CN115477634B - Analgesic compounds and medical uses thereof - Google Patents
Analgesic compounds and medical uses thereof Download PDFInfo
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- CN115477634B CN115477634B CN202211221019.XA CN202211221019A CN115477634B CN 115477634 B CN115477634 B CN 115477634B CN 202211221019 A CN202211221019 A CN 202211221019A CN 115477634 B CN115477634 B CN 115477634B
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- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- propyl
- methyl
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
Abstract
The invention relates to a compound shown in a formula I or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and application of the compound or the pharmaceutically acceptable salt thereof in preparing analgesic drugs.
Description
Technical Field
The present invention relates to compounds for analgesia or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds or pharmaceutically acceptable salts thereof as active ingredients, and the use of the compounds or pharmaceutically acceptable salts thereof for preparing analgesic drugs.
Background
The treatment of pain has long been a significant public health challenge, and the primary treatment for pain is the use of opioids, which are effective in alleviating pain, but patients taking opioids are addicted to the drug and at high risk of overdosing, 13.3 of which die from opioid overdosing in the united states per 100,000 people.
Analgesic effects of opioids such as morphine are produced by signaling through the Gi protein in the G protein, while many adverse effects, including respiratory depression and constipation, may be produced by signaling through the β -arestin pathway downstream of Mu Opioid Receptor (MOR) activation. The MOR deflection agonist can selectively activate the Gi protein pathway to avoid activating the beta-arestin pathway, and experiments prove that compared with a wild-type mouse, the mouse with the beta-arestin-2 knockdown shows that the analgesic effect of morphine is better, the drug tolerance is not easy to occur, and fewer respiratory depression and constipation are caused. Therefore, agonists specific for MOR and biased towards Gi signaling pathways are novel directions for perfect analgesics as therapeutic agents. The first mu-receptor biased agonist analgesic TRV130 injection has been approved by the United states FDA for marketing in month 2020, which has a milestone significance for mu-opioid receptor biased agonists, but TRV130 still has lower adverse effects clinically.
PZM21 is a newly discovered novel backbone molecule which is completely different from the chemical structure of the existing opioid analgesic, and experiments prove that PZM can strongly activate Gi/o and only cause low beta-arestin aggregation. PZM21 is therefore a potent MOR-biasing agonist, and has no apparent addiction. However, PZM21 still has to be further improved in analgesic activity.
Disclosure of Invention
The invention designs and synthesizes a series of compounds shown in a formula I:
wherein R is 1 Is hydrogen atom, hydroxy, C 1 –C 5 Alkoxy, halogen (F, cl, br) or C 1 –C 5 Straight-chain alkyl or branched alkyl, 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, C 1 –C 5 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 is inactive to the beta-arestin 2 pathway.
Based on the above results, the present invention has been completed.
The present invention provides a compound represented by formula I:
in formula I: r is R 1 Is hydrogen atom, hydroxy, C 1 –C 5 Alkoxy, halogen atoms (F, cl, br) or C 1 –C 5 Straight-chain alkyl or branched alkyl, 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, C 1 –C 5 N is an integer selected from 0 to 5, such as 0,1,2,3,4,5.
In certain embodiments, chiral carbon 2 in formula I is configured as R-type or S-type.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxy, C 1 –C 4 Alkoxy, halogen or C 1 –C 4 Straight chain alkyl or branched alkyl of (a).
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxy, C 1 –C 3 Alkoxy, halogen or C 1 –C 3 Straight chain alkyl or branched alkyl of (a).
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxy, C 1 –C 2 Alkoxy, halogen or C 1 –C 2 Straight chain alkyl or branched alkyl of (a).
In certain embodiments, R in formula I 1 Is a 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 or hydroxyA group, 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, hydroxy, methoxy, ethoxy, propoxy, F, cl, br, methyl, ethyl, propyl or n-butyl.
In certain embodiments, R in formula I 1 Is hydrogen atom, hydroxy, methoxy, ethoxy, F, cl, br, methyl, ethyl or propyl.
In certain embodiments, R in formula I 1 Is a hydrogen atom, methyl or ethyl.
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 Methoxy, ethoxy, propoxy or butoxy.
