |
| Ia-9 | 40 | 96.9 ** |
| Ib-1 | 40 | 92.4 ** |
| Ib-2 | 40 | 98.7 ** |
| Ib-3 | 40 | 95.3 ** |
| Ib-4 | 40 | 99.8 ** |
| Ib-5 | 40 | 99.7 ** |
| Ib-6 | 40 | 96.7 ** |
| Ib-7 | 40 | 95.4 ** |
| Ib-8 | 40 | 99.7 ** |
| Ib-9 | 40 | 96.4 ** |
| PZM21 | 40 | 19.5 |
| Morphine | 10 | 84.7 ** |
Note: ** p<0.01vs.control
as can be seen from the results in Table 2, the analgesic activity of the compound of the present invention is significantly higher than that of the positive drug PZM21 at the same dosage; the analgesic activity of the new compound at a dose of 40mg/kg is obviously higher than that of morphine at a dose of 10 mg/kg.
Example 21: detecting agonist activity of compounds on Mu Opioid Receptor (MOR)
MOR is coupled to Gi/o protein and inhibits the activity of adenylyl cyclase when MOR is bound to an agonist, thereby causing a decrease in intracellular cAMP concentration. Therefore, we can use compounds to stimulate MOR cells, then use Forskolin to increase the intracellular cAMP level, and finally use a cAMP detection kit to measure the change of the intracellular cAMP level to judge whether MOR is activated.
The main reagents are as follows: DMEM medium (GIBCO, cat No: 12800017); nanoBiT assay kit (promega, cat No: N2013); cAMP detection kit (cisbio, cat No:62AM4 PEJ).
HEK293 cells in logarithmic growth phase were trypsinized, suspended (containing 0.1% BSA,0.5mM IBMX) in serum-free medium and counted, added to a 384 well plate at 2000/5. Mu.l/well, followed by 5. Mu.l of test compound (final concentration gradient of 100. Mu.M, 10. Mu.M, 1. Mu.M, 100nM, 10nM, 1nM, 100pM and physiological saline/DMSO, 3 duplicate wells per concentration) and reacted at room temperature for 30min in the dark. Then 5. Mu.l Forskolin (final concentration 10. Mu.M) was added and the reaction was carried out for 30min at room temperature in the absence of light. After the reaction is finished, adding cAMP detection substrate, and reacting for 60min at room temperature in a dark place. After the reaction, the reaction was detected on an Envision2104 multifunctional microplate reader.
The activation rate (% Response) of each sample under each concentration condition was calculated by the following formula using DAMGO as a positive compound (provided by seikoxin group, national center for new drug screening).
％Response＝(L Sample -L Blank )/(L DAMGO -L Blank )×100％
L Sample Represents the value of the detection signal after the sample stimulation, L Blank Indicating a blank, i.e. a value of the detection signal, L, of physiological saline DMAGO Represents the value of the detection signal after 100. Mu.M stimulation of the positive control DAMGO.
TABLE 3 evaluation results of agonistic activity of the compound against MOR
From the results of Table 3It is known that the compounds of the invention exhibit low nanomolar agonistic activity, EC, on the Mu Opioid Receptor (MOR) in vitro 50 Values were lower than PZM21, indicating that the compound had greater agonistic activity to MOR than PZM21.
Example 22 test Compounds interact with MOR- β -arrestin-2.
NanoBit is a double subunit system based on NanoLuc luciferase, which can be used as a technique for detecting protein interactions in cells. Wherein the LgBiT (17.6 kDa) and SmBiT (11 amino acid) subunits, respectively, are fused to a protein of interest, the two subunits being brought into close proximity when the protein of interest interacts to form an enzyme with catalytic activity, capable of catalysing the luminescence of a luciferase substrate.
The MOR, ARRB2 and LgBiT and SmBiT fusion proteins are expressed in HEK293 cells and stimulated with a compound that, if MOR interacts with ARRB2, lgBiT and SmBiT come into proximity to form an enzyme with catalytic activity that catalyzes the luminescence of the luciferase substrate.
Transfecting HEK293 cells with plasmids expressing proteins of interest (MOR, ARRB 1/2) fused to LgBiT and SmBiT, respectively, by electroporation, seeding into a 96-well white opaque plate, at 37 deg.C, 5% 2 Culturing for 24h; adding 40 μ L DMEM (phenol red free) +10 μ L substrate, and incubating for 10min; adding compounds with different concentrations for incubation for 10min; the readings are carried out by an Envision2104 multifunctional microplate reader.
The activation rate (% Response) of each sample under each concentration condition was calculated by the following equation using DAMGO as a positive compound.
L Sample Represents the value of the detection signal after the sample stimulation, L Blank Represents the blank, i.e.the value of the detection signal, L, of the DMSO well DAMGO Represents the value of the detection signal after 100. Mu.M stimulation of the positive control DAMGO.