In certain embodiments, R in formula I 1 F, cl or Br.
In certain embodiments, R in formula I 1 Is methyl, 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, C 1 –C 5 Straight chain alkyl or branched alkyl of (a).
In certain embodiments, R in formula I 2 Is hydrogen atom, F, cl, br, -OH or C 1 –C 5 An alkoxy group.
In certain embodiments, R in formula I 2 Is a hydrogen atom, F, -OH or methoxy.
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 Straight chain alkyl or branched alkyl of (a).
In certain embodiments, the electron donating group is-NH 2 ，-OH，C 1 –C 3 Alkoxy or C 1 –C 3 Straight chain alkyl or branched alkyl of (a).
In certain embodiments, the electron donating group is-NH 2 ，-OH，C 1 –C 2 Alkoxy or C 1 –C 2 Straight chain alkyl or branched alkyl 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 a hydrogen atom, hydroxy, 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 compounds of formula I have a structure of formula Ia or formula Ib,
wherein R is 1 And R is 2 Is defined as in any embodiment of the invention.
In certain embodiments, the compound of formula I is selected from:
the invention also provides a pharmaceutical composition which contains the compound shown in the formula I or 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 the 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 medicines serving as analgesics.
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 medicines serving as mu opioid receptor biased agonists.
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 comprising 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 promote the administration to organisms, facilitate the absorption of active ingredients and thus 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, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin. The excipient is an additive except the main medicine in the pharmaceutical preparation, has stable property, no incompatibility with the main medicine, no side effect, no influence on curative effect, no easy deformation, dry cracking, mildew, worm damage, no harm to human body, no physiological effect, no chemical or physical effect with the main medicine, no influence on the content measurement of the main medicine and the like. Such as binders, fillers, disintegrants, lubricants in the tablet; wine, vinegar, medicinal juice and the like in the traditional Chinese medicine pill; a base portion in a semisolid formulation ointment, cream; preservatives, antioxidants, flavoring agents, fragrances, co-solvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. in liquid formulations may be referred to as excipients.
The compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof may be administered by the following routes: parenteral, topical, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes, or as an inhalant.
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 formulation, including, but not limited to, tablets, capsules, aqueous solutions or suspensions. Wherein the carrier used for the tablet generally comprises lactose and corn starch, and optionally a lubricant such as magnesium stearate. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, flavoring agent or coloring agent can be added into the oral preparation.
When applied topically to the skin, the compounds of the invention may be formulated in the form of suitable ointments, lotions or creams, in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for 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, hexadecene aryl 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 sterile injectable solutions. Among the carriers and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oils may also be used as solvents or suspending media, such as mono-or diglycerides.
Generally, an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day, sufficient to achieve a prophylactic or therapeutic effect. Suitably, the dosage 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 two days, or every three days, more typically 0.1 to 500mg/kg of subject body weight. An exemplary treatment regimen is once every two days or once weekly or monthly. The formulation is typically administered multiple times, and the interval between individual doses may be daily, weekly, monthly or yearly. Alternatively, the formulation may be administered in the form of a slow release formulation, in which case less frequent administration is required. Dosages and frequencies will vary depending on the half-life of the formulation in the subject. And may also vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered at relatively low frequency intervals over a long period of time. 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 stopped, and preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which a patient prophylactic regimen may be administered.
In certain embodiments, the synthesis of the compound shown in the formula Ia takes L-3-benzothiophene alanine (1 a) as a starting material, the L-3-benzothiophene alanine reacts with thionyl chloride and ammonia water to generate benzothiophene alaninamide (2 a), and the L-3-benzothiophene alaninamide reacts with ammonia water to generate an intermediate (4 a) through reductive amination and borane reduction; the 1-position hydrocarbon substituted benzylamine (5 a) reacts with phenyl p-nitro chloroformate to generate an intermediate (6 a), and the intermediate (6 a) reacts with 4a and triethylamine to obtain a target product Ia.
The synthetic route for the compounds of formula Ia is shown below:
in formula Ia, R 1 And R is 2 And n is as defined in any embodiment of the invention.