TABLE 4 evaluation of MOR-beta-arrestin-2 interaction by Compounds
*No measurable activity
As is clear from the results in Table 4, none of the compounds of the present invention, like PZM21, showed recruitment activity to MOR- β -arrestin-2 and β -arrestin-2 recruitment was 0 at 100. Mu.M concentration; while the control DAMGO showed significant β -arrestin-2 recruitment activity (EC) 50 =691.3 nM), indicating that the new compound is a MOR-biased agonist as well as the positive drug PZM21.
Although specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that, based upon the overall teachings of the disclosure, various modifications and alternatives to those details could be developed and still be encompassed by the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (10)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein R is 1 Is hydrogen atom, hydroxyl, C 1 –C 5 Alkoxy, halogen (F, cl, br) or C 1 –C 5 Straight-chain or branched alkyl of R 2 Is a hydrogen atom, an electron withdrawing group, including but not limited to-NO 2 ，-CN，-SO 3 H，-CF 3 ，-CCl 3 Halogen (F, cl, br), -CHO, -COOH, etc., electron donating groups including but not limited to-NH 2 ，-OH，C 1 –C 5 Alkoxy radical, C 1 –C 5 And n is an integer selected from 0 to 5, such as 0,1,2,3,4,5.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the configuration of chiral carbon 2 is R-type or S-type.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxyl, C 1 –C 4 Alkoxy, halogen or C 1 –C 4 The linear or branched alkyl groups of (a) or (b),
preferably, R 1 Is hydrogen atom, hydroxyl, C 1 –C 3 Alkoxy, halogen or C 1 –C 3 The linear or branched alkyl group of (a),
preferably, R 1 Is hydrogen atom, hydroxyl, C 1 –C 2 Alkoxy, halogen or C 1 –C 2 The linear or branched alkyl groups of (a) or (b),
preferably, R 1 Is hydrogen atom, hydroxy, methoxy, ethoxy, propoxy, butoxy, F, cl, br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl,
preferably, R 1 Is hydrogen atom, hydroxyl, methoxy, ethoxy, propoxy, butoxy, F, cl, br, methyl, ethyl, propyl, n-butyl or n-pentyl,
preferably, R 1 Is hydrogen atom, hydroxyl, methoxyl, ethoxyl, propoxyl, F, cl, br, methyl, ethyl, propyl or n-butyl,
preferably, R 1 Is hydrogen atom, hydroxyl, methoxyl, ethoxyl, F, cl, br, methyl, ethyl or propyl,
preferably, R 1 Is a hydrogen atom, a methyl group or an ethyl group,
preferably, R 1 Is hydroxyl, methoxy, ethoxy, F, cl or Br,
preferably, R 1 Is a hydrogen atom orThe methyl group is a group selected from the group consisting of,
preferably, R 1 Is methoxy, ethoxy, propoxy or butoxy,
preferably, R 1 Is F, cl or Br, and is,
preferably, R 1 Is methyl, ethyl, propyl, n-butyl or n-pentyl,
preferably, R 2 Is hydrogen atom, halogen (F, cl, br), -OH, C 1 –C 5 Alkoxy radical, C 1 –C 5 The linear or branched alkyl group of (a),
preferably, R 2 Is hydrogen atom, F, cl, br, -OH or C 1 –C 5 An alkoxy group(s),
preferably, R 2 Is hydrogen atom, F, -OH or methoxyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0,1,2,3, or 4,
preferably, n is 0,1,2 or 3,
preferably, n is 0,1 or 2,
preferably, n is 0 or 1.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 ，-OH，C 1 –C 4 Alkoxy or C 1 –C 4 The linear or branched alkyl group of (a),
preferably, the electron donating group is-NH 2 ，-OH，C 1 –C 3 Alkoxy or C 1 –C 3 The linear or branched alkyl group of (a),
preferably, the electron donating group is-NH 2 ，-OH，C 1 –C 2 Alkoxy or C 1 –C 2 The linear or branched alkyl group of (a),
preferably, the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl or 1-ethyl-propyl,
preferably, the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, n-butyl or n-pentyl,
preferably, the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl or n-butyl,
preferably, the electron donating group is-NH 2 -OH, methoxy, ethoxy, methyl, ethyl or propyl,
preferably, the electron donating group is-NH 2 -OH, methyl or ethyl,
preferably, the electron donating group is-NH 2 -OH, methoxy or ethoxy,
preferably, the electron donating group is-OH or methoxy,
preferably, the electron donating group is methoxy, ethoxy, propoxy or butoxy,
preferably, the electron donating group is-OH,
preferably, the electron donating group is methyl, ethyl, propyl, n-butyl or n-pentyl,
preferably, the electron donating group is methyl or ethyl.
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula Ia or Ib,
wherein R is 1 And R 2 Is as defined in any one of claims 1 to 5.
7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient, in association with a pharmaceutically acceptable excipient or carrier.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is a solution, tablet, capsule, or injection.
10. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as active ingredient in the manufacture of a medicament for use as an analgesic, or as a mu opioid receptor preferential agonist, or in the manufacture of a medicament for the treatment of pain.
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