In certain embodiments, the synthesis of the compound shown in the formula Ib takes L-3-benzothiophene alanine (1 a) as a starting material, the L-3-benzothiophene alanine reacts with thionyl chloride and ammonia water to generate benzothiophene alaninamide (2 a), and the L-3-benzothiophene alaninamide reacts with ammonia water to generate an intermediate (4 a) through reductive amination and borane reduction; the 1-position alkyl substituted phenethylamine (5 b) reacts with p-nitro phenyl chloroformate to generate an intermediate (6 b), and the intermediate (6 b) reacts with 4a and triethylamine to obtain a target product Ib.
The synthetic route for the compounds of formula Ib is shown below:
in the formula Ib, R 1 And R is 2 And n is as defined in any embodiment of the invention.
Detailed Description
The following examples further illustrate the invention in connection with its embodiments, and it should be understood that the following examples are illustrative of the invention and are not intended to limit the scope of the invention. The specific conditions are not noted in the examples below, and are carried out according to conventional conditions or manufacturer's recommendations. The raw materials used are conventional products which are commercially available without identifying the manufacturer.
Although many materials and methods of operation are known in the art for use in the following examples, the invention is nevertheless described in as much detail as possible. It will be clear to those skilled in the art that the materials and methods of operation used in the examples which follow are well known in the art, if not specifically described.
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)
A500 mL three-necked round bottom flask was taken, 10g (38.83 mmol) of L-3-benzothiophene alanine hydrochloride (1 a) was dissolved in methanol solution, 9.5g (78.17 mmol) of thionyl chloride was slowly added dropwise to 200mL of methanol under stirring in an ice water bath, after the dropwise addition was completed, the mixture was mixed with methanol solution of L-3-benzothiophene alanine hydrochloride, the reaction solution was gradually stirred at room temperature, the reaction was allowed to proceed for 10h, TLC detection was performed, and the stirring was turned off sufficiently. The reaction solution is decompressed and distilled in a rotary way to obtain white solid, and the white solid is concentrated and dried again after a proper amount of methanol is added for complete dissolution, and the operation is repeated twice. 400mL of ammonia water is slowly added dropwise into the round bottom flask under the condition of ice water bath stirring, methanol is slowly added dropwise until the methanol is fully dissolved, the reaction solution is warmed to room temperature, the reaction solution is stirred for 48h under the protection of argon, TLC detection reaction is fully carried out, and stirring is closed. Silica gel was added to a round bottom flask and column chromatography was performed using 200-300 mesh silica gel, and separation was performed using DCM: meoh=20:1 eluent to finally give (S) -2-amino-3- (3-benzothienyl) propanamide (2 a) as a white solid 7.90g in 92.43% yield.
1.2 Synthesis of (S) -3- (3-benzothienyl) -2- (dimethylamino) propanamide (3 a)
7g (31.81 mmol) of (S) -2-amino-3- (3-benzothienyl) propanamide (2 a) was weighed into a beaker, 200mL of methanol was added, stirred until well dissolved, the solution was transferred into a 500mL hydrogenation flask, 4g of 10% Pd/C was added, the Pd/C on the flask wall was flushed into the solution with a small amount of methanol, 29mL (387.63 mmol) of 40% formaldehyde solution was rapidly added, the hydrogenation reaction was carried out for 7h, TLC detection was complete, the hydrogenation reaction was stopped, suction filtration was carried out until the solution was clear, a small amount of silica gel powder was added and column chromatography separation was carried out using 200-300 mesh silica gel, separation was carried out using DCM: meOH=60:1 eluent, 3.33g of (S) -3- (3-benzothienyl) -2- (dimethylamino) propanamide (3 a) was obtained 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)
A500 mL three-necked round bottom flask was taken, 3g (12.1 mmol) of (S) -3- (3-benzothienyl) -2- (dimethylamino) propanamide (3 a) was transferred to the three-necked flask, a proper amount of ultra-dry THF was added to the three-necked flask under the protection of argon, 73mL (73 mmol) of 1M borane tetrahydrofuran complex solution was slowly added dropwise under stirring in an ice water bath, the dropwise addition was completed, the mixture was transferred to an oil bath pot, heated and refluxed for 18h, TLC detection was performed, and the reaction was completed. Stopping heating, cooling the reaction liquid to room temperature, slowly dropwise adding a proper amount of methanol solution until no bubbles are generated under the stirring condition, concentrating under reduced pressure to obtain an off-white solid, repeating the steps twice, adding a small amount of methanol solution, heating, refluxing and stirring until the methanol solution is fully dissolved, slowly dropwise adding ethyl acetate into the solution until a large amount of white solid is produced, filtering, adding excessive concentrated hydrochloric acid into the filtrate to fully form salt, concentrating under reduced pressure, drying, adding a small amount of silica gel powder, stirring, performing column chromatography separation and purification by using 200-300 meshes of silica gel, performing column chromatography separation by using an eluent of DCM: meOH=30:1, and obtaining 1.98g of (S) -3- (3-benzothienyl) -2- (N, N-dimethylamino) propylamine hydrochloride (4 a) as a white solid, wherein the yield is 60.43%.
1.4 Synthesis of 4-nitrophenyl benzyl carbamate (6 a-1)
0.5g (4.67 mmol) of benzylamine (5 a-1) was transferred to a round bottom flask, 100mL of ultra-dry THF and 1.25mL (7.13 mmol) of triethylamine were slowly added under stirring in an ice-water bath, 1g (5 mmol) of phenyl 4-nitrochloroformate was dissolved in a proper amount of ultra-dry THF solution under argon and slowly added dropwise to the reaction solution, and white smoke was generated during the dropwise addition. After the dropwise addition, stirring at room temperature, wherein the reaction liquid is white and milky white and turns yellow, reacting for 8h, performing TLC detection, performing post-treatment operation, diluting the reaction liquid by using 100mL of DCM, stirring uniformly, performing suction filtration, washing the filtrate twice by using saturated NaHCO3 solution and saturated NaCl solution, adding a small amount of silica gel powder for sample mixing, performing column chromatography separation and purification by using 200-300 meshes of silica gel, finally flushing the product by using a DCM (DCM: PE=5:1) eluent, merging the products, concentrating the products under reduced pressure, drying in an oven, and obtaining white solid 6 a-1.07 g with the yield of 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 0.3g (1.10 mmol) of 6a-1 in acetonitrile was added dropwise to the reaction solution, and the solution turned from colorless to yellow rapidly. After the dripping is finished, transferring the solution into an oil bath, heating to 90 ℃ in T, stirring at high temperature for 7 hours, monitoring the reaction to be complete by TLC, closing the reaction, shaking uniformly, filtering by suction, concentrating the filtrate under reduced pressure to dryness, using 30mL of isopropyl alcohol/ethyl acetate (1:2) mixed solvent to fully dissolve, washing three times by NaCO3/NaHCO3 (pH=9) mixed solvent, washing saturated NaCl solution once, concentrating under reduced pressure to dryness, adding 200-300 meshes of silica gel powder for sample mixing, separating and purifying by column chromatography, eluting with DCM (DCM: meOH=60:1) and the like, collecting the combined product to finally obtain 0.22g of transparent oily substance, and obtaining 81.68% of HRESIMS m/z 368.1791[ M+H ] ] + . 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-phenethyl) urea (Ia-2)
2.1 4-Nitrophenyl (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 for 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-phenethyl) urea (Ia-2)
In the synthesis of Ia-2, 4-nitrophenylbenzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (S) - (1-phenethyl) carbamate (6 a-2), and the other procedures were the same as for the synthesis of Ia-1 to give a yellow oil, ia-2.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-phenethyl) urea (Ia-3)
3.1 4-Nitrophenyl (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 for 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-phenethyl) urea (Ia-3)
In the synthesis of Ia-3, 4-nitrophenylbenzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (R) - (1-phenethyl) carbamate (6 a-3) and the other procedures were the same as for the synthesis of Ia-1 to give a yellow oil of Ia-3.HRESIMS m/z 382.1953[ 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 for 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)
In the synthesis of Ia-4, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-fluorobenzyl) carbamate (6 a-4), and the other operations were the same as for the synthesis of Ia-1, to give a yellow oil of Ia-4.HRESIMS m/z 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 for 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)
In the synthesis of Ia-5, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-fluorobenzyl) carbamate (6 a-5), and the other operations were the same as for the synthesis of Ia-1, to give a yellow oil of Ia-5.HRESI (HRESI)MS 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-hydroxy-benzyl amine (5 a-6), and the other operations were the same as for 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)
In the synthesis of Ia-6, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-hydroxybenzyl) carbamate (6 a-6), and the other operations were the same as for the synthesis of Ia-1, to give a yellow oil of Ia-6.HRESIMS m/z 384.1748[ 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-hydroxy-benzyl amine (5 a-7), and the other operations were the same as for the synthesis of 6a-1, to give 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 benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-hydroxybenzyl) carbamate (6 a-7), and the other operations were the same as for the synthesis of Ia-1, to give a yellow oil of Ia-7.HRESIMS m/z 384.1745[ 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-methoxybenzyl amine (5 a-8), and the other operations were the same as for 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)
In the synthesis of Ia-8, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-methoxybenzyl) carbamate (6 a-8), and the other operations were the same as for the synthesis of Ia-1, to give a yellow oil of Ia-8.HRESIMS m/z 398.1903[ 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-methoxybenzyl amine (5 a-9), and the other operations were the same as for 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)
In the synthesis of Ia-9, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-methoxybenzyl) carbamate (6 a-9), and the other operations were the same as for the synthesis of Ia-1, to give a yellow oil of Ia-9.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-nitrophenyl phenethyl carbamate (6 b-1)
In the synthesis of intermediate 6b-1, benzylamine (5 a-1) was replaced with (S) -1-phenethylamine (5 b-1), and the other operations were the same as for 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)
In the synthesis of Ib-1, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl phenethyl carbamate (6 b-1), and the other procedures were the same as for the synthesis of Ia-1, to give 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-phenylpropan-2-yl) urea (Ib-2)
11.1 4-Nitrophenyl (S) - (1-Benzen-2-yl) carbamate (6 b-2)
In the synthesis of intermediate 6b-2, benzylamine (5 a-1) was replaced with (S) -1-phenylpropan-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)
In the synthesis of Ib-2, 4-nitrophenylbenzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (S) - (1-phenylpropan-2-yl) carbamate (6 b-2), and the other procedures were the same as for the synthesis of Ia-1, to give Ib-2 as a yellow oil. HRESIMS m/z 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-Nitrophenyl-R) - (1-Benzen-2-yl) carbamate (6 b-3)
In the synthesis of intermediate 6b-3, benzylamine (5 a-1) was replaced with (R) -1-phenylpropan-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-phenylpropan-2-yl) urea (Ib-3)
In the synthesis of Ib-3, 4-nitrophenylbenzyl carbamate (6 a-1) was replaced with 4-nitrobenzene (R) - (1-phenylpropan-2-yl) carbamate (6 b-3), and the other procedures were the same as for the synthesis of Ia-1, to give Ib-3 as a yellow oil. HRESIMS m/z 396.2113[ 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)
In 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 for 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)
In the synthesis of Ib-4, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-fluorophenethyl) carbamate (6 b-4), and the other procedures were the same as for the synthesis of Ia-1, to give Ib-4 as a yellow oil. 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)
In 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 for 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)
In the synthesis of Ib-5, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-fluorophenethyl) carbamate (6 b-5), and the other procedures were the same as for the synthesis of Ia-1, to give 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)
In 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 for 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)
In the synthesis of Ib-6, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-hydroxyphenylethyl) carbamate (6 b-6), and the other procedures were the same as for the synthesis of Ia-1, to give Ib-6 as a yellow oil. HRESIMS m/z 398.1903[ 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)
In 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 for 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)
In the synthesis of Ib-7, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-hydroxyphenylethyl) carbamate (6 b-7), and the other procedures were the same as for the synthesis of Ia-1, to give a yellow oilAnd (3) a compound Ib-7.HRESIMS m/z 398.1905[ 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-methoxyphenylethyl) urea (Ib-8)
17.1 Synthesis of 4-nitrophenyl (3-methoxyphenethyl) carbamate (6 b-8)
In the synthesis of intermediate 6b-8, benzylamine (5 a-1) was replaced with 3-methoxyphenylethylamine (5 b-8), and the other operations were the same as for 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-methoxyphenylethyl) urea (Ib-8)
In the synthesis of Ib-8, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (3-methoxyphenylethyl) carbamate (6 b-8), and the other procedures were the same as for the synthesis of Ia-1, to give Ib-8 as a yellow oil. HRESIMS m/z 412.2057[ 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-methoxyphenylethyl) urea (Ib-9)
18.1 Synthesis of 4-nitrophenyl (4-methoxyphenethyl) carbamate (6 b-9)
In the synthesis of intermediate 6b-9, benzylamine (5 a-1) was replaced with 4-methoxyphenylethylamine (5 b-9), and the other operations were the same as for 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-methoxyphenylethyl) urea (Ib-9)
In the synthesis of Ib-9, 4-nitrophenyl benzyl carbamate (6 a-1) was replaced with 4-nitrophenyl (4-methoxyphenylethyl) carbamate (6 b-9), and the other procedures were the same as for the synthesis of Ia-1, to give 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: mouse acetic acid torsion model evaluation
ICR (CD-1) male mice (weighing 22-25 g) were randomly assigned to blank, positive, test compound groups, 8 per group, supplied by St Bei Fu (Beijing) Biotechnology Co., ltd (license number: SCXK (Beijing)) and then each group was given subcutaneously (positive PZM and test agent: 20 mg/kg), the blank was given the same volume of vehicle (physiological saline). After 30min of administration, the mice were intraperitoneally injected with 10mL/kg of a 1% acetic acid solution. The number of twists in 20min after intraperitoneal injection of acetic acid was recorded.
Percent of analgesia (%) = (number of vehicle in blank group-number of vehicle in administration group)/number of vehicle in blank group x 100%.
TABLE 1 acetic acid torsion model experimental results
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Note that: ** p<0.01vs.control
as can be seen 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 PZM.
Example 20: test evaluation of mice by licking foot with Hot plate
C57 female mice, 24-26 g, supplied by St Bei Fu (Beijing) laboratory animal Co., ltd.) generated license number: SCXK (Beijing) 2019-0010. The animals were randomly divided into a blank group, a positive group, and a test compound group, 8 animals per group, and then each group was subcutaneously administered (positive drug PZM and test drug), and the blank group was given the same volume of vehicle (physiological saline). The pre-dose pain threshold and the post-dose pain thresholds of 15, 30, 60, 90 and 120min were determined for each mouse, with the duration of each determination being determined to be 60s.
Percent (%) analgesia = (pain threshold-pain threshold before dosing)/(pain threshold before 60-dosing) ×100%.
Table 2 hot plate model test results
| Compounds of formula (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 that: ** p<0.01vs.control
as can be seen from the results in table 2, the compounds of the present invention have significantly stronger analgesic activity than the positive drug PZM at the same dose; the analgesic activity of the novel compound at a dosage of 40mg/kg is obviously higher than that of morphine at a dosage of 10 mg/kg.
Example 21: detection of agonistic Activity of Compounds on Mu Opioid Receptor (MOR)
MOR, coupled to the Gi/o protein, inhibits the activity of adenylate cyclase when combined with agonists, thereby causing a decrease in intracellular cAMP concentration. Therefore, we can stimulate MOR cells with compounds, then increase intracellular cAMP levels with Forskolin, and finally determine whether MOR is activated by measuring changes in intracellular cAMP levels with cAMP detection kit.
The main reagent comprises: DMEM medium (GIBCO, cat No. 12800017); nanoBiT detection kit (promega, cat No: N2013); cAMP detection kit (cisbio, cat No. 62AM4 PEJ).
HEK293 cells in the logarithmic growth phase were pancreatin digested, suspended in serum-free culture medium (containing 0.1%BSA,0.5mM IBMX) and counted, 384-well plates were added at 2000/5 μl/well, followed by 5 μl of test compounds (final concentration gradients of 100 μm, 10 μm, 1 μm, 100nM, 10nM, 1nM, 100pM and physiological saline/DMSO, 3 wells each) and reacted at room temperature in the absence of light for 30min. Then 5. Mu.l Forskolin (final concentration 10. Mu.M) was added and the reaction was kept away from light at room temperature for 30min. After the reaction, cAMP detection substrate is added, and the reaction is carried out at room temperature in a dark place for 60min. After the reaction is finished, the reaction is detected on an Envision2104 multifunctional microplate reader.
The activation rate (% Response) of each sample at each concentration was calculated using DAMGO as a positive compound (supplied by the national center for drug screening Xie Xin subject group) by the following formula.
％Response＝(L Sample -L Blank )/(L DAMGO -L Blank )×100％
L Sample Indicating the value of the detection signal after the stimulation of the sample, L Blank Indicating blank, i.e. detected signal value of physiological saline, L DMAGO The detection signal value after DAMGO stimulation of the positive control sample of 100. Mu.M is shown.
Table 3 results of evaluation of agonistic Activity of Compounds against MOR
As can be seen from the results in Table 3, the compounds of the present invention show a low nanomolar agonistic activity at the Mu Opioid Receptor (MOR) in vitro, EC 50 Values lower than PZM indicate that the compound has a higher agonistic activity against MOR than PZM.
Example 22 detection of compound interaction with MOR-beta-arestin-2.
NanoBit is a technology that is based on the dual subunit system of NanoLuc luciferase and can be used to detect intracellular protein interactions. Wherein the LgBiT (17.6 kDa) and SmBiT (11 amino acids) 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 a catalytically active enzyme capable of catalyzing the luminescence of a luciferase substrate.
MOR, arb 2 and LgBiT and SmBiT fusion proteins are expressed in HEK293 cells and stimulated with compounds that, if MOR interacts with arb 2, lgBiT and SmBiT come close to form an enzyme with catalytic activity that catalyzes the luminescence of the luciferase substrate.
HEK293 cells were transfected by electric shock with plasmids expressing proteins of interest (MOR, ARRB 1/2) fused to LgBiT and SmBiT, respectively, and seeded into 96-well white opaque plates at 37℃with 5% CO 2 Culturing for 24h; add 40. Mu.L DMEM (phenol red free) +10μl substrate and incubate for 10min; adding compounds with different concentrations and incubating for 10min; and reading by using an Envision 2104 multi-functional microplate reader.
The activation rate (% Response) of each sample at each concentration was calculated using DAMGO as a positive compound by the following formula.
L Sample Indicating the value of the detection signal after the stimulation of the sample, L Blank Indicating blank, i.e. signal value detected in DMSO wells, L DAMGO The detection signal value after DAMGO stimulation of the positive control sample of 100. Mu.M is shown.
Evaluation of MOR-beta-arestin-2 interaction by the Compounds of Table 4
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*No measurable activity
As can be seen from the results of Table 4, none of the compounds of the present invention exhibited recruitment activity for MOR- β -arestin-2 as does PZM, with a β -arestin-2 recruitment effect of 0 at a concentration of 100. Mu.M; whereas the control DAMGO showed significant beta-arestin-2 recruitment activity (EC 50 = 691.3 nM), indicating that the novel compounds are MOR-biased agonists as well as positive drug PZM.
While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure and that such modifications would be within the scope of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (45)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein R is 1 Is hydrogen atom, hydroxy, C 1 -C 5 Alkoxy, halogen or C 1 -C 5 A linear or branched alkyl group; r is R 2 Is hydrogen atom, electron withdrawing group or electron donating group, the electron withdrawing group is-NO 2 、-CN、-SO 3 H、-CF 3 、-CCl 3 Halogen, -CHO or-COOH, said electron donating group being-NH 2 、-OH、C 1 -C 5 Alkoxy or C 1 -C 5 A linear or branched alkyl group; n is an integer selected from 0-5.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, 4, or 5.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the halogen is F, cl or Br.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the configuration of chiral carbon 2 is R-type or S-type.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxy, C 1 -C 4 Alkoxy, halogen or C 1 -C 4 Straight chain alkyl or branched alkyl of (a).
6. The compound of claim 5An agent or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxy, C 1 -C 3 Alkoxy, halogen or C 1 -C 3 Straight chain alkyl or branched alkyl of (a).
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxy, C 1 -C 2 Alkoxy, halogen or C 1 -C 2 Straight chain alkyl or branched alkyl of (a).
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is a 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 or 1-ethyl-propyl.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxy, methoxy, ethoxy, propoxy, butoxy, F, cl, br, methyl, ethyl, propyl, n-butyl or n-pentyl.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxy, methoxy, ethoxy, propoxy, F, cl, br, methyl, ethyl, propyl or n-butyl.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydrogen atom, hydroxy, methoxy, ethoxy, F, cl, br, methyl, ethyl or propyl.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R 1 Is a hydrogen atom, methyl or ethyl.
13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R 1 Is hydroxyl, methoxy, ethoxy, F, cl or Br.
14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R 1 Is a hydrogen atom or a methyl group.
15. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1 Methoxy, ethoxy, propoxy or butoxy.
16. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R 1 F, cl or Br.
17. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein preferably R 1 Is methyl, ethyl, propyl, n-butyl or n-pentyl.
18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 Is hydrogen atom, halogen, -OH, C 1 -C 5 Alkoxy, C 1 -C 5 Straight chain alkyl or branched alkyl of (a).
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R 2 Is hydrogen atom, F, cl, br, -OH or C 1 -C 5 An alkoxy group.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R 2 Is a hydrogen atom, F, -OH or methoxy.
21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0,1,2,3, or 4.
22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein n is 0,1,2, or 3.
23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein n is 0,1, or 2.
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
25. 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 Straight chain alkyl or branched alkyl of (a).
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 ，-OH，C 1 -C 3 Alkoxy or C 1 -C 3 Straight chain alkyl or branched alkyl of (a).
27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 ，-OH，C 1 -C 2 Alkoxy or C 1 -C 2 Straight chain alkyl or branched alkyl of (a).
28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 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.
29. The compound of claim 28 or a pharmaceutically acceptable thereofA salt, wherein the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, n-butyl or n-pentyl.
30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 -OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl or n-butyl.
31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 -OH, methoxy, ethoxy, methyl, ethyl or propyl.
32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 -OH, methyl or ethyl.
33. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-NH 2 -OH, methoxy or ethoxy.
34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-OH or methoxy.
35. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is methoxy, ethoxy, propoxy, or butoxy.
36. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is-OH.
37. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is methyl, ethyl, propyl, n-butyl, or n-pentyl.
38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the electron donating group is methyl or ethyl.
39. The compound of any one of claim 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula Ia or formula Ib,
wherein R is 1 And R is 2 Is as defined in any one of claims 1 to 37.
40. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
41. a pharmaceutical composition comprising a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient or carrier.
42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition is a solution, a tablet, a capsule, or an injection.
43. Use of a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 41 or 42, for the manufacture of a medicament for use as an analgesic.
44. Use of a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 41 or 42, for the manufacture of a medicament as a mu opioid receptor-biased agonist.
45. Use of a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 41 or 42, in the manufacture of a medicament for the treatment of pain.
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| WO2018129393A1 (en) * | 2017-01-06 | 2018-07-12 | The Regents Of The University Of California | Mu opioid receptor modulators |
| CN111410647A (en) * | 2019-01-04 | 2020-07-14 | 中国人民解放军军事科学院军事医学研究院 | Mu opium receptor bias agonist and medical application thereof |
| CN112159401A (en) * | 2019-11-05 | 2021-01-01 | 中国人民解放军军事科学院军事医学研究院 | Biased agonist and medical application thereof |
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| WO2017007695A1 (en) * | 2015-07-09 | 2017-01-12 | The Regents Of The University Of California | Mu opioid receptor modulators |
| WO2018129393A1 (en) * | 2017-01-06 | 2018-07-12 | The Regents Of The University Of California | Mu opioid receptor modulators |
| CN111410647A (en) * | 2019-01-04 | 2020-07-14 | 中国人民解放军军事科学院军事医学研究院 | Mu opium receptor bias agonist and medical application thereof |
| CN112159401A (en) * | 2019-11-05 | 2021-01-01 | 中国人民解放军军事科学院军事医学研究院 | Biased agonist and medical application thereof |
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